Neil Osterweil

Repeat infusions of mesenchymal stromal stem cells appear to inhibit the development of chronic graft-versus-host disease (cGVHD) in patients who have undergone an allogeneic stem cell transplant.

The 2-year cumulative incidence of cGVHD among those randomized to receive repeated infusions of umbilical cord–derived mesenchymal stromal cells (MSCs) was half that of controls treated with a saline placebo, based on results from a randomized phase II, double blind trial in 124 patients with hematologic malignancies who underwent an HLA-haploidentical allogeneic hematopoietic stem cell transplantation (HSCT).

“Our goal was to minimize the incidence of cGVHD, reduce the severity of cGVHD, and demonstrate the safety of MSC infusions. We performed repeated infusions of MSCs once a month for a total of four rounds for each patient. Over the median 47-month posttransplantation period, the incidence of cGVHD was lower in the MSCs group than in the non-MSCs control group,” Lei Gao, MD, of the Third Military Medical University in Chongqing, China, and colleagues wrote in the Journal of Clinical Oncology (2016 Jul 11. doi: 10.1200/JCO.2015.65.3642).

Although cGVHD is associated with a reduced risk of leukemia relapse, it is still the leading cause of nonrelapse deaths after HSCT. The incidence of cGVHD is higher among recipients of HLA-haploidentical HSCT, in which the donor and recipient have identical HLA alleles on only one copy of chromosome, than among HLA-matched recipients, who have identical alleles on both copies.

The researchers randomly assigned 124 patients who had undergo HLA-haploidentical HSCT to receive either placebo or MSCs at a dose of 3 x 10⁷ cells/100 mL per month for four cycles beginning 4 months after HSCT

Of the 124 randomized patients, 12 discontinued the study due to cGVHD or disease progression.

The 2-year cumulative incidence of cGVHD among patients treated with MSCs was 27%, compared with 49% for placebo-treated controls (P = .021). Seven patients in the control group but none in the MSC-treated group developed typical lung cGVHD (P = .047).

The investigators also observed increases in memory B lymphocytes and regulatory T cells, and in the ratio of type 1 to type 2 T-helper cells, as well as a decrease in natural killer cells.

The finding that the MSC infusions increased the number of regulatory T cells while decreasing the incidence of cGVHD suggests that regulatory T cells play an inhibitory role, the investigators said.

The study was supported by the Chinese Academy of Sciences. Chinese National Natural Science Foundation, and other Chinese government grants. The authors reported having no relationships to disclose.

Repeat infusions of mesenchymal stromal stem cells appear to inhibit the development of chronic graft-versus-host disease (cGVHD) in patients who have undergone an allogeneic stem cell transplant.

The 2-year cumulative incidence of cGVHD among those randomized to receive repeated infusions of umbilical cord–derived mesenchymal stromal cells (MSCs) was half that of controls treated with a saline placebo, based on results from a randomized phase II, double blind trial in 124 patients with hematologic malignancies who underwent an HLA-haploidentical allogeneic hematopoietic stem cell transplantation (HSCT).

“Our goal was to minimize the incidence of cGVHD, reduce the severity of cGVHD, and demonstrate the safety of MSC infusions. We performed repeated infusions of MSCs once a month for a total of four rounds for each patient. Over the median 47-month posttransplantation period, the incidence of cGVHD was lower in the MSCs group than in the non-MSCs control group,” Lei Gao, MD, of the Third Military Medical University in Chongqing, China, and colleagues wrote in the Journal of Clinical Oncology (2016 Jul 11. doi: 10.1200/JCO.2015.65.3642).

Although cGVHD is associated with a reduced risk of leukemia relapse, it is still the leading cause of nonrelapse deaths after HSCT. The incidence of cGVHD is higher among recipients of HLA-haploidentical HSCT, in which the donor and recipient have identical HLA alleles on only one copy of chromosome, than among HLA-matched recipients, who have identical alleles on both copies.

The researchers randomly assigned 124 patients who had undergo HLA-haploidentical HSCT to receive either placebo or MSCs at a dose of 3 x 10⁷ cells/100 mL per month for four cycles beginning 4 months after HSCT

Of the 124 randomized patients, 12 discontinued the study due to cGVHD or disease progression.

The 2-year cumulative incidence of cGVHD among patients treated with MSCs was 27%, compared with 49% for placebo-treated controls (P = .021). Seven patients in the control group but none in the MSC-treated group developed typical lung cGVHD (P = .047).

The investigators also observed increases in memory B lymphocytes and regulatory T cells, and in the ratio of type 1 to type 2 T-helper cells, as well as a decrease in natural killer cells.

The finding that the MSC infusions increased the number of regulatory T cells while decreasing the incidence of cGVHD suggests that regulatory T cells play an inhibitory role, the investigators said.

The study was supported by the Chinese Academy of Sciences. Chinese National Natural Science Foundation, and other Chinese government grants. The authors reported having no relationships to disclose.

Repeat infusions of mesenchymal stromal stem cells appear to inhibit the development of chronic graft-versus-host disease (cGVHD) in patients who have undergone an allogeneic stem cell transplant.

The 2-year cumulative incidence of cGVHD among those randomized to receive repeated infusions of umbilical cord–derived mesenchymal stromal cells (MSCs) was half that of controls treated with a saline placebo, based on results from a randomized phase II, double blind trial in 124 patients with hematologic malignancies who underwent an HLA-haploidentical allogeneic hematopoietic stem cell transplantation (HSCT).

“Our goal was to minimize the incidence of cGVHD, reduce the severity of cGVHD, and demonstrate the safety of MSC infusions. We performed repeated infusions of MSCs once a month for a total of four rounds for each patient. Over the median 47-month posttransplantation period, the incidence of cGVHD was lower in the MSCs group than in the non-MSCs control group,” Lei Gao, MD, of the Third Military Medical University in Chongqing, China, and colleagues wrote in the Journal of Clinical Oncology (2016 Jul 11. doi: 10.1200/JCO.2015.65.3642).

Although cGVHD is associated with a reduced risk of leukemia relapse, it is still the leading cause of nonrelapse deaths after HSCT. The incidence of cGVHD is higher among recipients of HLA-haploidentical HSCT, in which the donor and recipient have identical HLA alleles on only one copy of chromosome, than among HLA-matched recipients, who have identical alleles on both copies.

The researchers randomly assigned 124 patients who had undergo HLA-haploidentical HSCT to receive either placebo or MSCs at a dose of 3 x 10⁷ cells/100 mL per month for four cycles beginning 4 months after HSCT

Of the 124 randomized patients, 12 discontinued the study due to cGVHD or disease progression.

The 2-year cumulative incidence of cGVHD among patients treated with MSCs was 27%, compared with 49% for placebo-treated controls (P = .021). Seven patients in the control group but none in the MSC-treated group developed typical lung cGVHD (P = .047).

The investigators also observed increases in memory B lymphocytes and regulatory T cells, and in the ratio of type 1 to type 2 T-helper cells, as well as a decrease in natural killer cells.

The finding that the MSC infusions increased the number of regulatory T cells while decreasing the incidence of cGVHD suggests that regulatory T cells play an inhibitory role, the investigators said.

The study was supported by the Chinese Academy of Sciences. Chinese National Natural Science Foundation, and other Chinese government grants. The authors reported having no relationships to disclose.

The multikinase inhibitor cabozantinib did not significantly improve overall survival, compared with prednisone in men with previously treated metastatic castration-resistant prostate cancer, reported investigators in the phase III COMET-1 trial.

Among 1,028 men with metastatic castration-resistant prostate cancer (mCRPC) median overall survival was 11.0 months for 682 patients randomly assigned to cabozantinib (Cabometyx), compared with 9.8 months for patients assigned to prednisone, a difference that was not statistically significant, reported Matthew Smith, MD, PhD, of Massachusetts General Hospital in Boston, and his colleagues.

RTEmagicC_e580418c7eedbd82c3_prostate_cancer_2.jpg.jpg

Cabozantinib was, however, associated with significant improvements over prednisone in bone scan response (BSR) at 12 weeks, radiographic progression-free survival (rPFS), and in effects on circulating tumor cells (CTCs), bone biomarkers, and symptomatic skeletal events (SSE), but not prostate-specific antigen (PSA)-related outcomes, the investigators reported (J Clin Oncol. 2016 Jul 11. doi: 10.1200/JCO.2015.65.5597).

“The biologic activities of cabozantinib are diverse, with bone effects, direct effects on cancer cells, and anti-angiogenic effects being demonstrated in preclinical models. It could be argued that the observed changes in BSR, bone biomarkers, and SSEs in our study are consistent with biologic effects in bone and bone metastases, and the improvements in CTCs suggest a direct antitumor effect, although the lack of improvement in PSA outcomes argues against such an effect,” they wrote.

Cabozantinib is an oral inhibitor of tyrosine kinases believed to be important factors in prostate cancer development and progression, including MET and vascular endothelial growth factor (VEGF) receptor 2.

In a phase II­ randomized discontinuation trial in men with mCRPC, cabozantinib was associated with reductions in soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in markers of bone turnover, pain, and use of narcotics.

To see whether the promising clinical activity observed in earlier studies could be sustained, the investigators conducted a phase III study comparing cabozantinib with prednisone in men with mCRPC who had experienced bone metastases and disease progression after therapy with docetaxel and abiraterone acetate and/or enzalutamide.

Patients were randomly assigned on a 2:1 basis to cabozantinib 60 mg once daily or prednisone 5 mg twice daily.

As noted before, there was no difference in overall survival, the primary endpoint, between the treatment groups, but BSR at 12 weeks was superior with cabozantinib, occurring in 42% vs. 3% of patients on prednisone (P less than .001). Radiographic PFS was also better with cabozantinib, at 5.6 vs. 2.8 months (hazard ratio, 0.48; P less than .001).

More patients on cabozantinib experienced grade 3 or greater adverse events (71% vs. 56%) and nearly three times as many patients discontinued the assigned drug because of adverse events (33% vs, 12%, respectively).

The study was supported by Exelixis. Dr. Smith disclosed a consulting/advisory role for Exelixis, and several coauthors reported research funding from the company. Dr. Alumkal and Dr. Beer disclosed research funding and/or consulting with various companies, not including Exelixis.

tor@frontlinemedcom.com

The multikinase inhibitor cabozantinib did not significantly improve overall survival, compared with prednisone in men with previously treated metastatic castration-resistant prostate cancer, reported investigators in the phase III COMET-1 trial.

Among 1,028 men with metastatic castration-resistant prostate cancer (mCRPC) median overall survival was 11.0 months for 682 patients randomly assigned to cabozantinib (Cabometyx), compared with 9.8 months for patients assigned to prednisone, a difference that was not statistically significant, reported Matthew Smith, MD, PhD, of Massachusetts General Hospital in Boston, and his colleagues.

RTEmagicC_e580418c7eedbd82c3_prostate_cancer_2.jpg.jpg

Cabozantinib was, however, associated with significant improvements over prednisone in bone scan response (BSR) at 12 weeks, radiographic progression-free survival (rPFS), and in effects on circulating tumor cells (CTCs), bone biomarkers, and symptomatic skeletal events (SSE), but not prostate-specific antigen (PSA)-related outcomes, the investigators reported (J Clin Oncol. 2016 Jul 11. doi: 10.1200/JCO.2015.65.5597).

“The biologic activities of cabozantinib are diverse, with bone effects, direct effects on cancer cells, and anti-angiogenic effects being demonstrated in preclinical models. It could be argued that the observed changes in BSR, bone biomarkers, and SSEs in our study are consistent with biologic effects in bone and bone metastases, and the improvements in CTCs suggest a direct antitumor effect, although the lack of improvement in PSA outcomes argues against such an effect,” they wrote.

Cabozantinib is an oral inhibitor of tyrosine kinases believed to be important factors in prostate cancer development and progression, including MET and vascular endothelial growth factor (VEGF) receptor 2.

In a phase II­ randomized discontinuation trial in men with mCRPC, cabozantinib was associated with reductions in soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in markers of bone turnover, pain, and use of narcotics.

To see whether the promising clinical activity observed in earlier studies could be sustained, the investigators conducted a phase III study comparing cabozantinib with prednisone in men with mCRPC who had experienced bone metastases and disease progression after therapy with docetaxel and abiraterone acetate and/or enzalutamide.

Patients were randomly assigned on a 2:1 basis to cabozantinib 60 mg once daily or prednisone 5 mg twice daily.

As noted before, there was no difference in overall survival, the primary endpoint, between the treatment groups, but BSR at 12 weeks was superior with cabozantinib, occurring in 42% vs. 3% of patients on prednisone (P less than .001). Radiographic PFS was also better with cabozantinib, at 5.6 vs. 2.8 months (hazard ratio, 0.48; P less than .001).

More patients on cabozantinib experienced grade 3 or greater adverse events (71% vs. 56%) and nearly three times as many patients discontinued the assigned drug because of adverse events (33% vs, 12%, respectively).

The study was supported by Exelixis. Dr. Smith disclosed a consulting/advisory role for Exelixis, and several coauthors reported research funding from the company. Dr. Alumkal and Dr. Beer disclosed research funding and/or consulting with various companies, not including Exelixis.

tor@frontlinemedcom.com

The multikinase inhibitor cabozantinib did not significantly improve overall survival, compared with prednisone in men with previously treated metastatic castration-resistant prostate cancer, reported investigators in the phase III COMET-1 trial.

Among 1,028 men with metastatic castration-resistant prostate cancer (mCRPC) median overall survival was 11.0 months for 682 patients randomly assigned to cabozantinib (Cabometyx), compared with 9.8 months for patients assigned to prednisone, a difference that was not statistically significant, reported Matthew Smith, MD, PhD, of Massachusetts General Hospital in Boston, and his colleagues.

RTEmagicC_e580418c7eedbd82c3_prostate_cancer_2.jpg.jpg

Cabozantinib was, however, associated with significant improvements over prednisone in bone scan response (BSR) at 12 weeks, radiographic progression-free survival (rPFS), and in effects on circulating tumor cells (CTCs), bone biomarkers, and symptomatic skeletal events (SSE), but not prostate-specific antigen (PSA)-related outcomes, the investigators reported (J Clin Oncol. 2016 Jul 11. doi: 10.1200/JCO.2015.65.5597).

“The biologic activities of cabozantinib are diverse, with bone effects, direct effects on cancer cells, and anti-angiogenic effects being demonstrated in preclinical models. It could be argued that the observed changes in BSR, bone biomarkers, and SSEs in our study are consistent with biologic effects in bone and bone metastases, and the improvements in CTCs suggest a direct antitumor effect, although the lack of improvement in PSA outcomes argues against such an effect,” they wrote.

Cabozantinib is an oral inhibitor of tyrosine kinases believed to be important factors in prostate cancer development and progression, including MET and vascular endothelial growth factor (VEGF) receptor 2.

In a phase II­ randomized discontinuation trial in men with mCRPC, cabozantinib was associated with reductions in soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in markers of bone turnover, pain, and use of narcotics.

To see whether the promising clinical activity observed in earlier studies could be sustained, the investigators conducted a phase III study comparing cabozantinib with prednisone in men with mCRPC who had experienced bone metastases and disease progression after therapy with docetaxel and abiraterone acetate and/or enzalutamide.

Patients were randomly assigned on a 2:1 basis to cabozantinib 60 mg once daily or prednisone 5 mg twice daily.

As noted before, there was no difference in overall survival, the primary endpoint, between the treatment groups, but BSR at 12 weeks was superior with cabozantinib, occurring in 42% vs. 3% of patients on prednisone (P less than .001). Radiographic PFS was also better with cabozantinib, at 5.6 vs. 2.8 months (hazard ratio, 0.48; P less than .001).

More patients on cabozantinib experienced grade 3 or greater adverse events (71% vs. 56%) and nearly three times as many patients discontinued the assigned drug because of adverse events (33% vs, 12%, respectively).

The study was supported by Exelixis. Dr. Smith disclosed a consulting/advisory role for Exelixis, and several coauthors reported research funding from the company. Dr. Alumkal and Dr. Beer disclosed research funding and/or consulting with various companies, not including Exelixis.

tor@frontlinemedcom.com

Long-term follow-up from two randomized trials shows that the treatment advantage initially seen by adding radiotherapy to the CHOP regimen in patients with limited-stage diffuse large B-cell lymphoma disappeared over time.

After a median follow-up of nearly 18 years, there were no significant differences in either progression-free survival (PFS) or overall survival between patients who had received standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 8 cycles (CHOP8), or 3 cycles of CHOP with involved-field radiotherapy (CHOP3RT), reported Deborah M. Stephens, DO, of the University of Utah in Salt Lake City, and her colleagues.

The addition of rituximab to CHOP plus involved-field radiotherapy (IFRT) in a separate cohort did not appear to reduce the continued relapse risk, the investigators noted (J Clin Oncol. 2016 Jul. doi: 10.1200/JCO.2015.65.4582).

The findings suggest that long-term follow-up of patients enrolled in clinical trials may provide clinically important additional information, and that limited-stage diffuse large B-cell lymphoma (DLBCL) may have a biology that is distinctly different from that of advanced stage DLBCL, the investigators wrote.

Initial results from the SWOG (Southwest Oncology Group) Study 8736, published after a median follow-up of 4.4 years, showed that CHOP3RT was associated with significantly better 5-year PFS and OS rates, compared with patients treated with CHOP8.

A second trial, SWOG Study 0014, looked at the addition of rituximab (Rituxan) to CHOP plus IFRT in patients with high-risk DLBCL with at least one adverse feature of the stage-modified International Prognostic Index. In this trial, after a median follow-up of 5.3 years, 4-year PFS was 88%, and 4-year OS was 92%.

5 years not enough

Results of both trials were published around the 5-year follow-up mark. However, an analysis of 10-year follow-up data from the S8736 trial, published only as an abstract (Blood. 98:724a-725a, 2001; abstr 3024), showed that “the survival curves for CHOP8 and CHOP3RT, surprisingly, began to overlap,” Dr. Stephens and her colleagues wrote.

“Additionally, for both S8736 and S0014, no plateau had been reached in the PFS curves. These data contrasted the expected cure rates for advanced-stage DLBCL, leading to the hypothesis that limited-stage DLBCL may have a unique biology from its advanced-stage counterpart,” they added.

Although more than half of patients with advanced-stage diffuse large B-cell lymphoma (DLBCL) can be cured with anthracycline-based chemotherapy, cure rates are markedly lower among patients with limited-stage disease, defined as Ann Arbor stage I or II, confined to a single irradiation field. Limited-stage disease accounts for approximately one-third DLBCL cases.

To see whether the trends observed at 10 years continued, the investigators conducted a survival analysis from S8736 and compared the data from similar patients in the S0014 study.

They found that after a median follow-up of 17.7 years in S8736, median PFS was 12.0 years for patients treated with CHOP8, and 11.1 years for patients treated with CHOP3RT, a difference that was not statistically significant.

Median OS was 13.0 and 13.7 years, respectively, and was also not significant.

In S0014, after a median follow-up of 12 years, the 5-year OS rate was 82%, and 10-year rate was 67%. In this trial, the investigators observed “a persistent pattern of relapse despite the addition of rituximab.”

“The populations were not entirely identical; however, even the addition of rituximab as per S0014 to combined-modality therapy did not seem to mitigate the continued relapse risk, underscoring the value of prolonged observation of clinical trial patients and possible unique biology of limited-stage DLBCL,” Dr. Stephens and her associates wrote.

The study was sponsored by grants from the National Institutes of Health. Dr. Stephens reported having no financial disclosures. Several coauthors disclosed research funding, consulting, speakers’ bureau participation or travel expenses from various oncology drug makers.

Long-term follow-up from two randomized trials shows that the treatment advantage initially seen by adding radiotherapy to the CHOP regimen in patients with limited-stage diffuse large B-cell lymphoma disappeared over time.

After a median follow-up of nearly 18 years, there were no significant differences in either progression-free survival (PFS) or overall survival between patients who had received standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 8 cycles (CHOP8), or 3 cycles of CHOP with involved-field radiotherapy (CHOP3RT), reported Deborah M. Stephens, DO, of the University of Utah in Salt Lake City, and her colleagues.

The addition of rituximab to CHOP plus involved-field radiotherapy (IFRT) in a separate cohort did not appear to reduce the continued relapse risk, the investigators noted (J Clin Oncol. 2016 Jul. doi: 10.1200/JCO.2015.65.4582).

The findings suggest that long-term follow-up of patients enrolled in clinical trials may provide clinically important additional information, and that limited-stage diffuse large B-cell lymphoma (DLBCL) may have a biology that is distinctly different from that of advanced stage DLBCL, the investigators wrote.

Initial results from the SWOG (Southwest Oncology Group) Study 8736, published after a median follow-up of 4.4 years, showed that CHOP3RT was associated with significantly better 5-year PFS and OS rates, compared with patients treated with CHOP8.

A second trial, SWOG Study 0014, looked at the addition of rituximab (Rituxan) to CHOP plus IFRT in patients with high-risk DLBCL with at least one adverse feature of the stage-modified International Prognostic Index. In this trial, after a median follow-up of 5.3 years, 4-year PFS was 88%, and 4-year OS was 92%.

5 years not enough

Results of both trials were published around the 5-year follow-up mark. However, an analysis of 10-year follow-up data from the S8736 trial, published only as an abstract (Blood. 98:724a-725a, 2001; abstr 3024), showed that “the survival curves for CHOP8 and CHOP3RT, surprisingly, began to overlap,” Dr. Stephens and her colleagues wrote.

“Additionally, for both S8736 and S0014, no plateau had been reached in the PFS curves. These data contrasted the expected cure rates for advanced-stage DLBCL, leading to the hypothesis that limited-stage DLBCL may have a unique biology from its advanced-stage counterpart,” they added.

Although more than half of patients with advanced-stage diffuse large B-cell lymphoma (DLBCL) can be cured with anthracycline-based chemotherapy, cure rates are markedly lower among patients with limited-stage disease, defined as Ann Arbor stage I or II, confined to a single irradiation field. Limited-stage disease accounts for approximately one-third DLBCL cases.

To see whether the trends observed at 10 years continued, the investigators conducted a survival analysis from S8736 and compared the data from similar patients in the S0014 study.

They found that after a median follow-up of 17.7 years in S8736, median PFS was 12.0 years for patients treated with CHOP8, and 11.1 years for patients treated with CHOP3RT, a difference that was not statistically significant.

Median OS was 13.0 and 13.7 years, respectively, and was also not significant.

In S0014, after a median follow-up of 12 years, the 5-year OS rate was 82%, and 10-year rate was 67%. In this trial, the investigators observed “a persistent pattern of relapse despite the addition of rituximab.”

“The populations were not entirely identical; however, even the addition of rituximab as per S0014 to combined-modality therapy did not seem to mitigate the continued relapse risk, underscoring the value of prolonged observation of clinical trial patients and possible unique biology of limited-stage DLBCL,” Dr. Stephens and her associates wrote.

The study was sponsored by grants from the National Institutes of Health. Dr. Stephens reported having no financial disclosures. Several coauthors disclosed research funding, consulting, speakers’ bureau participation or travel expenses from various oncology drug makers.

Long-term follow-up from two randomized trials shows that the treatment advantage initially seen by adding radiotherapy to the CHOP regimen in patients with limited-stage diffuse large B-cell lymphoma disappeared over time.

After a median follow-up of nearly 18 years, there were no significant differences in either progression-free survival (PFS) or overall survival between patients who had received standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 8 cycles (CHOP8), or 3 cycles of CHOP with involved-field radiotherapy (CHOP3RT), reported Deborah M. Stephens, DO, of the University of Utah in Salt Lake City, and her colleagues.

The addition of rituximab to CHOP plus involved-field radiotherapy (IFRT) in a separate cohort did not appear to reduce the continued relapse risk, the investigators noted (J Clin Oncol. 2016 Jul. doi: 10.1200/JCO.2015.65.4582).

The findings suggest that long-term follow-up of patients enrolled in clinical trials may provide clinically important additional information, and that limited-stage diffuse large B-cell lymphoma (DLBCL) may have a biology that is distinctly different from that of advanced stage DLBCL, the investigators wrote.

Initial results from the SWOG (Southwest Oncology Group) Study 8736, published after a median follow-up of 4.4 years, showed that CHOP3RT was associated with significantly better 5-year PFS and OS rates, compared with patients treated with CHOP8.

A second trial, SWOG Study 0014, looked at the addition of rituximab (Rituxan) to CHOP plus IFRT in patients with high-risk DLBCL with at least one adverse feature of the stage-modified International Prognostic Index. In this trial, after a median follow-up of 5.3 years, 4-year PFS was 88%, and 4-year OS was 92%.

5 years not enough

Results of both trials were published around the 5-year follow-up mark. However, an analysis of 10-year follow-up data from the S8736 trial, published only as an abstract (Blood. 98:724a-725a, 2001; abstr 3024), showed that “the survival curves for CHOP8 and CHOP3RT, surprisingly, began to overlap,” Dr. Stephens and her colleagues wrote.

“Additionally, for both S8736 and S0014, no plateau had been reached in the PFS curves. These data contrasted the expected cure rates for advanced-stage DLBCL, leading to the hypothesis that limited-stage DLBCL may have a unique biology from its advanced-stage counterpart,” they added.

Although more than half of patients with advanced-stage diffuse large B-cell lymphoma (DLBCL) can be cured with anthracycline-based chemotherapy, cure rates are markedly lower among patients with limited-stage disease, defined as Ann Arbor stage I or II, confined to a single irradiation field. Limited-stage disease accounts for approximately one-third DLBCL cases.

To see whether the trends observed at 10 years continued, the investigators conducted a survival analysis from S8736 and compared the data from similar patients in the S0014 study.

They found that after a median follow-up of 17.7 years in S8736, median PFS was 12.0 years for patients treated with CHOP8, and 11.1 years for patients treated with CHOP3RT, a difference that was not statistically significant.

Median OS was 13.0 and 13.7 years, respectively, and was also not significant.

In S0014, after a median follow-up of 12 years, the 5-year OS rate was 82%, and 10-year rate was 67%. In this trial, the investigators observed “a persistent pattern of relapse despite the addition of rituximab.”

“The populations were not entirely identical; however, even the addition of rituximab as per S0014 to combined-modality therapy did not seem to mitigate the continued relapse risk, underscoring the value of prolonged observation of clinical trial patients and possible unique biology of limited-stage DLBCL,” Dr. Stephens and her associates wrote.

The study was sponsored by grants from the National Institutes of Health. Dr. Stephens reported having no financial disclosures. Several coauthors disclosed research funding, consulting, speakers’ bureau participation or travel expenses from various oncology drug makers.

The prevalence of inherited mutations in DNA repair genes such as BRCA2 in men with metastatic prostate cancer may be as high as 12%, investigators in a multicenter study report.

The prevalence of presumably harmful mutations in men with metastatic disease was more than twice that of men with localized prostate cancer, and men with metastatic prostate cancer had a 3- to 19-fold higher risk for having mutations in individual DNA repair genes, compared with men without prostate cancer in a population-wide genetic sample, reported Colin C. Pritchard, MD, PhD, of the University of Washington in Seattle and colleagues.

RTEmagicC_e8b2bbe356035076f5_Genes_DNA_4.jpg.jpg

“Because the high frequency of DNA repair gene mutations is not exclusive to an early-onset phenotype and is associated with clinically and histologically aggressive disease, with compelling evidence for therapeutic relevance, it may be of interest to routinely examine all men with metastatic prostate cancer for the presence of germline mutations in DNA repair genes,” the investigators suggest (N Engl J Med. 2016 July. doi: 10.1056/NEJMoa1603144).

The findings point to possible therapeutic interventions for men with advanced prostate cancer with identified germline mutations in DNA repair genes, such as poly (ADP-ribose) polymerase (PARP) inhibitors or platinum compound–based chemotherapy,

To date, the only genetic factors known to be associated with aggressive prostate cancer and prostate cancer–specific mortality are mutations in DNA repair genes such as BRCA1 and BRCA2, CHEK2, and PALB2. The frequency of mutations in these genes among men with localized prostate cancer in general is relatively low, accounting for just a few percentage points of familial prostate cancer cases in a sample unselected for family predisposition, the authors noted.

To determine the frequency of mutations in advanced disease, the investigators reviewed genetic data on 692 men with metastatic prostate cancer who were enrolled in one of seven cases series and were unselected for family history of cancer or age at diagnosis.

They used multiplex genetic sequencing assays to look for mutation in 20 DNA repair genes that are associated with autosomal dominant cancer predisposition syndromes.

They found 84 presumably harmful mutations in 82 men, for an overall prevalence of 11.8%. In contrast, the frequency of germline DNA repair mutations among 499 men in the Cancer Genome Atlas prostate cancer study, including men with high-risk disease, was 4.6%, the authors noted.

The mutations occurred in 16 different genes, including, in order of prevalence, BRCA2, ATM, CHEL2, BRCA1, RAD51D and PALB2. There were no significant differences in mutation frequencies by either family history of prostate cancer or age at diagnosis.

The authors also estimated the prevalence of DNA repair gene mutations among the general population by looking at a sample of 53,105 persons without a known diagnosis of cancer who were included in the Exome Aggregation Consortium. Men with metastatic prostate cancer had a fivefold risk for having any deleterious DNA repair mutation, compared with the general population (P less than .001).

The relative risk of mutations in individual genes for men with metastatic disease, compared with men in the control sample, ranged from 3.1 for CHEK2 (P = .002) to 18.6 for BRCA2 (P less than .001).

The study was supported by a Stand Up To Cancer–Prostate Cancer Foundation (SU2C-PCF) International Prostate Cancer Dream Team Translational Cancer Research Grant and awards from the National Institutes of Health, Department of Defense, and prostate cancer foundation. Several authors reported receiving research fees, grants, honoraria, and/or travel expenses from various pharmaceutical companies.

tor@frontlinemedcom.com

The prevalence of inherited mutations in DNA repair genes such as BRCA2 in men with metastatic prostate cancer may be as high as 12%, investigators in a multicenter study report.

The prevalence of presumably harmful mutations in men with metastatic disease was more than twice that of men with localized prostate cancer, and men with metastatic prostate cancer had a 3- to 19-fold higher risk for having mutations in individual DNA repair genes, compared with men without prostate cancer in a population-wide genetic sample, reported Colin C. Pritchard, MD, PhD, of the University of Washington in Seattle and colleagues.

RTEmagicC_e8b2bbe356035076f5_Genes_DNA_4.jpg.jpg

“Because the high frequency of DNA repair gene mutations is not exclusive to an early-onset phenotype and is associated with clinically and histologically aggressive disease, with compelling evidence for therapeutic relevance, it may be of interest to routinely examine all men with metastatic prostate cancer for the presence of germline mutations in DNA repair genes,” the investigators suggest (N Engl J Med. 2016 July. doi: 10.1056/NEJMoa1603144).

The findings point to possible therapeutic interventions for men with advanced prostate cancer with identified germline mutations in DNA repair genes, such as poly (ADP-ribose) polymerase (PARP) inhibitors or platinum compound–based chemotherapy,

To date, the only genetic factors known to be associated with aggressive prostate cancer and prostate cancer–specific mortality are mutations in DNA repair genes such as BRCA1 and BRCA2, CHEK2, and PALB2. The frequency of mutations in these genes among men with localized prostate cancer in general is relatively low, accounting for just a few percentage points of familial prostate cancer cases in a sample unselected for family predisposition, the authors noted.

To determine the frequency of mutations in advanced disease, the investigators reviewed genetic data on 692 men with metastatic prostate cancer who were enrolled in one of seven cases series and were unselected for family history of cancer or age at diagnosis.

They used multiplex genetic sequencing assays to look for mutation in 20 DNA repair genes that are associated with autosomal dominant cancer predisposition syndromes.

They found 84 presumably harmful mutations in 82 men, for an overall prevalence of 11.8%. In contrast, the frequency of germline DNA repair mutations among 499 men in the Cancer Genome Atlas prostate cancer study, including men with high-risk disease, was 4.6%, the authors noted.

The mutations occurred in 16 different genes, including, in order of prevalence, BRCA2, ATM, CHEL2, BRCA1, RAD51D and PALB2. There were no significant differences in mutation frequencies by either family history of prostate cancer or age at diagnosis.

The authors also estimated the prevalence of DNA repair gene mutations among the general population by looking at a sample of 53,105 persons without a known diagnosis of cancer who were included in the Exome Aggregation Consortium. Men with metastatic prostate cancer had a fivefold risk for having any deleterious DNA repair mutation, compared with the general population (P less than .001).

The relative risk of mutations in individual genes for men with metastatic disease, compared with men in the control sample, ranged from 3.1 for CHEK2 (P = .002) to 18.6 for BRCA2 (P less than .001).

The study was supported by a Stand Up To Cancer–Prostate Cancer Foundation (SU2C-PCF) International Prostate Cancer Dream Team Translational Cancer Research Grant and awards from the National Institutes of Health, Department of Defense, and prostate cancer foundation. Several authors reported receiving research fees, grants, honoraria, and/or travel expenses from various pharmaceutical companies.

tor@frontlinemedcom.com

The prevalence of inherited mutations in DNA repair genes such as BRCA2 in men with metastatic prostate cancer may be as high as 12%, investigators in a multicenter study report.

The prevalence of presumably harmful mutations in men with metastatic disease was more than twice that of men with localized prostate cancer, and men with metastatic prostate cancer had a 3- to 19-fold higher risk for having mutations in individual DNA repair genes, compared with men without prostate cancer in a population-wide genetic sample, reported Colin C. Pritchard, MD, PhD, of the University of Washington in Seattle and colleagues.

RTEmagicC_e8b2bbe356035076f5_Genes_DNA_4.jpg.jpg

“Because the high frequency of DNA repair gene mutations is not exclusive to an early-onset phenotype and is associated with clinically and histologically aggressive disease, with compelling evidence for therapeutic relevance, it may be of interest to routinely examine all men with metastatic prostate cancer for the presence of germline mutations in DNA repair genes,” the investigators suggest (N Engl J Med. 2016 July. doi: 10.1056/NEJMoa1603144).

The findings point to possible therapeutic interventions for men with advanced prostate cancer with identified germline mutations in DNA repair genes, such as poly (ADP-ribose) polymerase (PARP) inhibitors or platinum compound–based chemotherapy,

To date, the only genetic factors known to be associated with aggressive prostate cancer and prostate cancer–specific mortality are mutations in DNA repair genes such as BRCA1 and BRCA2, CHEK2, and PALB2. The frequency of mutations in these genes among men with localized prostate cancer in general is relatively low, accounting for just a few percentage points of familial prostate cancer cases in a sample unselected for family predisposition, the authors noted.

To determine the frequency of mutations in advanced disease, the investigators reviewed genetic data on 692 men with metastatic prostate cancer who were enrolled in one of seven cases series and were unselected for family history of cancer or age at diagnosis.

They used multiplex genetic sequencing assays to look for mutation in 20 DNA repair genes that are associated with autosomal dominant cancer predisposition syndromes.

They found 84 presumably harmful mutations in 82 men, for an overall prevalence of 11.8%. In contrast, the frequency of germline DNA repair mutations among 499 men in the Cancer Genome Atlas prostate cancer study, including men with high-risk disease, was 4.6%, the authors noted.

The mutations occurred in 16 different genes, including, in order of prevalence, BRCA2, ATM, CHEL2, BRCA1, RAD51D and PALB2. There were no significant differences in mutation frequencies by either family history of prostate cancer or age at diagnosis.

The authors also estimated the prevalence of DNA repair gene mutations among the general population by looking at a sample of 53,105 persons without a known diagnosis of cancer who were included in the Exome Aggregation Consortium. Men with metastatic prostate cancer had a fivefold risk for having any deleterious DNA repair mutation, compared with the general population (P less than .001).

The relative risk of mutations in individual genes for men with metastatic disease, compared with men in the control sample, ranged from 3.1 for CHEK2 (P = .002) to 18.6 for BRCA2 (P less than .001).

The study was supported by a Stand Up To Cancer–Prostate Cancer Foundation (SU2C-PCF) International Prostate Cancer Dream Team Translational Cancer Research Grant and awards from the National Institutes of Health, Department of Defense, and prostate cancer foundation. Several authors reported receiving research fees, grants, honoraria, and/or travel expenses from various pharmaceutical companies.

tor@frontlinemedcom.com

Combination chemotherapy with bendamustine, gemcitabine, and vinorelbine can induce high complete response rates among patients with relapsed or refractory Hodgkin lymphoma (HL) who are candidates for autologous stem cell transplantation, final results of a phase II study show.

Among 59 patients enrolled in the multicenter study, 49 (83%) had responses, including 43 (73%) who achieved a complete response (CR), and 6 (10%) who had a partial response after 4 cycles of chemotherapy with bendamustine (Treanda), gemcitabine (Gemzar), and vinorelbine (BeGEV).

Of the 49 patients with responses, 43 went on to autologous stem cell transplant (ASCT), reported Armando Santoro, MD, from the Humanitas Cancer Center in Rozzano, Italy.

“These findings provide a strong rationale for further development of the BeGEV regimen,” the investigators wrote in a study published online in the Journal of Clinical Oncology (2016 Jul 5. doi: 10.1200/JCO.2016.66.4466).

The investigators had previously shown that a regimen of ifosfamide, gemcitabine, and vinorelbine (IEGV) as salvage chemotherapy prior to ASCT was associated with an 81% overall response rate (ORR) 54% CR rate.

Because bendamustine has shown good activity as monotherapy against relapsed/refractory HL, they conducted a phase II study with an IEGV-like regimen in which bendamustine would be substituted for ifosfamide, to determine whether the substitution could improve response rates.

They enrolled 59 consecutive patients aged 18 years and older with HL that had relapsed or was refractory to one previous line of chemotherapy. Patients were treated with gemcitabine 800 mg/m² on days 1 and 4, vinorelbine 20 mg/m² on day 1, and bendamustine 90 mg/m² on days 2 and 3. Patients also received prednisolone 100 mg/day for days 1 to 4. The patients were treated for four 21-day cycles.

Patients who achieved either a complete or partial response after completion of the four planned cycles then underwent myeloablative therapy with carmustine or fotemustine plus etoposide, cytarabine, and melphalan, followed by reinfusion of mobilized CD34-positive circulating stem cells.

Grade 3 or 4 hematologic toxicities included thrombocytopenia and neutropenia, which occurred in eight patients each. Fifty-five of 57 total evaluable patients had successful mobilization and harvesting of CD34-positive cells, and, as noted before, 43 went on to ASCT.

After a median follow-up of 29 months, the 2-year progression-free survival (PFS) rate for the total population was 62%, and the overall survival rates was nearly 78%. For patients who went on to ASCT, the 2-year PFS rate was 81%, and the 2-year survival rate was 89%.

The authors noted that BeGV was associated with higher CR rates than IEGV, and with “excellent” stem cell mobilization activity and engraftment. Additionally, BeGV has a favorable toxicity profile, because of the absence of ifosfamide which is known to significantly increase risk for hemorrhagic cystitis.

“Because the number of novel agents that may be added in the pretransplantation therapy setting is growing, direct comparisons of combinations incorporating novel agents with BeGEV and other regimens will be necessary to identify the best salvage strategy for relapsed and refractory HL,” the authors wrote.

The study was supported in part by a grant from Mundipharma Pharmaceuticals. Two coauthors disclosed consulting/advisory roles and travel accommodations and expenses from the company.

Combination chemotherapy with bendamustine, gemcitabine, and vinorelbine can induce high complete response rates among patients with relapsed or refractory Hodgkin lymphoma (HL) who are candidates for autologous stem cell transplantation, final results of a phase II study show.

Among 59 patients enrolled in the multicenter study, 49 (83%) had responses, including 43 (73%) who achieved a complete response (CR), and 6 (10%) who had a partial response after 4 cycles of chemotherapy with bendamustine (Treanda), gemcitabine (Gemzar), and vinorelbine (BeGEV).

Of the 49 patients with responses, 43 went on to autologous stem cell transplant (ASCT), reported Armando Santoro, MD, from the Humanitas Cancer Center in Rozzano, Italy.

“These findings provide a strong rationale for further development of the BeGEV regimen,” the investigators wrote in a study published online in the Journal of Clinical Oncology (2016 Jul 5. doi: 10.1200/JCO.2016.66.4466).

The investigators had previously shown that a regimen of ifosfamide, gemcitabine, and vinorelbine (IEGV) as salvage chemotherapy prior to ASCT was associated with an 81% overall response rate (ORR) 54% CR rate.

Because bendamustine has shown good activity as monotherapy against relapsed/refractory HL, they conducted a phase II study with an IEGV-like regimen in which bendamustine would be substituted for ifosfamide, to determine whether the substitution could improve response rates.

They enrolled 59 consecutive patients aged 18 years and older with HL that had relapsed or was refractory to one previous line of chemotherapy. Patients were treated with gemcitabine 800 mg/m² on days 1 and 4, vinorelbine 20 mg/m² on day 1, and bendamustine 90 mg/m² on days 2 and 3. Patients also received prednisolone 100 mg/day for days 1 to 4. The patients were treated for four 21-day cycles.

Patients who achieved either a complete or partial response after completion of the four planned cycles then underwent myeloablative therapy with carmustine or fotemustine plus etoposide, cytarabine, and melphalan, followed by reinfusion of mobilized CD34-positive circulating stem cells.

Grade 3 or 4 hematologic toxicities included thrombocytopenia and neutropenia, which occurred in eight patients each. Fifty-five of 57 total evaluable patients had successful mobilization and harvesting of CD34-positive cells, and, as noted before, 43 went on to ASCT.

After a median follow-up of 29 months, the 2-year progression-free survival (PFS) rate for the total population was 62%, and the overall survival rates was nearly 78%. For patients who went on to ASCT, the 2-year PFS rate was 81%, and the 2-year survival rate was 89%.

The authors noted that BeGV was associated with higher CR rates than IEGV, and with “excellent” stem cell mobilization activity and engraftment. Additionally, BeGV has a favorable toxicity profile, because of the absence of ifosfamide which is known to significantly increase risk for hemorrhagic cystitis.

“Because the number of novel agents that may be added in the pretransplantation therapy setting is growing, direct comparisons of combinations incorporating novel agents with BeGEV and other regimens will be necessary to identify the best salvage strategy for relapsed and refractory HL,” the authors wrote.

The study was supported in part by a grant from Mundipharma Pharmaceuticals. Two coauthors disclosed consulting/advisory roles and travel accommodations and expenses from the company.

Combination chemotherapy with bendamustine, gemcitabine, and vinorelbine can induce high complete response rates among patients with relapsed or refractory Hodgkin lymphoma (HL) who are candidates for autologous stem cell transplantation, final results of a phase II study show.

Among 59 patients enrolled in the multicenter study, 49 (83%) had responses, including 43 (73%) who achieved a complete response (CR), and 6 (10%) who had a partial response after 4 cycles of chemotherapy with bendamustine (Treanda), gemcitabine (Gemzar), and vinorelbine (BeGEV).

Of the 49 patients with responses, 43 went on to autologous stem cell transplant (ASCT), reported Armando Santoro, MD, from the Humanitas Cancer Center in Rozzano, Italy.

“These findings provide a strong rationale for further development of the BeGEV regimen,” the investigators wrote in a study published online in the Journal of Clinical Oncology (2016 Jul 5. doi: 10.1200/JCO.2016.66.4466).

The investigators had previously shown that a regimen of ifosfamide, gemcitabine, and vinorelbine (IEGV) as salvage chemotherapy prior to ASCT was associated with an 81% overall response rate (ORR) 54% CR rate.

Because bendamustine has shown good activity as monotherapy against relapsed/refractory HL, they conducted a phase II study with an IEGV-like regimen in which bendamustine would be substituted for ifosfamide, to determine whether the substitution could improve response rates.

They enrolled 59 consecutive patients aged 18 years and older with HL that had relapsed or was refractory to one previous line of chemotherapy. Patients were treated with gemcitabine 800 mg/m² on days 1 and 4, vinorelbine 20 mg/m² on day 1, and bendamustine 90 mg/m² on days 2 and 3. Patients also received prednisolone 100 mg/day for days 1 to 4. The patients were treated for four 21-day cycles.

Patients who achieved either a complete or partial response after completion of the four planned cycles then underwent myeloablative therapy with carmustine or fotemustine plus etoposide, cytarabine, and melphalan, followed by reinfusion of mobilized CD34-positive circulating stem cells.

Grade 3 or 4 hematologic toxicities included thrombocytopenia and neutropenia, which occurred in eight patients each. Fifty-five of 57 total evaluable patients had successful mobilization and harvesting of CD34-positive cells, and, as noted before, 43 went on to ASCT.

After a median follow-up of 29 months, the 2-year progression-free survival (PFS) rate for the total population was 62%, and the overall survival rates was nearly 78%. For patients who went on to ASCT, the 2-year PFS rate was 81%, and the 2-year survival rate was 89%.

The authors noted that BeGV was associated with higher CR rates than IEGV, and with “excellent” stem cell mobilization activity and engraftment. Additionally, BeGV has a favorable toxicity profile, because of the absence of ifosfamide which is known to significantly increase risk for hemorrhagic cystitis.

“Because the number of novel agents that may be added in the pretransplantation therapy setting is growing, direct comparisons of combinations incorporating novel agents with BeGEV and other regimens will be necessary to identify the best salvage strategy for relapsed and refractory HL,” the authors wrote.

The study was supported in part by a grant from Mundipharma Pharmaceuticals. Two coauthors disclosed consulting/advisory roles and travel accommodations and expenses from the company.

Taking a step toward the goal of personalized medicine, investigators in the multicenter, adaptive I-SPY 2 trial report that tailoring neoadjuvant therapy combinations to specific cancer subtypes in women with high-risk breast cancer will likely result in higher rates of pathological complete responses for at least two subtypes, including patients with triple-negative disease.

Among women with triple-negative breast cancer (tumors lacking human epidermal growth factor receptor 2 [HER2], estrogen, and progesterone receptors) in the phase II trial, a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and carboplatin added to paclitaxel was associated with an estimated 51% pathological complete response (pCR) rate, compared with 26% for patients treated with weekly paclitaxel alone. The predicted probability of success in a phase III trial with the combination was 88%, reported Hope S. Rugo, MD, director of the Breast Oncology Clinical Trials Program at the University of California San Francisco, and her colleagues in I-SPY 2.

RTEmagicC_a616a8f9ad468bbcb0_Rugo_Hope_S_CA_dec13.jpg.jpg

“The experience with veliparib-carboplatin in our trial shows the advantage of an adaptively randomized phase II platform trial for matching therapies with biomarker subsets to better inform the design of phase III trials so that they can be more focused, smaller, and faster. Future patients stand to benefit, but trial participants benefit as well in that exposure to ineffective therapy is minimized,” the investigators wrote (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513749).

Partial results from this trial were reported at the 2013 San Antonio Breast Cancer Symposium.

On the basis of these phase II data, an ongoing phase III neoadjuvant trial is comparing standard chemotherapy alone, with carboplatin, or with veliparib plus carboplatin as treatment for triple-negative breast cancer, Dr. Rugo and her associates said.

In another arm of I-SPY 2 involving a subset of patients with HER2-positive, hormone receptor–negative cancers, the mean estimated pCR rate was 56% for patients treated with the investigational tyrosine-kinase inhibitor (TKI) neratinib, compared with an estimated 33% among patients treated with anti-HER2 agent trastuzumab (Herceptin). All the participants received standard neoadjuvant therapy, which consisted of 12 cycles of paclitaxel, followed by 4 cycles of doxorubicin and cyclophosphamide. The estimated probability of success in phase III with neratinib was 79%, reported John W. Park, MD, of University of California San Francisco, and his coauthors on behalf of I-SPY 2 investigators (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513750).

On the basis of this phase II study, and to reflect the current standard of dual HER-targeting, the investigators are proceeding with a phase III trial comparing neratinib as neoadjuvant therapy added to pertuzumab (Perjeta), trastuzumab, and a taxane vs. the three latter drugs, and against a combination of neratinib, trastuzumab, and taxane, all followed by doxorubicin and cyclophosphamide.

Partial results of the phase II trial were reported at the 2013 annual meeting of the American Association for Cancer Research.

Nimble trial, tailored therapies

I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2) is an ongoing “platform” trial exploring the use of new drugs combined with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

Women with stage II or III breast cancers with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 (human epidermal growth factor receptor 2) status, hormone receptor status, and genetic risk factors based on a 70-gene assay. The patients are then randomized within each biomarker subtype to receive standard therapy with or without an investigational agent.

Each sub-trial has a primary endpoint of an improvement in pathological complete response compared with the standard of care. Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Regimens that have a high Bayesian predictive probability of success in a subsequent phase III neoadjuvant trial within the biomarker signature in which they performed well are eligible for moving on to phase III trials.

Triple-negative disease

Among the subgroup of patients with triple-negative disease, 72 were assigned to receive veliparib 50 mg by mouth twice daily for 12 weeks, plus carboplatin at a dose intended to achieve a pharmacologic area under the concentration versus time curve of 6 mg/hour per liter on weeks 1, 4, 7, and 10, plus intravenous paclitaxel at a dose of 80 mg/m². An additional 44 patients (controls) were randomized to receive paclitaxel alone.

Following paclitaxel alone or with the combination, all patients received doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four doses, followed by myeloid growth factor support as appropriate. Following treatment, all patients underwent surgery that included axillary node sampling in accordance with National Comprehensive Cancer Network (NCCN) and local practice guidelines. Adjuvant radiation and endocrine therapy were recommended in accordance with standard guidelines.

The rate of grade 3 or greater hematologic toxic effects in this trial arm was higher in patients treated with veliparib-carboplatin, with neutropenia rates of 71% versus 2% for controls. Adverse events occurring only in patients on veliparib-carboplatin were thrombocytopenia in 21%, anemia in 28%, and febrile neutropenia in 1%. Among patients who had received the combination, toxic effects were higher during doxorubicin-cyclophosphamide therapy.

HR-negative disease

Patients with hormone receptor–negative disease received standard neoadjuvant chemotherapy with 12 weekly cycles of paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide as described before, with or without oral neratinib 240 mg per day. Patients in the control group who had HER2-positive cancers also received trastuzumab for the first 12 weeks with a loading dose of 4 mg per kilogram of body weight in the first cycle, followed by a maintenance dose of 2 mg per kilogram in cycles 2 through 12.

Surgery, including sentinel-node dissection in patients with node-negative cancer and axillary-node dissection in those with node-positive cancer at diagnosis, was performed according to NCCN and local practice guidelines, and adjuvant radiation and endocrine therapy were recommended according to standard guidelines.

The protocol was modified to included diarrhea prophylaxis with loperamide among patients assigned to receive neratinib.

A total of 127 patients were assigned to neratinib, and 115 of these patients were evaluable for response. Controls included 84 patients, of whom 78 were evaluable. At baseline, more patients in the neratinib group had HER2-positive tumors. Neratinib reached the prespecified efficacy threshold only within the HER2-positive, HR-negative group.

Diarrhea was the most common adverse event, with grade 3 or greater diarrhea occurring among 38% of patients assigned to neratinib. Vomiting and elevated liver enzymes were also more frequent with neratinib.

I-SPY 2 is supported by QuantumLeap Healthcare Collaborative, the Foundation for the National Institutes of Health (from 2010 through 2012) and the National Cancer Institute. Dr. Park reported receiving lecture fees and travel support from Genentech and Pfizer, and receiving royalties from patents. Dr. Rugo reported grants to her institution from BioMarin, and unpaid steering committee participation for BioMarin and AbbVie. Multiple co-authors reported financial relationships of various kinds.

Taking a step toward the goal of personalized medicine, investigators in the multicenter, adaptive I-SPY 2 trial report that tailoring neoadjuvant therapy combinations to specific cancer subtypes in women with high-risk breast cancer will likely result in higher rates of pathological complete responses for at least two subtypes, including patients with triple-negative disease.

Among women with triple-negative breast cancer (tumors lacking human epidermal growth factor receptor 2 [HER2], estrogen, and progesterone receptors) in the phase II trial, a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and carboplatin added to paclitaxel was associated with an estimated 51% pathological complete response (pCR) rate, compared with 26% for patients treated with weekly paclitaxel alone. The predicted probability of success in a phase III trial with the combination was 88%, reported Hope S. Rugo, MD, director of the Breast Oncology Clinical Trials Program at the University of California San Francisco, and her colleagues in I-SPY 2.

RTEmagicC_a616a8f9ad468bbcb0_Rugo_Hope_S_CA_dec13.jpg.jpg

“The experience with veliparib-carboplatin in our trial shows the advantage of an adaptively randomized phase II platform trial for matching therapies with biomarker subsets to better inform the design of phase III trials so that they can be more focused, smaller, and faster. Future patients stand to benefit, but trial participants benefit as well in that exposure to ineffective therapy is minimized,” the investigators wrote (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513749).

Partial results from this trial were reported at the 2013 San Antonio Breast Cancer Symposium.

On the basis of these phase II data, an ongoing phase III neoadjuvant trial is comparing standard chemotherapy alone, with carboplatin, or with veliparib plus carboplatin as treatment for triple-negative breast cancer, Dr. Rugo and her associates said.

In another arm of I-SPY 2 involving a subset of patients with HER2-positive, hormone receptor–negative cancers, the mean estimated pCR rate was 56% for patients treated with the investigational tyrosine-kinase inhibitor (TKI) neratinib, compared with an estimated 33% among patients treated with anti-HER2 agent trastuzumab (Herceptin). All the participants received standard neoadjuvant therapy, which consisted of 12 cycles of paclitaxel, followed by 4 cycles of doxorubicin and cyclophosphamide. The estimated probability of success in phase III with neratinib was 79%, reported John W. Park, MD, of University of California San Francisco, and his coauthors on behalf of I-SPY 2 investigators (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513750).

On the basis of this phase II study, and to reflect the current standard of dual HER-targeting, the investigators are proceeding with a phase III trial comparing neratinib as neoadjuvant therapy added to pertuzumab (Perjeta), trastuzumab, and a taxane vs. the three latter drugs, and against a combination of neratinib, trastuzumab, and taxane, all followed by doxorubicin and cyclophosphamide.

Partial results of the phase II trial were reported at the 2013 annual meeting of the American Association for Cancer Research.

Nimble trial, tailored therapies

I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2) is an ongoing “platform” trial exploring the use of new drugs combined with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

Women with stage II or III breast cancers with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 (human epidermal growth factor receptor 2) status, hormone receptor status, and genetic risk factors based on a 70-gene assay. The patients are then randomized within each biomarker subtype to receive standard therapy with or without an investigational agent.

Each sub-trial has a primary endpoint of an improvement in pathological complete response compared with the standard of care. Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Regimens that have a high Bayesian predictive probability of success in a subsequent phase III neoadjuvant trial within the biomarker signature in which they performed well are eligible for moving on to phase III trials.

Triple-negative disease

Among the subgroup of patients with triple-negative disease, 72 were assigned to receive veliparib 50 mg by mouth twice daily for 12 weeks, plus carboplatin at a dose intended to achieve a pharmacologic area under the concentration versus time curve of 6 mg/hour per liter on weeks 1, 4, 7, and 10, plus intravenous paclitaxel at a dose of 80 mg/m². An additional 44 patients (controls) were randomized to receive paclitaxel alone.

Following paclitaxel alone or with the combination, all patients received doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four doses, followed by myeloid growth factor support as appropriate. Following treatment, all patients underwent surgery that included axillary node sampling in accordance with National Comprehensive Cancer Network (NCCN) and local practice guidelines. Adjuvant radiation and endocrine therapy were recommended in accordance with standard guidelines.

The rate of grade 3 or greater hematologic toxic effects in this trial arm was higher in patients treated with veliparib-carboplatin, with neutropenia rates of 71% versus 2% for controls. Adverse events occurring only in patients on veliparib-carboplatin were thrombocytopenia in 21%, anemia in 28%, and febrile neutropenia in 1%. Among patients who had received the combination, toxic effects were higher during doxorubicin-cyclophosphamide therapy.

HR-negative disease

Patients with hormone receptor–negative disease received standard neoadjuvant chemotherapy with 12 weekly cycles of paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide as described before, with or without oral neratinib 240 mg per day. Patients in the control group who had HER2-positive cancers also received trastuzumab for the first 12 weeks with a loading dose of 4 mg per kilogram of body weight in the first cycle, followed by a maintenance dose of 2 mg per kilogram in cycles 2 through 12.

Surgery, including sentinel-node dissection in patients with node-negative cancer and axillary-node dissection in those with node-positive cancer at diagnosis, was performed according to NCCN and local practice guidelines, and adjuvant radiation and endocrine therapy were recommended according to standard guidelines.

The protocol was modified to included diarrhea prophylaxis with loperamide among patients assigned to receive neratinib.

A total of 127 patients were assigned to neratinib, and 115 of these patients were evaluable for response. Controls included 84 patients, of whom 78 were evaluable. At baseline, more patients in the neratinib group had HER2-positive tumors. Neratinib reached the prespecified efficacy threshold only within the HER2-positive, HR-negative group.

Diarrhea was the most common adverse event, with grade 3 or greater diarrhea occurring among 38% of patients assigned to neratinib. Vomiting and elevated liver enzymes were also more frequent with neratinib.

I-SPY 2 is supported by QuantumLeap Healthcare Collaborative, the Foundation for the National Institutes of Health (from 2010 through 2012) and the National Cancer Institute. Dr. Park reported receiving lecture fees and travel support from Genentech and Pfizer, and receiving royalties from patents. Dr. Rugo reported grants to her institution from BioMarin, and unpaid steering committee participation for BioMarin and AbbVie. Multiple co-authors reported financial relationships of various kinds.

Taking a step toward the goal of personalized medicine, investigators in the multicenter, adaptive I-SPY 2 trial report that tailoring neoadjuvant therapy combinations to specific cancer subtypes in women with high-risk breast cancer will likely result in higher rates of pathological complete responses for at least two subtypes, including patients with triple-negative disease.

Among women with triple-negative breast cancer (tumors lacking human epidermal growth factor receptor 2 [HER2], estrogen, and progesterone receptors) in the phase II trial, a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and carboplatin added to paclitaxel was associated with an estimated 51% pathological complete response (pCR) rate, compared with 26% for patients treated with weekly paclitaxel alone. The predicted probability of success in a phase III trial with the combination was 88%, reported Hope S. Rugo, MD, director of the Breast Oncology Clinical Trials Program at the University of California San Francisco, and her colleagues in I-SPY 2.

RTEmagicC_a616a8f9ad468bbcb0_Rugo_Hope_S_CA_dec13.jpg.jpg

“The experience with veliparib-carboplatin in our trial shows the advantage of an adaptively randomized phase II platform trial for matching therapies with biomarker subsets to better inform the design of phase III trials so that they can be more focused, smaller, and faster. Future patients stand to benefit, but trial participants benefit as well in that exposure to ineffective therapy is minimized,” the investigators wrote (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513749).

Partial results from this trial were reported at the 2013 San Antonio Breast Cancer Symposium.

On the basis of these phase II data, an ongoing phase III neoadjuvant trial is comparing standard chemotherapy alone, with carboplatin, or with veliparib plus carboplatin as treatment for triple-negative breast cancer, Dr. Rugo and her associates said.

In another arm of I-SPY 2 involving a subset of patients with HER2-positive, hormone receptor–negative cancers, the mean estimated pCR rate was 56% for patients treated with the investigational tyrosine-kinase inhibitor (TKI) neratinib, compared with an estimated 33% among patients treated with anti-HER2 agent trastuzumab (Herceptin). All the participants received standard neoadjuvant therapy, which consisted of 12 cycles of paclitaxel, followed by 4 cycles of doxorubicin and cyclophosphamide. The estimated probability of success in phase III with neratinib was 79%, reported John W. Park, MD, of University of California San Francisco, and his coauthors on behalf of I-SPY 2 investigators (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513750).

On the basis of this phase II study, and to reflect the current standard of dual HER-targeting, the investigators are proceeding with a phase III trial comparing neratinib as neoadjuvant therapy added to pertuzumab (Perjeta), trastuzumab, and a taxane vs. the three latter drugs, and against a combination of neratinib, trastuzumab, and taxane, all followed by doxorubicin and cyclophosphamide.

Partial results of the phase II trial were reported at the 2013 annual meeting of the American Association for Cancer Research.

Nimble trial, tailored therapies

I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2) is an ongoing “platform” trial exploring the use of new drugs combined with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

Women with stage II or III breast cancers with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 (human epidermal growth factor receptor 2) status, hormone receptor status, and genetic risk factors based on a 70-gene assay. The patients are then randomized within each biomarker subtype to receive standard therapy with or without an investigational agent.

Each sub-trial has a primary endpoint of an improvement in pathological complete response compared with the standard of care. Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Regimens that have a high Bayesian predictive probability of success in a subsequent phase III neoadjuvant trial within the biomarker signature in which they performed well are eligible for moving on to phase III trials.

Triple-negative disease

Among the subgroup of patients with triple-negative disease, 72 were assigned to receive veliparib 50 mg by mouth twice daily for 12 weeks, plus carboplatin at a dose intended to achieve a pharmacologic area under the concentration versus time curve of 6 mg/hour per liter on weeks 1, 4, 7, and 10, plus intravenous paclitaxel at a dose of 80 mg/m². An additional 44 patients (controls) were randomized to receive paclitaxel alone.

Following paclitaxel alone or with the combination, all patients received doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four doses, followed by myeloid growth factor support as appropriate. Following treatment, all patients underwent surgery that included axillary node sampling in accordance with National Comprehensive Cancer Network (NCCN) and local practice guidelines. Adjuvant radiation and endocrine therapy were recommended in accordance with standard guidelines.

The rate of grade 3 or greater hematologic toxic effects in this trial arm was higher in patients treated with veliparib-carboplatin, with neutropenia rates of 71% versus 2% for controls. Adverse events occurring only in patients on veliparib-carboplatin were thrombocytopenia in 21%, anemia in 28%, and febrile neutropenia in 1%. Among patients who had received the combination, toxic effects were higher during doxorubicin-cyclophosphamide therapy.

HR-negative disease

Patients with hormone receptor–negative disease received standard neoadjuvant chemotherapy with 12 weekly cycles of paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide as described before, with or without oral neratinib 240 mg per day. Patients in the control group who had HER2-positive cancers also received trastuzumab for the first 12 weeks with a loading dose of 4 mg per kilogram of body weight in the first cycle, followed by a maintenance dose of 2 mg per kilogram in cycles 2 through 12.

Surgery, including sentinel-node dissection in patients with node-negative cancer and axillary-node dissection in those with node-positive cancer at diagnosis, was performed according to NCCN and local practice guidelines, and adjuvant radiation and endocrine therapy were recommended according to standard guidelines.

The protocol was modified to included diarrhea prophylaxis with loperamide among patients assigned to receive neratinib.

A total of 127 patients were assigned to neratinib, and 115 of these patients were evaluable for response. Controls included 84 patients, of whom 78 were evaluable. At baseline, more patients in the neratinib group had HER2-positive tumors. Neratinib reached the prespecified efficacy threshold only within the HER2-positive, HR-negative group.

Diarrhea was the most common adverse event, with grade 3 or greater diarrhea occurring among 38% of patients assigned to neratinib. Vomiting and elevated liver enzymes were also more frequent with neratinib.

I-SPY 2 is supported by QuantumLeap Healthcare Collaborative, the Foundation for the National Institutes of Health (from 2010 through 2012) and the National Cancer Institute. Dr. Park reported receiving lecture fees and travel support from Genentech and Pfizer, and receiving royalties from patents. Dr. Rugo reported grants to her institution from BioMarin, and unpaid steering committee participation for BioMarin and AbbVie. Multiple co-authors reported financial relationships of various kinds.

Women with BRCA1 mutations who undergo risk-reducing ovary and fallopian tube removal without concomitant hysterectomy appear to be at increased risk for serous or serous-like endometrial carcinoma, results of a long-term prospective study suggest.

Among 1,083 women with deleterious mutations in BRCA1, BRCA2, or both who underwent risk-reducing salpingo-oophorectomy (RRSO) without hysterectomy, there was no overall increase in the incidence of uterine corpus cancers, compared with the background population. But among women with BRCA1 mutations, however, there was increased risk for serous/serous-like endometrial carcinomas, which comprise only 10% of endometrial cancers, but account for about 40% of endometrial cancer deaths, reported Catherine A. Shu, MD, of Columbia University, New York, and her colleagues (JAMA Oncol. 2016 Jun 30. doi: 10.1001/jamaoncol.2016.1820).

RTEmagicC_7b8567d637ef626ad0_Genes_DNA_1.jpg.jpg

“Our results suggest that BRCA1+ women are at increased risk for serous/serous-like endometrial carcinoma. Although instability in the estimated magnitude of this risk remains, we believe that the possibility of this cancer should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women,” they wrote.

Salpingo-oophorectomy to reduce risk for breast, ovarian, and fallopian-tube cancers is a standard option for women with BRCA mutations, but it’s unclear whether concomitant hysterectomy offers additional benefit, or adds only morbidity.

To help clarify the issue, investigators at nine comprehensive cancer centers enrolled 627 women with BRCA1 mutations, 453 with BRCA2 mutations, and 3 with mutations in both genes who underwent RRSO without either prior or concomitant hysterectomy. They then followed the patients for a median of 5.1 years after the date of ascertainment, receipt of BRCA testing results, or RRSO.

There were a total of 8 incident uterine cancers over the course of follow-up, compared with 4.3 that would be expected based on Surveillance, Epidemiology, and End Results (SEER) data. The observed-to-expected incidence ratio was 1.9, and was not statistically significant.

In addition, when the investigators stratified by subtype, there was no increased risk for endometrioid endometrial carcinoma or sarcoma.

However, there were five cases of serous/serous-like endometrial carcinomas occurring from 7.2 to 12, 9 years after surgery. The patients included four women positive for BRCA1 mutations, and one positive for BRCA2.

In the SEER population, 0.18 incident cases would be expected, translating into an observed-to-expected ratio for women with BRCA1 of 22.2 (P less than .001). For BRCA2, however, the ratio was 6.4, and was not statistically significant.

In the three serous/serous-like tumors from women positive for BRCA1, tumor analysis showed loss of the wild-type BRCA1 gene and/or loss of protein expression.

Finally to see whether the results could have been confounded by a history of breast cancer or exposure to tamoxifen, which is associated with a small but significant increase in risk for endometrial cancer, the investigators looked at the serous/serous-like subtype tumors, 4 of which occurred among 727 women with history of breast cancer, compared with 0.26 expected (observed-to-expected ratio 15.5, P less than .001). Among 356 women with no history of breast cancer, the expected incidence was 0.08, and the observed-to-expected ratio was 12.6 (not significant).

There were 3 serous/serous-like carcinomas among 273 women with tamoxifen exposure (expected rate 0.12, observed-to-expected ratio, 24.4, P less than .001) and two occurring in 655 women without tamoxifen exposure (expected 0.18, observed-to-expected ratio 11.3, P = .01).

The authors noted that with minimally invasive approaches, the additional surgical risks, mortality rates, and costs of adding concomitant hysterectomy to RRSO are relatively modest and may be an acceptable trade-off for some high-risk patients.

“[I]f the present results are confirmed by future studies, hysterectomy with bilateral salpingo-oophorectomy may become the preferred risk-reducing surgical approach for BRCA1+ women. However, even if these results are confirmed, RRSO alone may still have a role for BRCA1+ women if strong reasons exist for uterine retention, such as dense pelvic adhesions or desire for future pregnancy using assisted reproductive approaches,” they wrote.

Women with BRCA1 mutations who undergo risk-reducing ovary and fallopian tube removal without concomitant hysterectomy appear to be at increased risk for serous or serous-like endometrial carcinoma, results of a long-term prospective study suggest.

Among 1,083 women with deleterious mutations in BRCA1, BRCA2, or both who underwent risk-reducing salpingo-oophorectomy (RRSO) without hysterectomy, there was no overall increase in the incidence of uterine corpus cancers, compared with the background population. But among women with BRCA1 mutations, however, there was increased risk for serous/serous-like endometrial carcinomas, which comprise only 10% of endometrial cancers, but account for about 40% of endometrial cancer deaths, reported Catherine A. Shu, MD, of Columbia University, New York, and her colleagues (JAMA Oncol. 2016 Jun 30. doi: 10.1001/jamaoncol.2016.1820).

RTEmagicC_7b8567d637ef626ad0_Genes_DNA_1.jpg.jpg

“Our results suggest that BRCA1+ women are at increased risk for serous/serous-like endometrial carcinoma. Although instability in the estimated magnitude of this risk remains, we believe that the possibility of this cancer should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women,” they wrote.

Salpingo-oophorectomy to reduce risk for breast, ovarian, and fallopian-tube cancers is a standard option for women with BRCA mutations, but it’s unclear whether concomitant hysterectomy offers additional benefit, or adds only morbidity.

To help clarify the issue, investigators at nine comprehensive cancer centers enrolled 627 women with BRCA1 mutations, 453 with BRCA2 mutations, and 3 with mutations in both genes who underwent RRSO without either prior or concomitant hysterectomy. They then followed the patients for a median of 5.1 years after the date of ascertainment, receipt of BRCA testing results, or RRSO.

There were a total of 8 incident uterine cancers over the course of follow-up, compared with 4.3 that would be expected based on Surveillance, Epidemiology, and End Results (SEER) data. The observed-to-expected incidence ratio was 1.9, and was not statistically significant.

In addition, when the investigators stratified by subtype, there was no increased risk for endometrioid endometrial carcinoma or sarcoma.

However, there were five cases of serous/serous-like endometrial carcinomas occurring from 7.2 to 12, 9 years after surgery. The patients included four women positive for BRCA1 mutations, and one positive for BRCA2.

In the SEER population, 0.18 incident cases would be expected, translating into an observed-to-expected ratio for women with BRCA1 of 22.2 (P less than .001). For BRCA2, however, the ratio was 6.4, and was not statistically significant.

In the three serous/serous-like tumors from women positive for BRCA1, tumor analysis showed loss of the wild-type BRCA1 gene and/or loss of protein expression.

Finally to see whether the results could have been confounded by a history of breast cancer or exposure to tamoxifen, which is associated with a small but significant increase in risk for endometrial cancer, the investigators looked at the serous/serous-like subtype tumors, 4 of which occurred among 727 women with history of breast cancer, compared with 0.26 expected (observed-to-expected ratio 15.5, P less than .001). Among 356 women with no history of breast cancer, the expected incidence was 0.08, and the observed-to-expected ratio was 12.6 (not significant).

There were 3 serous/serous-like carcinomas among 273 women with tamoxifen exposure (expected rate 0.12, observed-to-expected ratio, 24.4, P less than .001) and two occurring in 655 women without tamoxifen exposure (expected 0.18, observed-to-expected ratio 11.3, P = .01).

The authors noted that with minimally invasive approaches, the additional surgical risks, mortality rates, and costs of adding concomitant hysterectomy to RRSO are relatively modest and may be an acceptable trade-off for some high-risk patients.

“[I]f the present results are confirmed by future studies, hysterectomy with bilateral salpingo-oophorectomy may become the preferred risk-reducing surgical approach for BRCA1+ women. However, even if these results are confirmed, RRSO alone may still have a role for BRCA1+ women if strong reasons exist for uterine retention, such as dense pelvic adhesions or desire for future pregnancy using assisted reproductive approaches,” they wrote.

Women with BRCA1 mutations who undergo risk-reducing ovary and fallopian tube removal without concomitant hysterectomy appear to be at increased risk for serous or serous-like endometrial carcinoma, results of a long-term prospective study suggest.

Among 1,083 women with deleterious mutations in BRCA1, BRCA2, or both who underwent risk-reducing salpingo-oophorectomy (RRSO) without hysterectomy, there was no overall increase in the incidence of uterine corpus cancers, compared with the background population. But among women with BRCA1 mutations, however, there was increased risk for serous/serous-like endometrial carcinomas, which comprise only 10% of endometrial cancers, but account for about 40% of endometrial cancer deaths, reported Catherine A. Shu, MD, of Columbia University, New York, and her colleagues (JAMA Oncol. 2016 Jun 30. doi: 10.1001/jamaoncol.2016.1820).

RTEmagicC_7b8567d637ef626ad0_Genes_DNA_1.jpg.jpg

“Our results suggest that BRCA1+ women are at increased risk for serous/serous-like endometrial carcinoma. Although instability in the estimated magnitude of this risk remains, we believe that the possibility of this cancer should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women,” they wrote.

Salpingo-oophorectomy to reduce risk for breast, ovarian, and fallopian-tube cancers is a standard option for women with BRCA mutations, but it’s unclear whether concomitant hysterectomy offers additional benefit, or adds only morbidity.

To help clarify the issue, investigators at nine comprehensive cancer centers enrolled 627 women with BRCA1 mutations, 453 with BRCA2 mutations, and 3 with mutations in both genes who underwent RRSO without either prior or concomitant hysterectomy. They then followed the patients for a median of 5.1 years after the date of ascertainment, receipt of BRCA testing results, or RRSO.

There were a total of 8 incident uterine cancers over the course of follow-up, compared with 4.3 that would be expected based on Surveillance, Epidemiology, and End Results (SEER) data. The observed-to-expected incidence ratio was 1.9, and was not statistically significant.

In addition, when the investigators stratified by subtype, there was no increased risk for endometrioid endometrial carcinoma or sarcoma.

However, there were five cases of serous/serous-like endometrial carcinomas occurring from 7.2 to 12, 9 years after surgery. The patients included four women positive for BRCA1 mutations, and one positive for BRCA2.

In the SEER population, 0.18 incident cases would be expected, translating into an observed-to-expected ratio for women with BRCA1 of 22.2 (P less than .001). For BRCA2, however, the ratio was 6.4, and was not statistically significant.

In the three serous/serous-like tumors from women positive for BRCA1, tumor analysis showed loss of the wild-type BRCA1 gene and/or loss of protein expression.

Finally to see whether the results could have been confounded by a history of breast cancer or exposure to tamoxifen, which is associated with a small but significant increase in risk for endometrial cancer, the investigators looked at the serous/serous-like subtype tumors, 4 of which occurred among 727 women with history of breast cancer, compared with 0.26 expected (observed-to-expected ratio 15.5, P less than .001). Among 356 women with no history of breast cancer, the expected incidence was 0.08, and the observed-to-expected ratio was 12.6 (not significant).

There were 3 serous/serous-like carcinomas among 273 women with tamoxifen exposure (expected rate 0.12, observed-to-expected ratio, 24.4, P less than .001) and two occurring in 655 women without tamoxifen exposure (expected 0.18, observed-to-expected ratio 11.3, P = .01).

The authors noted that with minimally invasive approaches, the additional surgical risks, mortality rates, and costs of adding concomitant hysterectomy to RRSO are relatively modest and may be an acceptable trade-off for some high-risk patients.

“[I]f the present results are confirmed by future studies, hysterectomy with bilateral salpingo-oophorectomy may become the preferred risk-reducing surgical approach for BRCA1+ women. However, even if these results are confirmed, RRSO alone may still have a role for BRCA1+ women if strong reasons exist for uterine retention, such as dense pelvic adhesions or desire for future pregnancy using assisted reproductive approaches,” they wrote.

COPENHAGEN – Nivolumab may be an effective salvage therapy option for adults with Hodgkin lymphoma whose disease has progressed despite transplant and treatment with brentuximab vedotin, investigators reported.

In a subcohort of patients from the Checkmate 205 phase II trial, 80 patients with Hodgkin lymphoma who had disease progression following autologous stem cell transplant (ASCT) and brentuximab vedotin (Adcetris), nivolumab (Opdivo) therapy was associated with a 53% objective response rate according to independent reviewers, reported Dr. Anas Younes, chief of the lymphoma service at Memorial Sloan Kettering Cancer Center, New York.

RTEmagicC_706f4d265e38fc20cb_Younes_Anas_NYC.jpg.jpg

“The PD-1 checkpoint inhibitor nivolumab is an important new treatment to address unmet needs in patients with classical Hodgkin lymphoma with progressive disease and limited treatment options, especially after autologous transplant,” he said at a briefing at the annual congress of the European Hematology Association.

Objective response rates as determined by both investigators and independent reviewers were “impressive,” and had “encouraging durability,” he added. The median duration of response at time of data cutoff was 7.8 months, and the majority of patients had ongoing responses at the time of the analysis, Dr. Younes said.

Nivolumab was recently approved by the Food and Drug Administration for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after ASCT followed by brentuximab vedotin.

In the Checkmate 205 registrational trial, 80 patients (median age 37, range 18-72 years) were assigned to receive nivolumab 3 mg/kg intravenously every 2 weeks. Patients were evaluated for response by both an independent radiologic review committee (IRRC) and investigators, using 2007 International Working Group response criteria. After a median follow-up of 8.9 months, the IRRC-rated objective response rate, the primary endpoint, was 66%, including 8.8% complete remissions (CR), and 57.5% partial remissions (PR).

Dr. Younes showed a waterfall plot indicating that nearly all patients had some degree of tumor regression, and all but one patient among the responders had tumor reductions of 50% or greater from baseline.

Among 43 patients who had had no response to brentuximab vedotin, subsequent treatment with nivolumab was associated with an IRRC-rated objective response rate of 72%. As noted, the median duration of response was 7.8 months, and the median time to response was 2.1 months.

As of the last follow-up, 33 of the 53 patients with IRRC-rated responses had retained response. The IRRC-determined 6-month progression-free survival rate was 77%, and the overall survival rate was 99%.

In all, 72 patients (90%) had a treatment-related adverse event. The most common events occurring in 15% or more of patients were fatigue, infusion-related reactions, and rash. Most of the immune-mediated adverse events were of low grade and manageable, and there were no treatment-related deaths, Dr. Younes said.

Briefing moderator Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who was not involved in the study, asked whether nivolumab can be considered as a bridge to other therapies in this population.

Dr. Younes said that the “natural progression of a single-agent therapy that has efficacy is to combine it with other active agents, or use maybe in the adjuvant or maintenance setting in certain circumstances.”

“I don’t expect single-agent nivolumab to cure our patients,” he added.

A similarly designed clinical trial, MK-3457-087/KEYNOTE-087, is exploring the use of pembrolizumab (Keytruda). This trial is ongoing but does not have published data as yet.

Checkmate 205 is sponsored by Bristol-Myers Squibb. Dr. Younes has served as a consultant/advisor, received honoraria and/or research funding from Gilead Sciences, Curis, Incyte, Janssen, Seattle Genetics, Novartis, Celgene, Millennium, and Sanofi. Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – Nivolumab may be an effective salvage therapy option for adults with Hodgkin lymphoma whose disease has progressed despite transplant and treatment with brentuximab vedotin, investigators reported.

In a subcohort of patients from the Checkmate 205 phase II trial, 80 patients with Hodgkin lymphoma who had disease progression following autologous stem cell transplant (ASCT) and brentuximab vedotin (Adcetris), nivolumab (Opdivo) therapy was associated with a 53% objective response rate according to independent reviewers, reported Dr. Anas Younes, chief of the lymphoma service at Memorial Sloan Kettering Cancer Center, New York.

RTEmagicC_706f4d265e38fc20cb_Younes_Anas_NYC.jpg.jpg

“The PD-1 checkpoint inhibitor nivolumab is an important new treatment to address unmet needs in patients with classical Hodgkin lymphoma with progressive disease and limited treatment options, especially after autologous transplant,” he said at a briefing at the annual congress of the European Hematology Association.

Objective response rates as determined by both investigators and independent reviewers were “impressive,” and had “encouraging durability,” he added. The median duration of response at time of data cutoff was 7.8 months, and the majority of patients had ongoing responses at the time of the analysis, Dr. Younes said.

Nivolumab was recently approved by the Food and Drug Administration for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after ASCT followed by brentuximab vedotin.

In the Checkmate 205 registrational trial, 80 patients (median age 37, range 18-72 years) were assigned to receive nivolumab 3 mg/kg intravenously every 2 weeks. Patients were evaluated for response by both an independent radiologic review committee (IRRC) and investigators, using 2007 International Working Group response criteria. After a median follow-up of 8.9 months, the IRRC-rated objective response rate, the primary endpoint, was 66%, including 8.8% complete remissions (CR), and 57.5% partial remissions (PR).

Dr. Younes showed a waterfall plot indicating that nearly all patients had some degree of tumor regression, and all but one patient among the responders had tumor reductions of 50% or greater from baseline.

Among 43 patients who had had no response to brentuximab vedotin, subsequent treatment with nivolumab was associated with an IRRC-rated objective response rate of 72%. As noted, the median duration of response was 7.8 months, and the median time to response was 2.1 months.

As of the last follow-up, 33 of the 53 patients with IRRC-rated responses had retained response. The IRRC-determined 6-month progression-free survival rate was 77%, and the overall survival rate was 99%.

In all, 72 patients (90%) had a treatment-related adverse event. The most common events occurring in 15% or more of patients were fatigue, infusion-related reactions, and rash. Most of the immune-mediated adverse events were of low grade and manageable, and there were no treatment-related deaths, Dr. Younes said.

Briefing moderator Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who was not involved in the study, asked whether nivolumab can be considered as a bridge to other therapies in this population.

Dr. Younes said that the “natural progression of a single-agent therapy that has efficacy is to combine it with other active agents, or use maybe in the adjuvant or maintenance setting in certain circumstances.”

“I don’t expect single-agent nivolumab to cure our patients,” he added.

A similarly designed clinical trial, MK-3457-087/KEYNOTE-087, is exploring the use of pembrolizumab (Keytruda). This trial is ongoing but does not have published data as yet.

Checkmate 205 is sponsored by Bristol-Myers Squibb. Dr. Younes has served as a consultant/advisor, received honoraria and/or research funding from Gilead Sciences, Curis, Incyte, Janssen, Seattle Genetics, Novartis, Celgene, Millennium, and Sanofi. Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – Nivolumab may be an effective salvage therapy option for adults with Hodgkin lymphoma whose disease has progressed despite transplant and treatment with brentuximab vedotin, investigators reported.

In a subcohort of patients from the Checkmate 205 phase II trial, 80 patients with Hodgkin lymphoma who had disease progression following autologous stem cell transplant (ASCT) and brentuximab vedotin (Adcetris), nivolumab (Opdivo) therapy was associated with a 53% objective response rate according to independent reviewers, reported Dr. Anas Younes, chief of the lymphoma service at Memorial Sloan Kettering Cancer Center, New York.

RTEmagicC_706f4d265e38fc20cb_Younes_Anas_NYC.jpg.jpg

“The PD-1 checkpoint inhibitor nivolumab is an important new treatment to address unmet needs in patients with classical Hodgkin lymphoma with progressive disease and limited treatment options, especially after autologous transplant,” he said at a briefing at the annual congress of the European Hematology Association.

Objective response rates as determined by both investigators and independent reviewers were “impressive,” and had “encouraging durability,” he added. The median duration of response at time of data cutoff was 7.8 months, and the majority of patients had ongoing responses at the time of the analysis, Dr. Younes said.

Nivolumab was recently approved by the Food and Drug Administration for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after ASCT followed by brentuximab vedotin.

In the Checkmate 205 registrational trial, 80 patients (median age 37, range 18-72 years) were assigned to receive nivolumab 3 mg/kg intravenously every 2 weeks. Patients were evaluated for response by both an independent radiologic review committee (IRRC) and investigators, using 2007 International Working Group response criteria. After a median follow-up of 8.9 months, the IRRC-rated objective response rate, the primary endpoint, was 66%, including 8.8% complete remissions (CR), and 57.5% partial remissions (PR).

Dr. Younes showed a waterfall plot indicating that nearly all patients had some degree of tumor regression, and all but one patient among the responders had tumor reductions of 50% or greater from baseline.

Among 43 patients who had had no response to brentuximab vedotin, subsequent treatment with nivolumab was associated with an IRRC-rated objective response rate of 72%. As noted, the median duration of response was 7.8 months, and the median time to response was 2.1 months.

As of the last follow-up, 33 of the 53 patients with IRRC-rated responses had retained response. The IRRC-determined 6-month progression-free survival rate was 77%, and the overall survival rate was 99%.

In all, 72 patients (90%) had a treatment-related adverse event. The most common events occurring in 15% or more of patients were fatigue, infusion-related reactions, and rash. Most of the immune-mediated adverse events were of low grade and manageable, and there were no treatment-related deaths, Dr. Younes said.

Briefing moderator Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who was not involved in the study, asked whether nivolumab can be considered as a bridge to other therapies in this population.

Dr. Younes said that the “natural progression of a single-agent therapy that has efficacy is to combine it with other active agents, or use maybe in the adjuvant or maintenance setting in certain circumstances.”

“I don’t expect single-agent nivolumab to cure our patients,” he added.

A similarly designed clinical trial, MK-3457-087/KEYNOTE-087, is exploring the use of pembrolizumab (Keytruda). This trial is ongoing but does not have published data as yet.

Checkmate 205 is sponsored by Bristol-Myers Squibb. Dr. Younes has served as a consultant/advisor, received honoraria and/or research funding from Gilead Sciences, Curis, Incyte, Janssen, Seattle Genetics, Novartis, Celgene, Millennium, and Sanofi. Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – It’s early days yet, but results look highly promising for the ability of an experimental gene-transfer therapy to improve coagulation parameters in patients with severe hemophilia B.

In a phase I/II dose-escalation study, a single 1-hour infusion of the gene-transfer product, labeled SPK-9001, resulted in factor IX activity levels ranging from 25% to 39% of normal in four men with severe or moderately severe hemophilia B, reported Dr. Katherine A High, president and chief scientific officer of Spark Therapeutics, maker of the product.

RTEmagicC_27f5c3527e8a8a4824_genes_photo.jpg.jpg

“One of the most remarkable features of the data in my mind has been a very consistent performance,” she said at a briefing at the annual congress of the European Hematology Association.

The product consists of a vector containing a novel bio-engineered adeno-associated virus (AAV) capsid with tropism for liver, and a factor IX cassette that carries a strong liver-specific promoter to drive the expression of the factor IX variant, dubbed factor IX Padua.

“The hypothesis of the work was that if we could engineer a vector efficient enough, we would be able to infuse it at a dose low enough that it would drive loads of expression greater than 12% of normal, which in previous work has been shown to be associated with an absence of joint bleeds in natural history studies of people with mild disease, and that infusion at a low dose would eliminate the need for any type of immune suppression with steroids,” Dr. High said.

Other attempts at genetic engineering in patients with hemophilia B have been hampered by the need to use high doses of vector that can induce an immune response, thereby negating the benefit of therapy.

In this ongoing study, conducted in Mississippi, Pennsylvania, and California, males 18 and older with a confirmed diagnosis of hemophilia B (defined as equal to or less than 2 IU/dL or 2% endogenous factor IX) who have received 50 or more days of exposure to factor IX products are enrolled. The patients must have a minimum average of four bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions, no measurable factor IX inhibitor as assessed by the central laboratory, and no prior history of inhibitors to factor IX protein.

In an oral session at the congress, Dr. Spencer Sullivan, assistant professor of pediatrics and medicine at the University of Mississippi Medical Center in Jackson, presented data on four men whose age ranges from 18 to 47 years.

In the dose-escalation phase of the study, the patients received single infusions of SPK-9001 at an initial starting dose of 5 x 1011 vector genomes of body weight. They were followed for 7-26 weeks after gene transfer for factor IX activity levels, liver enzymes, bleeding episode, and factor usage. As of May 22, 2016, the first four patients showed factor IX activity levels of 32%, 39%, 25%, and 27% of normal, respectively.

All subjects are currently off prophylactic factor IX infusions. During the course of follow-up, one patient infused himself with factor IX once, treating himself 2 days after vector infusion for a suspected ankle bleed.

Asked by a reporter how durable the effect was, Dr. High replied that in dog models of hemophilia B the effect of the gene transfer has been durable.

The best evidence to date of durability in humans, she said, comes from investigators at University College in London (England), who found that if patients can make it past the first 8-10 weeks without developing an immune response to the transfer product, they are likely to do well, and to have a durable effect, she said.

Dr. Anton Hagenbeek, from the Academic Medical Center, University of Amsterdam, who moderated the briefing but was not involved in the study, said that Dr. High was “to be congratulated for these best data ever seen.”

He asked, facetiously, whether she thought that “thousands of patients would buy a ticket to Philadelphia.” The “City of Brotherly Love” is home to one of the trial sites and to Spark headquarters.

The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – It’s early days yet, but results look highly promising for the ability of an experimental gene-transfer therapy to improve coagulation parameters in patients with severe hemophilia B.

In a phase I/II dose-escalation study, a single 1-hour infusion of the gene-transfer product, labeled SPK-9001, resulted in factor IX activity levels ranging from 25% to 39% of normal in four men with severe or moderately severe hemophilia B, reported Dr. Katherine A High, president and chief scientific officer of Spark Therapeutics, maker of the product.

RTEmagicC_27f5c3527e8a8a4824_genes_photo.jpg.jpg

“One of the most remarkable features of the data in my mind has been a very consistent performance,” she said at a briefing at the annual congress of the European Hematology Association.

The product consists of a vector containing a novel bio-engineered adeno-associated virus (AAV) capsid with tropism for liver, and a factor IX cassette that carries a strong liver-specific promoter to drive the expression of the factor IX variant, dubbed factor IX Padua.

“The hypothesis of the work was that if we could engineer a vector efficient enough, we would be able to infuse it at a dose low enough that it would drive loads of expression greater than 12% of normal, which in previous work has been shown to be associated with an absence of joint bleeds in natural history studies of people with mild disease, and that infusion at a low dose would eliminate the need for any type of immune suppression with steroids,” Dr. High said.

Other attempts at genetic engineering in patients with hemophilia B have been hampered by the need to use high doses of vector that can induce an immune response, thereby negating the benefit of therapy.

In this ongoing study, conducted in Mississippi, Pennsylvania, and California, males 18 and older with a confirmed diagnosis of hemophilia B (defined as equal to or less than 2 IU/dL or 2% endogenous factor IX) who have received 50 or more days of exposure to factor IX products are enrolled. The patients must have a minimum average of four bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions, no measurable factor IX inhibitor as assessed by the central laboratory, and no prior history of inhibitors to factor IX protein.

In an oral session at the congress, Dr. Spencer Sullivan, assistant professor of pediatrics and medicine at the University of Mississippi Medical Center in Jackson, presented data on four men whose age ranges from 18 to 47 years.

In the dose-escalation phase of the study, the patients received single infusions of SPK-9001 at an initial starting dose of 5 x 1011 vector genomes of body weight. They were followed for 7-26 weeks after gene transfer for factor IX activity levels, liver enzymes, bleeding episode, and factor usage. As of May 22, 2016, the first four patients showed factor IX activity levels of 32%, 39%, 25%, and 27% of normal, respectively.

All subjects are currently off prophylactic factor IX infusions. During the course of follow-up, one patient infused himself with factor IX once, treating himself 2 days after vector infusion for a suspected ankle bleed.

Asked by a reporter how durable the effect was, Dr. High replied that in dog models of hemophilia B the effect of the gene transfer has been durable.

The best evidence to date of durability in humans, she said, comes from investigators at University College in London (England), who found that if patients can make it past the first 8-10 weeks without developing an immune response to the transfer product, they are likely to do well, and to have a durable effect, she said.

Dr. Anton Hagenbeek, from the Academic Medical Center, University of Amsterdam, who moderated the briefing but was not involved in the study, said that Dr. High was “to be congratulated for these best data ever seen.”

He asked, facetiously, whether she thought that “thousands of patients would buy a ticket to Philadelphia.” The “City of Brotherly Love” is home to one of the trial sites and to Spark headquarters.

The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – It’s early days yet, but results look highly promising for the ability of an experimental gene-transfer therapy to improve coagulation parameters in patients with severe hemophilia B.

In a phase I/II dose-escalation study, a single 1-hour infusion of the gene-transfer product, labeled SPK-9001, resulted in factor IX activity levels ranging from 25% to 39% of normal in four men with severe or moderately severe hemophilia B, reported Dr. Katherine A High, president and chief scientific officer of Spark Therapeutics, maker of the product.

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“One of the most remarkable features of the data in my mind has been a very consistent performance,” she said at a briefing at the annual congress of the European Hematology Association.

The product consists of a vector containing a novel bio-engineered adeno-associated virus (AAV) capsid with tropism for liver, and a factor IX cassette that carries a strong liver-specific promoter to drive the expression of the factor IX variant, dubbed factor IX Padua.

“The hypothesis of the work was that if we could engineer a vector efficient enough, we would be able to infuse it at a dose low enough that it would drive loads of expression greater than 12% of normal, which in previous work has been shown to be associated with an absence of joint bleeds in natural history studies of people with mild disease, and that infusion at a low dose would eliminate the need for any type of immune suppression with steroids,” Dr. High said.

Other attempts at genetic engineering in patients with hemophilia B have been hampered by the need to use high doses of vector that can induce an immune response, thereby negating the benefit of therapy.

In this ongoing study, conducted in Mississippi, Pennsylvania, and California, males 18 and older with a confirmed diagnosis of hemophilia B (defined as equal to or less than 2 IU/dL or 2% endogenous factor IX) who have received 50 or more days of exposure to factor IX products are enrolled. The patients must have a minimum average of four bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions, no measurable factor IX inhibitor as assessed by the central laboratory, and no prior history of inhibitors to factor IX protein.

In an oral session at the congress, Dr. Spencer Sullivan, assistant professor of pediatrics and medicine at the University of Mississippi Medical Center in Jackson, presented data on four men whose age ranges from 18 to 47 years.

In the dose-escalation phase of the study, the patients received single infusions of SPK-9001 at an initial starting dose of 5 x 1011 vector genomes of body weight. They were followed for 7-26 weeks after gene transfer for factor IX activity levels, liver enzymes, bleeding episode, and factor usage. As of May 22, 2016, the first four patients showed factor IX activity levels of 32%, 39%, 25%, and 27% of normal, respectively.

All subjects are currently off prophylactic factor IX infusions. During the course of follow-up, one patient infused himself with factor IX once, treating himself 2 days after vector infusion for a suspected ankle bleed.

Asked by a reporter how durable the effect was, Dr. High replied that in dog models of hemophilia B the effect of the gene transfer has been durable.

The best evidence to date of durability in humans, she said, comes from investigators at University College in London (England), who found that if patients can make it past the first 8-10 weeks without developing an immune response to the transfer product, they are likely to do well, and to have a durable effect, she said.

Dr. Anton Hagenbeek, from the Academic Medical Center, University of Amsterdam, who moderated the briefing but was not involved in the study, said that Dr. High was “to be congratulated for these best data ever seen.”

He asked, facetiously, whether she thought that “thousands of patients would buy a ticket to Philadelphia.” The “City of Brotherly Love” is home to one of the trial sites and to Spark headquarters.

The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – A study from seven Nordic and Baltic countries adds to the growing body of evidence that young adults with acute lymphoblastic leukemia do better when they are treated like children – that is, with a standard pediatric chemotherapy regimen.

In a study of 221 patients from the age of 18 to 45 with acute lymphoblastic leukemia (ALL) treated with a pediatric regimen and followed for a median of 4 years, the event-free survival rate was 73%, compared with 42% for historical controls, reported Dr. Nina Toft from Herlev (Denmark) University Hospital.

“We have improved the survival for ALL patients 18 to 45 years, and we show that the cure rates are close to those of children. If you compare an adult in the standard-risk group with a child in the standard-risk group, there’s no difference,” she said at a briefing at the annual congress of the European Hematology Association (EHA).

The findings support those from an earlier study reported at the 2014 annual meeting of the American Society of Hematology. That study, conducted by Dr. Wendy Stock of the University of Chicago Medical Center and her colleagues showed that among 296 adolescents and young adults with ALL treated with an intensive pediatric chemotherapy combination regimen rather than a less-intensive adult regimen, the rate of overall survival (OS) at 2 years was 78%, and the event-free survival (EFS) rate was 66%.

In the current study, Dr. Toft and her colleagues looked at event-free survival among 1,509 children and adults (up to age 45) diagnosed with Philadelphia chromosome-negative ALL from July 2008 through December 2014.

The patients were treated in Sweden, Norway, Iceland, Finland Denmark, Lithuania, and Estonia, and all received the Nordic Society for Pediatric Hematology and Oncology (NOPHO)–ALL 2008 protocol, consisting of induction with prednisolone, vincristine, doxorubicin, and pegylated (PEG) asparaginase; consolidation for patients with standard- and intermediate-risk disease, with mercaptopurine, vincristine, PEG asparaginase, and methotrexate; and additional intensive combination chemotherapy for patients with high-risk disease, followed by maintenance with mercaptopurine and/or methotrexate, PEG asparaginase, vincristine, and dexamethasone.

Of the 1,509 patients, 1,022 were children from 1 to 9 years, 266 were preteens/adolescents (10-17 years), and 221 were adults up to age 45.

All patients were stratified by clinical, cytogenetic, and other factors into one of four risk groups: standard, intermediate, high risk, or high risk in first remission after a hematopoietic stem cell transplant, and all were treated with the NOPHO-ALL 2008 protocol.

The investigators found that in general older patients had higher-risk disease. Nonetheless, treatment intervals and severe toxicities, with the exception of osteonecrosis and thrombosis, were “almost identical” between adults and children, Dr. Toft said.

After a median of 4 years of follow-up, 16 patients, 3 of whom were adults, had died during the induction phase, and 50 patients (12 adults) had died in first remission.

There were a total of 123 relapses (36 among adults), and 1 adult and 12 children were diagnosed with a second malignancy.

Overall 5-year EFS rates were 88% for patients aged 1-9 years, 79% for those 10-17 years, and 73% for those 18-45, and these differences were significant (P less than .001). However, when EFS was stratified by risk group, EFS rates were lower only for adults with intermediate-risk disease (78% vs. 90% for 1- to 9-year-olds and 82% for 10- to 17-year-olds, P = .002).

Although the investigators did not formally report overall survival data, it was approximately 95% among all children in the cohort, and approximately 76% among the adults, Dr. Toft said in response to a reporter.

“What we need now is further cooperation, because we need to unite and get more patients so that we can show new developments faster. We also need to find new risk criteria, because of the intermediate-risk group; something is missing for the adults. We need more cytogenetics, we need something to define the patients as high risk or not,” Dr. Toft said.

“We also need new drugs, because with this method we’ve reached the limit of toxicity,” she added.

The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.

COPENHAGEN – A study from seven Nordic and Baltic countries adds to the growing body of evidence that young adults with acute lymphoblastic leukemia do better when they are treated like children – that is, with a standard pediatric chemotherapy regimen.

In a study of 221 patients from the age of 18 to 45 with acute lymphoblastic leukemia (ALL) treated with a pediatric regimen and followed for a median of 4 years, the event-free survival rate was 73%, compared with 42% for historical controls, reported Dr. Nina Toft from Herlev (Denmark) University Hospital.

“We have improved the survival for ALL patients 18 to 45 years, and we show that the cure rates are close to those of children. If you compare an adult in the standard-risk group with a child in the standard-risk group, there’s no difference,” she said at a briefing at the annual congress of the European Hematology Association (EHA).

The findings support those from an earlier study reported at the 2014 annual meeting of the American Society of Hematology. That study, conducted by Dr. Wendy Stock of the University of Chicago Medical Center and her colleagues showed that among 296 adolescents and young adults with ALL treated with an intensive pediatric chemotherapy combination regimen rather than a less-intensive adult regimen, the rate of overall survival (OS) at 2 years was 78%, and the event-free survival (EFS) rate was 66%.

In the current study, Dr. Toft and her colleagues looked at event-free survival among 1,509 children and adults (up to age 45) diagnosed with Philadelphia chromosome-negative ALL from July 2008 through December 2014.

The patients were treated in Sweden, Norway, Iceland, Finland Denmark, Lithuania, and Estonia, and all received the Nordic Society for Pediatric Hematology and Oncology (NOPHO)–ALL 2008 protocol, consisting of induction with prednisolone, vincristine, doxorubicin, and pegylated (PEG) asparaginase; consolidation for patients with standard- and intermediate-risk disease, with mercaptopurine, vincristine, PEG asparaginase, and methotrexate; and additional intensive combination chemotherapy for patients with high-risk disease, followed by maintenance with mercaptopurine and/or methotrexate, PEG asparaginase, vincristine, and dexamethasone.

Of the 1,509 patients, 1,022 were children from 1 to 9 years, 266 were preteens/adolescents (10-17 years), and 221 were adults up to age 45.

All patients were stratified by clinical, cytogenetic, and other factors into one of four risk groups: standard, intermediate, high risk, or high risk in first remission after a hematopoietic stem cell transplant, and all were treated with the NOPHO-ALL 2008 protocol.

The investigators found that in general older patients had higher-risk disease. Nonetheless, treatment intervals and severe toxicities, with the exception of osteonecrosis and thrombosis, were “almost identical” between adults and children, Dr. Toft said.

After a median of 4 years of follow-up, 16 patients, 3 of whom were adults, had died during the induction phase, and 50 patients (12 adults) had died in first remission.

There were a total of 123 relapses (36 among adults), and 1 adult and 12 children were diagnosed with a second malignancy.

Overall 5-year EFS rates were 88% for patients aged 1-9 years, 79% for those 10-17 years, and 73% for those 18-45, and these differences were significant (P less than .001). However, when EFS was stratified by risk group, EFS rates were lower only for adults with intermediate-risk disease (78% vs. 90% for 1- to 9-year-olds and 82% for 10- to 17-year-olds, P = .002).

Although the investigators did not formally report overall survival data, it was approximately 95% among all children in the cohort, and approximately 76% among the adults, Dr. Toft said in response to a reporter.

“What we need now is further cooperation, because we need to unite and get more patients so that we can show new developments faster. We also need to find new risk criteria, because of the intermediate-risk group; something is missing for the adults. We need more cytogenetics, we need something to define the patients as high risk or not,” Dr. Toft said.

“We also need new drugs, because with this method we’ve reached the limit of toxicity,” she added.

The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.

COPENHAGEN – A study from seven Nordic and Baltic countries adds to the growing body of evidence that young adults with acute lymphoblastic leukemia do better when they are treated like children – that is, with a standard pediatric chemotherapy regimen.

In a study of 221 patients from the age of 18 to 45 with acute lymphoblastic leukemia (ALL) treated with a pediatric regimen and followed for a median of 4 years, the event-free survival rate was 73%, compared with 42% for historical controls, reported Dr. Nina Toft from Herlev (Denmark) University Hospital.

“We have improved the survival for ALL patients 18 to 45 years, and we show that the cure rates are close to those of children. If you compare an adult in the standard-risk group with a child in the standard-risk group, there’s no difference,” she said at a briefing at the annual congress of the European Hematology Association (EHA).

The findings support those from an earlier study reported at the 2014 annual meeting of the American Society of Hematology. That study, conducted by Dr. Wendy Stock of the University of Chicago Medical Center and her colleagues showed that among 296 adolescents and young adults with ALL treated with an intensive pediatric chemotherapy combination regimen rather than a less-intensive adult regimen, the rate of overall survival (OS) at 2 years was 78%, and the event-free survival (EFS) rate was 66%.

In the current study, Dr. Toft and her colleagues looked at event-free survival among 1,509 children and adults (up to age 45) diagnosed with Philadelphia chromosome-negative ALL from July 2008 through December 2014.

The patients were treated in Sweden, Norway, Iceland, Finland Denmark, Lithuania, and Estonia, and all received the Nordic Society for Pediatric Hematology and Oncology (NOPHO)–ALL 2008 protocol, consisting of induction with prednisolone, vincristine, doxorubicin, and pegylated (PEG) asparaginase; consolidation for patients with standard- and intermediate-risk disease, with mercaptopurine, vincristine, PEG asparaginase, and methotrexate; and additional intensive combination chemotherapy for patients with high-risk disease, followed by maintenance with mercaptopurine and/or methotrexate, PEG asparaginase, vincristine, and dexamethasone.

Of the 1,509 patients, 1,022 were children from 1 to 9 years, 266 were preteens/adolescents (10-17 years), and 221 were adults up to age 45.

All patients were stratified by clinical, cytogenetic, and other factors into one of four risk groups: standard, intermediate, high risk, or high risk in first remission after a hematopoietic stem cell transplant, and all were treated with the NOPHO-ALL 2008 protocol.

The investigators found that in general older patients had higher-risk disease. Nonetheless, treatment intervals and severe toxicities, with the exception of osteonecrosis and thrombosis, were “almost identical” between adults and children, Dr. Toft said.

After a median of 4 years of follow-up, 16 patients, 3 of whom were adults, had died during the induction phase, and 50 patients (12 adults) had died in first remission.

There were a total of 123 relapses (36 among adults), and 1 adult and 12 children were diagnosed with a second malignancy.

Overall 5-year EFS rates were 88% for patients aged 1-9 years, 79% for those 10-17 years, and 73% for those 18-45, and these differences were significant (P less than .001). However, when EFS was stratified by risk group, EFS rates were lower only for adults with intermediate-risk disease (78% vs. 90% for 1- to 9-year-olds and 82% for 10- to 17-year-olds, P = .002).

Although the investigators did not formally report overall survival data, it was approximately 95% among all children in the cohort, and approximately 76% among the adults, Dr. Toft said in response to a reporter.

“What we need now is further cooperation, because we need to unite and get more patients so that we can show new developments faster. We also need to find new risk criteria, because of the intermediate-risk group; something is missing for the adults. We need more cytogenetics, we need something to define the patients as high risk or not,” Dr. Toft said.

“We also need new drugs, because with this method we’ve reached the limit of toxicity,” she added.

The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.