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Niraparib maintenance offers continued benefit in some with recurrent ovarian cancer
The final analysis showed a significant difference in second progression-free survival (PFS2) with niraparib versus placebo, but only in patients with germline BRCA mutations.
The overall survival analysis was limited because the study was not powered to detect differences in OS. Still, the investigators found a trend toward better OS with niraparib in patients who had germline BRCA mutations.
These results were presented at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11139).
The final analysis of this study was muddied by missing data for many of the 553 patients originally randomized, according to Ursula Matulonis, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study’s results at the meeting.
“Since 2014, approvals of PARP [poly (ADP-ribose) polymerase] inhibitors worldwide in different lines of ovarian cancer therapy have revolutionized the treatment of women with ovarian cancer,” Dr. Matulonis said. “During the time from the initial results of the NOVA study in 2016 to this final analysis, PARP inhibitors have become available commercially globally.”
The wider availability of PARP inhibitors led to premature unblinding and withdrawals from the trial, resulting in missing data for a large proportion of patients.
Initial results
In the primary analysis of the trial, the median PFS was 21 months among patients with germline BRCA mutations who received niraparib and 5.5 months for patients with germline BRCA mutations who received placebo (P < .001).
Among patients with no germline BRCA mutations, the median PFS was 9.3 months for those who received niraparib and 3.9 months for placebo-treated controls (P < .001).
At the time of the primary PFS analysis in 2016, 155 of the 553 patients originally enrolled had left the study for reasons other than death.
In both treatment cohorts, a large number of patients were unblinded as to their treatment assignments by investigators, which required them to withdraw consent from the study under the protocol, resulting in the aforementioned loss of some data on subsequent therapy and survival status.
Final results: PFS2 and OS
At the time of the final data lock on Oct. 1, 2020, the mean follow-up was 67 months (5.6 years).
In all, 64 patients originally assigned to niraparib were still on study (28 in the germline BRCA mutation cohort and 36 in the nonmutated cohort), as were 28 patients originally assigned to placebo (9 and 19, respectively).
For the final analysis, the investigators were able to retrieve survival data on 51% of the patients originally enrolled, either through protocol amendments and obtaining consent again or through national databases.
Although crossover to the niraparib arm was not allowed on study, patients could receive a PARP inhibitor following disease progression or study withdrawal. Because of discontinuations, data on postprogression therapy were missing for 138 of the 553 patients (25%).
The hazard ratio for PFS2 with niraparib versus placebo was 0.67 for patients with germline BRCA mutations (95% confidence interval, 0.479-0.948) and 0.81 for patients without the mutations (95% CI, 0.632-1.050).
In an analysis adjusted for subsequent PARP inhibitor therapy, there was no significant difference in median OS between the niraparib and placebo arms, regardless of mutation status. In the cohort without BRCA mutations, the median OS was 31.3 months with niraparib and 35.9 months with placebo (HR, 0.97; 95% CI, 0.74-1.26).
However, there was a trend toward improved OS with niraparib among patients with germline BRCA mutations. The median OS was 43.8 months with niraparib and 34.1 months with placebo (HR, 0.66; 95% CI, 0.44-0.99).
Safety: MDS/AML
Hematologic treatment-emergent adverse events occurred primarily in the first year of niraparib treatment. The incidence of grade 3 or greater thrombocytopenia decreased from 33.8% at 1 year to 2.8% in years 2-3. The incidence of anemia decreased from 25.6% to 0.7%, and the neutropenia incidence decreased from 19.3% to 2.1%.
At last follow-up, 13 patients in the niraparib arm (3.5%) and 3 in the placebo arm (1.7%) had developed myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).
The incidence of MDS/AML was 6.6% among patients with germline BRCA mutations who received niraparib, noted invited discussant Deborah K. Armstrong, MD, of the Johns Hopkins Kimmel Cancer Center in Baltimore.
That incidence was nearly as high as the 8% incidence of MDS/AML seen among similar patients in the SOLO-2 trial of olaparib maintenance, she noted.
This observation raises the question “of whether more extensive prior therapy or the longer duration of PARP inhibitor therapy in patients who have recurrent platinum-sensitive disease is the biggest contributor to that,” she said.
Dr. Armstrong commented that it remains to be seen whether the incidence of MDS/AML will increase with longer follow-up, particularly among patients who were more heavily pretreated with chemotherapy prior to PARP inhibitor maintenance, and in patients who remain on a PARP inhibitor until progression in ongoing trials of PARP inhibitors as frontline therapy.
The ENGOT-OV16/NOVA trial was funded by GlaxoSmithKline. Dr. Matulonis reported consulting/advisory fees from Merck, Novartis, and NextCure. Dr. Armstrong disclosed relationships with several companies, not including GlaxoSmithKline.
The final analysis showed a significant difference in second progression-free survival (PFS2) with niraparib versus placebo, but only in patients with germline BRCA mutations.
The overall survival analysis was limited because the study was not powered to detect differences in OS. Still, the investigators found a trend toward better OS with niraparib in patients who had germline BRCA mutations.
These results were presented at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11139).
The final analysis of this study was muddied by missing data for many of the 553 patients originally randomized, according to Ursula Matulonis, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study’s results at the meeting.
“Since 2014, approvals of PARP [poly (ADP-ribose) polymerase] inhibitors worldwide in different lines of ovarian cancer therapy have revolutionized the treatment of women with ovarian cancer,” Dr. Matulonis said. “During the time from the initial results of the NOVA study in 2016 to this final analysis, PARP inhibitors have become available commercially globally.”
The wider availability of PARP inhibitors led to premature unblinding and withdrawals from the trial, resulting in missing data for a large proportion of patients.
Initial results
In the primary analysis of the trial, the median PFS was 21 months among patients with germline BRCA mutations who received niraparib and 5.5 months for patients with germline BRCA mutations who received placebo (P < .001).
Among patients with no germline BRCA mutations, the median PFS was 9.3 months for those who received niraparib and 3.9 months for placebo-treated controls (P < .001).
At the time of the primary PFS analysis in 2016, 155 of the 553 patients originally enrolled had left the study for reasons other than death.
In both treatment cohorts, a large number of patients were unblinded as to their treatment assignments by investigators, which required them to withdraw consent from the study under the protocol, resulting in the aforementioned loss of some data on subsequent therapy and survival status.
Final results: PFS2 and OS
At the time of the final data lock on Oct. 1, 2020, the mean follow-up was 67 months (5.6 years).
In all, 64 patients originally assigned to niraparib were still on study (28 in the germline BRCA mutation cohort and 36 in the nonmutated cohort), as were 28 patients originally assigned to placebo (9 and 19, respectively).
For the final analysis, the investigators were able to retrieve survival data on 51% of the patients originally enrolled, either through protocol amendments and obtaining consent again or through national databases.
Although crossover to the niraparib arm was not allowed on study, patients could receive a PARP inhibitor following disease progression or study withdrawal. Because of discontinuations, data on postprogression therapy were missing for 138 of the 553 patients (25%).
The hazard ratio for PFS2 with niraparib versus placebo was 0.67 for patients with germline BRCA mutations (95% confidence interval, 0.479-0.948) and 0.81 for patients without the mutations (95% CI, 0.632-1.050).
In an analysis adjusted for subsequent PARP inhibitor therapy, there was no significant difference in median OS between the niraparib and placebo arms, regardless of mutation status. In the cohort without BRCA mutations, the median OS was 31.3 months with niraparib and 35.9 months with placebo (HR, 0.97; 95% CI, 0.74-1.26).
However, there was a trend toward improved OS with niraparib among patients with germline BRCA mutations. The median OS was 43.8 months with niraparib and 34.1 months with placebo (HR, 0.66; 95% CI, 0.44-0.99).
Safety: MDS/AML
Hematologic treatment-emergent adverse events occurred primarily in the first year of niraparib treatment. The incidence of grade 3 or greater thrombocytopenia decreased from 33.8% at 1 year to 2.8% in years 2-3. The incidence of anemia decreased from 25.6% to 0.7%, and the neutropenia incidence decreased from 19.3% to 2.1%.
At last follow-up, 13 patients in the niraparib arm (3.5%) and 3 in the placebo arm (1.7%) had developed myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).
The incidence of MDS/AML was 6.6% among patients with germline BRCA mutations who received niraparib, noted invited discussant Deborah K. Armstrong, MD, of the Johns Hopkins Kimmel Cancer Center in Baltimore.
That incidence was nearly as high as the 8% incidence of MDS/AML seen among similar patients in the SOLO-2 trial of olaparib maintenance, she noted.
This observation raises the question “of whether more extensive prior therapy or the longer duration of PARP inhibitor therapy in patients who have recurrent platinum-sensitive disease is the biggest contributor to that,” she said.
Dr. Armstrong commented that it remains to be seen whether the incidence of MDS/AML will increase with longer follow-up, particularly among patients who were more heavily pretreated with chemotherapy prior to PARP inhibitor maintenance, and in patients who remain on a PARP inhibitor until progression in ongoing trials of PARP inhibitors as frontline therapy.
The ENGOT-OV16/NOVA trial was funded by GlaxoSmithKline. Dr. Matulonis reported consulting/advisory fees from Merck, Novartis, and NextCure. Dr. Armstrong disclosed relationships with several companies, not including GlaxoSmithKline.
The final analysis showed a significant difference in second progression-free survival (PFS2) with niraparib versus placebo, but only in patients with germline BRCA mutations.
The overall survival analysis was limited because the study was not powered to detect differences in OS. Still, the investigators found a trend toward better OS with niraparib in patients who had germline BRCA mutations.
These results were presented at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11139).
The final analysis of this study was muddied by missing data for many of the 553 patients originally randomized, according to Ursula Matulonis, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study’s results at the meeting.
“Since 2014, approvals of PARP [poly (ADP-ribose) polymerase] inhibitors worldwide in different lines of ovarian cancer therapy have revolutionized the treatment of women with ovarian cancer,” Dr. Matulonis said. “During the time from the initial results of the NOVA study in 2016 to this final analysis, PARP inhibitors have become available commercially globally.”
The wider availability of PARP inhibitors led to premature unblinding and withdrawals from the trial, resulting in missing data for a large proportion of patients.
Initial results
In the primary analysis of the trial, the median PFS was 21 months among patients with germline BRCA mutations who received niraparib and 5.5 months for patients with germline BRCA mutations who received placebo (P < .001).
Among patients with no germline BRCA mutations, the median PFS was 9.3 months for those who received niraparib and 3.9 months for placebo-treated controls (P < .001).
At the time of the primary PFS analysis in 2016, 155 of the 553 patients originally enrolled had left the study for reasons other than death.
In both treatment cohorts, a large number of patients were unblinded as to their treatment assignments by investigators, which required them to withdraw consent from the study under the protocol, resulting in the aforementioned loss of some data on subsequent therapy and survival status.
Final results: PFS2 and OS
At the time of the final data lock on Oct. 1, 2020, the mean follow-up was 67 months (5.6 years).
In all, 64 patients originally assigned to niraparib were still on study (28 in the germline BRCA mutation cohort and 36 in the nonmutated cohort), as were 28 patients originally assigned to placebo (9 and 19, respectively).
For the final analysis, the investigators were able to retrieve survival data on 51% of the patients originally enrolled, either through protocol amendments and obtaining consent again or through national databases.
Although crossover to the niraparib arm was not allowed on study, patients could receive a PARP inhibitor following disease progression or study withdrawal. Because of discontinuations, data on postprogression therapy were missing for 138 of the 553 patients (25%).
The hazard ratio for PFS2 with niraparib versus placebo was 0.67 for patients with germline BRCA mutations (95% confidence interval, 0.479-0.948) and 0.81 for patients without the mutations (95% CI, 0.632-1.050).
In an analysis adjusted for subsequent PARP inhibitor therapy, there was no significant difference in median OS between the niraparib and placebo arms, regardless of mutation status. In the cohort without BRCA mutations, the median OS was 31.3 months with niraparib and 35.9 months with placebo (HR, 0.97; 95% CI, 0.74-1.26).
However, there was a trend toward improved OS with niraparib among patients with germline BRCA mutations. The median OS was 43.8 months with niraparib and 34.1 months with placebo (HR, 0.66; 95% CI, 0.44-0.99).
Safety: MDS/AML
Hematologic treatment-emergent adverse events occurred primarily in the first year of niraparib treatment. The incidence of grade 3 or greater thrombocytopenia decreased from 33.8% at 1 year to 2.8% in years 2-3. The incidence of anemia decreased from 25.6% to 0.7%, and the neutropenia incidence decreased from 19.3% to 2.1%.
At last follow-up, 13 patients in the niraparib arm (3.5%) and 3 in the placebo arm (1.7%) had developed myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).
The incidence of MDS/AML was 6.6% among patients with germline BRCA mutations who received niraparib, noted invited discussant Deborah K. Armstrong, MD, of the Johns Hopkins Kimmel Cancer Center in Baltimore.
That incidence was nearly as high as the 8% incidence of MDS/AML seen among similar patients in the SOLO-2 trial of olaparib maintenance, she noted.
This observation raises the question “of whether more extensive prior therapy or the longer duration of PARP inhibitor therapy in patients who have recurrent platinum-sensitive disease is the biggest contributor to that,” she said.
Dr. Armstrong commented that it remains to be seen whether the incidence of MDS/AML will increase with longer follow-up, particularly among patients who were more heavily pretreated with chemotherapy prior to PARP inhibitor maintenance, and in patients who remain on a PARP inhibitor until progression in ongoing trials of PARP inhibitors as frontline therapy.
The ENGOT-OV16/NOVA trial was funded by GlaxoSmithKline. Dr. Matulonis reported consulting/advisory fees from Merck, Novartis, and NextCure. Dr. Armstrong disclosed relationships with several companies, not including GlaxoSmithKline.
FROM SGO 2021
Biomarkers predict efficacy of DKN-01 in endometrial cancer
Among 29 patients with heavily pretreated EEC, outcomes of DKN-01 monotherapy were best in patients with Wnt activating mutations, high levels of DKK1 expression, or PIK3CA activating mutations.
Patients in these groups had better disease control rates and progression-free survival (PFS), reported Rebecca C. Arend, MD, of the University of Alabama at Birmingham.
“Future development will focus on biomarker-selected patients, specifically patients with Wnt activating mutations, high tumoral DKK1, and PIK3CA activating mutations,” Dr. Arend said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10717).
She explained that DKK1 has been shown to modulate signaling in the Wnt/beta-catenin pathway, a key regulator of cellular functions in humans and animals that has been highly conserved throughout evolution.
“DKK1 activates P13 kinase/AKT signaling by binding to the CKAP4 receptor to promote tumor growth,” Dr. Arend explained.
Focus on monotherapy
Dr. Arend and colleagues conducted a phase 2 basket trial of DKN-01 either as monotherapy or in combination with paclitaxel in patients with EEC, epithelial ovarian cancer, and carcinosarcoma (malignant mixed Mullerian tumor). The trial design required at least 50% of patients to have Wnt signaling alterations.
Dr. Arend reported results for 29 patients with EEC who received DKN-01 monotherapy.
There were nine patients with Wnt activating mutations. None of them achieved a complete response (CR) or partial response (PR), but six had stable disease (SD), for a disease control rate of 67%. Of the 20 patients without Wnt activating mutations, 1 achieved a CR, 1 achieved a PR, and 3 had SD, for a disease control rate of 25%.
The median PFS was 5.5 months in patients with Wnt activating mutations and 1.8 months in patients without the mutations.
“Importantly, patients whose tumors have a Wnt activating mutation have a correlation with increased tumoral expression of DKK1 by 14.4-fold higher,” Dr. Arend noted.
When she and her colleagues analyzed patients by DKK1 expression, the team found that high levels of DKK1 correlated with better clinical outcomes. The disease control rate was 57% for patients in the highest third of DKK1 expression (1 PR, 3 SD) vs. 7% (1 SD) for those in the lowest two-thirds. The median PFS was 3 months and 1.8 months, respectively.
Of the seven patients whose tumors could not be evaluated for DKK1 expression, one patient had a CR and 5 had SD, for a disease control rate of 86%. The median PFS in this group was 8.0 months. Three of these patients had known Wnt activating mutations.
“Given this correlation [between] higher DKK1 expression [and] Wnt activating mutations, one could consider that, at a minimum, these patients would have had a higher DKK1 expression as well,” Dr. Arend said.
She and her colleagues also found that patients with PIK3CA activating mutations and two or fewer prior lines of therapy had a 33% overall response rate (1 CR, 1 PR), compared with 0% for patients without these mutations who had two or fewer prior therapies. Patients with PIK3CA activating mutations also had a better disease control rate (67% vs. 40%) and median PFS (5.6 months vs. 1.8 months).
Although Dr. Arend did not present safety data from the study at SGO 2021, she reported some data in a video investor call for Leap Therapeutics, which is developing DKN-01. She said the most common treatment-emergent adverse events with DKN-01 were nausea in 28.8% of patients, fatigue in 26.7%, and constipation in 11.5%. Serious events included acute kidney injury, dyspnea, nausea, and peripheral edema (occurring in 1.9% of patients each).
Monotherapy or combination?
In the question-and-answer session following Dr. Arend’s presentation, comoderator Joyce Liu, MD, of the Dana-Farber Cancer Institute in Boston, said that “even in the DKK1-high tumors, the activity of DKN-01 as a monotherapy is a little bit limited.”
She asked whether the future of targeting inhibitors in the Wnt/beta-catenin pathway will be limited to biomarker-specific populations or if agents such as DKN-01 should be used in combinations.
“I do think that we need a lot more data to determine,” Dr. Arend replied. “I think that there may be a subset of patients, especially those that don’t tolerate the [lenvatinib/pembrolizumab] combo who may have an upregulation of beta-catenin or a Wnt mutation who could benefit from monotherapy.”
Dr. Arend added that data from her lab and others suggest that DKN-01 in combination with other agents holds promise for improving outcomes in biomarker-selected populations.
The current study is funded by Leap Therapeutics. Dr. Arend disclosed advisory board activity for the company and others. Dr. Liu reported personal fees from several companies, not including Leap Therapeutics.
Among 29 patients with heavily pretreated EEC, outcomes of DKN-01 monotherapy were best in patients with Wnt activating mutations, high levels of DKK1 expression, or PIK3CA activating mutations.
Patients in these groups had better disease control rates and progression-free survival (PFS), reported Rebecca C. Arend, MD, of the University of Alabama at Birmingham.
“Future development will focus on biomarker-selected patients, specifically patients with Wnt activating mutations, high tumoral DKK1, and PIK3CA activating mutations,” Dr. Arend said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10717).
She explained that DKK1 has been shown to modulate signaling in the Wnt/beta-catenin pathway, a key regulator of cellular functions in humans and animals that has been highly conserved throughout evolution.
“DKK1 activates P13 kinase/AKT signaling by binding to the CKAP4 receptor to promote tumor growth,” Dr. Arend explained.
Focus on monotherapy
Dr. Arend and colleagues conducted a phase 2 basket trial of DKN-01 either as monotherapy or in combination with paclitaxel in patients with EEC, epithelial ovarian cancer, and carcinosarcoma (malignant mixed Mullerian tumor). The trial design required at least 50% of patients to have Wnt signaling alterations.
Dr. Arend reported results for 29 patients with EEC who received DKN-01 monotherapy.
There were nine patients with Wnt activating mutations. None of them achieved a complete response (CR) or partial response (PR), but six had stable disease (SD), for a disease control rate of 67%. Of the 20 patients without Wnt activating mutations, 1 achieved a CR, 1 achieved a PR, and 3 had SD, for a disease control rate of 25%.
The median PFS was 5.5 months in patients with Wnt activating mutations and 1.8 months in patients without the mutations.
“Importantly, patients whose tumors have a Wnt activating mutation have a correlation with increased tumoral expression of DKK1 by 14.4-fold higher,” Dr. Arend noted.
When she and her colleagues analyzed patients by DKK1 expression, the team found that high levels of DKK1 correlated with better clinical outcomes. The disease control rate was 57% for patients in the highest third of DKK1 expression (1 PR, 3 SD) vs. 7% (1 SD) for those in the lowest two-thirds. The median PFS was 3 months and 1.8 months, respectively.
Of the seven patients whose tumors could not be evaluated for DKK1 expression, one patient had a CR and 5 had SD, for a disease control rate of 86%. The median PFS in this group was 8.0 months. Three of these patients had known Wnt activating mutations.
“Given this correlation [between] higher DKK1 expression [and] Wnt activating mutations, one could consider that, at a minimum, these patients would have had a higher DKK1 expression as well,” Dr. Arend said.
She and her colleagues also found that patients with PIK3CA activating mutations and two or fewer prior lines of therapy had a 33% overall response rate (1 CR, 1 PR), compared with 0% for patients without these mutations who had two or fewer prior therapies. Patients with PIK3CA activating mutations also had a better disease control rate (67% vs. 40%) and median PFS (5.6 months vs. 1.8 months).
Although Dr. Arend did not present safety data from the study at SGO 2021, she reported some data in a video investor call for Leap Therapeutics, which is developing DKN-01. She said the most common treatment-emergent adverse events with DKN-01 were nausea in 28.8% of patients, fatigue in 26.7%, and constipation in 11.5%. Serious events included acute kidney injury, dyspnea, nausea, and peripheral edema (occurring in 1.9% of patients each).
Monotherapy or combination?
In the question-and-answer session following Dr. Arend’s presentation, comoderator Joyce Liu, MD, of the Dana-Farber Cancer Institute in Boston, said that “even in the DKK1-high tumors, the activity of DKN-01 as a monotherapy is a little bit limited.”
She asked whether the future of targeting inhibitors in the Wnt/beta-catenin pathway will be limited to biomarker-specific populations or if agents such as DKN-01 should be used in combinations.
“I do think that we need a lot more data to determine,” Dr. Arend replied. “I think that there may be a subset of patients, especially those that don’t tolerate the [lenvatinib/pembrolizumab] combo who may have an upregulation of beta-catenin or a Wnt mutation who could benefit from monotherapy.”
Dr. Arend added that data from her lab and others suggest that DKN-01 in combination with other agents holds promise for improving outcomes in biomarker-selected populations.
The current study is funded by Leap Therapeutics. Dr. Arend disclosed advisory board activity for the company and others. Dr. Liu reported personal fees from several companies, not including Leap Therapeutics.
Among 29 patients with heavily pretreated EEC, outcomes of DKN-01 monotherapy were best in patients with Wnt activating mutations, high levels of DKK1 expression, or PIK3CA activating mutations.
Patients in these groups had better disease control rates and progression-free survival (PFS), reported Rebecca C. Arend, MD, of the University of Alabama at Birmingham.
“Future development will focus on biomarker-selected patients, specifically patients with Wnt activating mutations, high tumoral DKK1, and PIK3CA activating mutations,” Dr. Arend said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10717).
She explained that DKK1 has been shown to modulate signaling in the Wnt/beta-catenin pathway, a key regulator of cellular functions in humans and animals that has been highly conserved throughout evolution.
“DKK1 activates P13 kinase/AKT signaling by binding to the CKAP4 receptor to promote tumor growth,” Dr. Arend explained.
Focus on monotherapy
Dr. Arend and colleagues conducted a phase 2 basket trial of DKN-01 either as monotherapy or in combination with paclitaxel in patients with EEC, epithelial ovarian cancer, and carcinosarcoma (malignant mixed Mullerian tumor). The trial design required at least 50% of patients to have Wnt signaling alterations.
Dr. Arend reported results for 29 patients with EEC who received DKN-01 monotherapy.
There were nine patients with Wnt activating mutations. None of them achieved a complete response (CR) or partial response (PR), but six had stable disease (SD), for a disease control rate of 67%. Of the 20 patients without Wnt activating mutations, 1 achieved a CR, 1 achieved a PR, and 3 had SD, for a disease control rate of 25%.
The median PFS was 5.5 months in patients with Wnt activating mutations and 1.8 months in patients without the mutations.
“Importantly, patients whose tumors have a Wnt activating mutation have a correlation with increased tumoral expression of DKK1 by 14.4-fold higher,” Dr. Arend noted.
When she and her colleagues analyzed patients by DKK1 expression, the team found that high levels of DKK1 correlated with better clinical outcomes. The disease control rate was 57% for patients in the highest third of DKK1 expression (1 PR, 3 SD) vs. 7% (1 SD) for those in the lowest two-thirds. The median PFS was 3 months and 1.8 months, respectively.
Of the seven patients whose tumors could not be evaluated for DKK1 expression, one patient had a CR and 5 had SD, for a disease control rate of 86%. The median PFS in this group was 8.0 months. Three of these patients had known Wnt activating mutations.
“Given this correlation [between] higher DKK1 expression [and] Wnt activating mutations, one could consider that, at a minimum, these patients would have had a higher DKK1 expression as well,” Dr. Arend said.
She and her colleagues also found that patients with PIK3CA activating mutations and two or fewer prior lines of therapy had a 33% overall response rate (1 CR, 1 PR), compared with 0% for patients without these mutations who had two or fewer prior therapies. Patients with PIK3CA activating mutations also had a better disease control rate (67% vs. 40%) and median PFS (5.6 months vs. 1.8 months).
Although Dr. Arend did not present safety data from the study at SGO 2021, she reported some data in a video investor call for Leap Therapeutics, which is developing DKN-01. She said the most common treatment-emergent adverse events with DKN-01 were nausea in 28.8% of patients, fatigue in 26.7%, and constipation in 11.5%. Serious events included acute kidney injury, dyspnea, nausea, and peripheral edema (occurring in 1.9% of patients each).
Monotherapy or combination?
In the question-and-answer session following Dr. Arend’s presentation, comoderator Joyce Liu, MD, of the Dana-Farber Cancer Institute in Boston, said that “even in the DKK1-high tumors, the activity of DKN-01 as a monotherapy is a little bit limited.”
She asked whether the future of targeting inhibitors in the Wnt/beta-catenin pathway will be limited to biomarker-specific populations or if agents such as DKN-01 should be used in combinations.
“I do think that we need a lot more data to determine,” Dr. Arend replied. “I think that there may be a subset of patients, especially those that don’t tolerate the [lenvatinib/pembrolizumab] combo who may have an upregulation of beta-catenin or a Wnt mutation who could benefit from monotherapy.”
Dr. Arend added that data from her lab and others suggest that DKN-01 in combination with other agents holds promise for improving outcomes in biomarker-selected populations.
The current study is funded by Leap Therapeutics. Dr. Arend disclosed advisory board activity for the company and others. Dr. Liu reported personal fees from several companies, not including Leap Therapeutics.
FROM SGO 2021
Gynecologic cancer patients at risk of insurance loss, ‘catastrophic’ costs
A retrospective study of respondents to the Medical Expenditure Panel Survey showed that more than one in five gynecologic cancer patients reported losing health insurance for at least 1 month every year, and more than one in four reported having catastrophic health expenses annually.
Benjamin Albright, MD, of Duke University Medical Center in Durham, N.C., presented these results at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10303).
“We found gynecologic cancer patients to have high rates of insurance churn and catastrophic health expenditures, particularly among the poor,” Dr. Albright said. “Traditional static measurements clearly underestimate the impact of uninsurance, with over 20% of patients reporting some period of uninsurance annually.”
There was no evidence of improvement in any outcome after the implementation of the ACA, compared with the pre-ACA period, “though our assessment was limited in estimate precision by small sample size,” Dr. Albright acknowledged.
Dynamic, not static
Oncology researchers who study access to care and financial toxicities often consider insurance status as a static characteristic, but in the U.S. health care system, the reality is quite different, with insurance status fluctuating by employment or ability to pay, sometimes on a month-to-month basis, according to Dr. Albright.
Citing the Commonwealth Fund’s definition of catastrophic health expenditures as “spending over 10% of income on health care,” Dr. Albright noted that the prevalence of catastrophic out-of-pocket costs “is also relatively poorly described among cancer patients, particularly in accounting for family spending and income dynamics.
“The Affordable Care Act contained measures to address both of these concerns, including coverage protections and expansions, and spending regulations,” he said.
Dr. Albright and colleagues at Duke and Memorial Sloan Kettering Cancer Center in New York assessed insurance churn and catastrophic health expenditures among gynecologic cancer patients, attempting to determine whether the ACA had helped to limit insurance churn and keep costs manageable.
Representative sample
The investigators conducted a retrospective study of data from Medical Expenditure Panel Survey respondents from 2006 through 2017, a period that spanned the implementation of the ACA in 2010.
The sample included 684 women younger than 65 years reporting care in the given year related to a gynecologic cancer diagnosis. The civilian, noninstitutionalized sample was weighted to represent an estimated average annual population of 533,000 persons. The population was majority White (87%) and non-Hispanic (85.5%).
The investigators found that, compared with the overall U.S. population of people under 65, gynecologic cancer patients were more likely to have incomes of 250% or less of the federal poverty line (45.1% vs. 32.2%, P < .001).
The cancer patients were more likely than was the general population to have less than full-time employment, with 15.2% and 10.5%, respectively, reporting a job change or job loss; 55.3% and 44.1%, respectively, being employed only part of a given year; and 38.6% and 32.4%, respectively, being unemployed for a full year (P < .05 for each comparison).
Gynecologic cancer patients continued to experience insurance troubles and financial hardships after the ACA went into effect, with 8.8% reporting loss of insurance, 18.7% reporting a change in insurance, 21.7% being uninsured for at least 1 month, and 8.4% being uninsured for an entire year.
In addition, 12.8% of gynecologic cancer patients reported catastrophic health expenditures in out-of-pocket costs alone, and 28.0% spent more than 10% of their income on health care when the cost of premiums was factored in.
The numbers were even worse for non-White and Hispanic patients, with 25.9% reporting an insurance change (vs. 16.3% for non-Hispanic Whites) and 30.2% reporting a period of not being insured (vs. 18.7% for non-Hispanic Whites). There were no differences in catastrophic health expenditures by race/ethnicity, however.
Not surprisingly, patients from low-income families had significantly higher probability of having catastrophic expenditures, at 22.7% vs. 3.0% for higher-income families for out-of-pocket expenses alone (P < .001), and 35.3% vs. 20.8%, respectively, when the cost of premiums was included (P = .01).
On the other hand, patients with full-year Medicaid coverage were less likely to suffer from catastrophic costs than were privately-insured patients, at 15.3% vs. 31.3% in the overall sample (P = .02), and 11.5% vs. 62.1% of low-income vs. higher-income patients (P < .001).
There was a trend toward lower catastrophic health expenditures among low-income patients after full implementation of the ACA – 2014-2017 – compared with 2006-2009, but this difference was not statistically significant.
How to change it
In a panel discussion following the presentation, comoderator Eloise Chapman-Davis, MD, of Weill Cornell Medicine in New York, said to Dr. Albright, “As we look to improve equity within our subspecialty, I would like to ask you to comment on how you believe your abstract will inform our gyn-oncology culture and speak to what changes that you believe are needed to better advocate for our patients.”
“I think that our abstract really shows the prevalence of the problems of financial toxicity and of instability in the insurance market in the U.S.,” he replied. “I think it points out that we need to be more proactive about identifying patients and seeking out patients who may be having issues related to financial toxicity, to try to refer people to resources sooner and upfront.”
The investigators did not list a funding source for the study. Dr. Albright and Dr. Chapman-Davis reported having no conflicts of interest.
A retrospective study of respondents to the Medical Expenditure Panel Survey showed that more than one in five gynecologic cancer patients reported losing health insurance for at least 1 month every year, and more than one in four reported having catastrophic health expenses annually.
Benjamin Albright, MD, of Duke University Medical Center in Durham, N.C., presented these results at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10303).
“We found gynecologic cancer patients to have high rates of insurance churn and catastrophic health expenditures, particularly among the poor,” Dr. Albright said. “Traditional static measurements clearly underestimate the impact of uninsurance, with over 20% of patients reporting some period of uninsurance annually.”
There was no evidence of improvement in any outcome after the implementation of the ACA, compared with the pre-ACA period, “though our assessment was limited in estimate precision by small sample size,” Dr. Albright acknowledged.
Dynamic, not static
Oncology researchers who study access to care and financial toxicities often consider insurance status as a static characteristic, but in the U.S. health care system, the reality is quite different, with insurance status fluctuating by employment or ability to pay, sometimes on a month-to-month basis, according to Dr. Albright.
Citing the Commonwealth Fund’s definition of catastrophic health expenditures as “spending over 10% of income on health care,” Dr. Albright noted that the prevalence of catastrophic out-of-pocket costs “is also relatively poorly described among cancer patients, particularly in accounting for family spending and income dynamics.
“The Affordable Care Act contained measures to address both of these concerns, including coverage protections and expansions, and spending regulations,” he said.
Dr. Albright and colleagues at Duke and Memorial Sloan Kettering Cancer Center in New York assessed insurance churn and catastrophic health expenditures among gynecologic cancer patients, attempting to determine whether the ACA had helped to limit insurance churn and keep costs manageable.
Representative sample
The investigators conducted a retrospective study of data from Medical Expenditure Panel Survey respondents from 2006 through 2017, a period that spanned the implementation of the ACA in 2010.
The sample included 684 women younger than 65 years reporting care in the given year related to a gynecologic cancer diagnosis. The civilian, noninstitutionalized sample was weighted to represent an estimated average annual population of 533,000 persons. The population was majority White (87%) and non-Hispanic (85.5%).
The investigators found that, compared with the overall U.S. population of people under 65, gynecologic cancer patients were more likely to have incomes of 250% or less of the federal poverty line (45.1% vs. 32.2%, P < .001).
The cancer patients were more likely than was the general population to have less than full-time employment, with 15.2% and 10.5%, respectively, reporting a job change or job loss; 55.3% and 44.1%, respectively, being employed only part of a given year; and 38.6% and 32.4%, respectively, being unemployed for a full year (P < .05 for each comparison).
Gynecologic cancer patients continued to experience insurance troubles and financial hardships after the ACA went into effect, with 8.8% reporting loss of insurance, 18.7% reporting a change in insurance, 21.7% being uninsured for at least 1 month, and 8.4% being uninsured for an entire year.
In addition, 12.8% of gynecologic cancer patients reported catastrophic health expenditures in out-of-pocket costs alone, and 28.0% spent more than 10% of their income on health care when the cost of premiums was factored in.
The numbers were even worse for non-White and Hispanic patients, with 25.9% reporting an insurance change (vs. 16.3% for non-Hispanic Whites) and 30.2% reporting a period of not being insured (vs. 18.7% for non-Hispanic Whites). There were no differences in catastrophic health expenditures by race/ethnicity, however.
Not surprisingly, patients from low-income families had significantly higher probability of having catastrophic expenditures, at 22.7% vs. 3.0% for higher-income families for out-of-pocket expenses alone (P < .001), and 35.3% vs. 20.8%, respectively, when the cost of premiums was included (P = .01).
On the other hand, patients with full-year Medicaid coverage were less likely to suffer from catastrophic costs than were privately-insured patients, at 15.3% vs. 31.3% in the overall sample (P = .02), and 11.5% vs. 62.1% of low-income vs. higher-income patients (P < .001).
There was a trend toward lower catastrophic health expenditures among low-income patients after full implementation of the ACA – 2014-2017 – compared with 2006-2009, but this difference was not statistically significant.
How to change it
In a panel discussion following the presentation, comoderator Eloise Chapman-Davis, MD, of Weill Cornell Medicine in New York, said to Dr. Albright, “As we look to improve equity within our subspecialty, I would like to ask you to comment on how you believe your abstract will inform our gyn-oncology culture and speak to what changes that you believe are needed to better advocate for our patients.”
“I think that our abstract really shows the prevalence of the problems of financial toxicity and of instability in the insurance market in the U.S.,” he replied. “I think it points out that we need to be more proactive about identifying patients and seeking out patients who may be having issues related to financial toxicity, to try to refer people to resources sooner and upfront.”
The investigators did not list a funding source for the study. Dr. Albright and Dr. Chapman-Davis reported having no conflicts of interest.
A retrospective study of respondents to the Medical Expenditure Panel Survey showed that more than one in five gynecologic cancer patients reported losing health insurance for at least 1 month every year, and more than one in four reported having catastrophic health expenses annually.
Benjamin Albright, MD, of Duke University Medical Center in Durham, N.C., presented these results at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10303).
“We found gynecologic cancer patients to have high rates of insurance churn and catastrophic health expenditures, particularly among the poor,” Dr. Albright said. “Traditional static measurements clearly underestimate the impact of uninsurance, with over 20% of patients reporting some period of uninsurance annually.”
There was no evidence of improvement in any outcome after the implementation of the ACA, compared with the pre-ACA period, “though our assessment was limited in estimate precision by small sample size,” Dr. Albright acknowledged.
Dynamic, not static
Oncology researchers who study access to care and financial toxicities often consider insurance status as a static characteristic, but in the U.S. health care system, the reality is quite different, with insurance status fluctuating by employment or ability to pay, sometimes on a month-to-month basis, according to Dr. Albright.
Citing the Commonwealth Fund’s definition of catastrophic health expenditures as “spending over 10% of income on health care,” Dr. Albright noted that the prevalence of catastrophic out-of-pocket costs “is also relatively poorly described among cancer patients, particularly in accounting for family spending and income dynamics.
“The Affordable Care Act contained measures to address both of these concerns, including coverage protections and expansions, and spending regulations,” he said.
Dr. Albright and colleagues at Duke and Memorial Sloan Kettering Cancer Center in New York assessed insurance churn and catastrophic health expenditures among gynecologic cancer patients, attempting to determine whether the ACA had helped to limit insurance churn and keep costs manageable.
Representative sample
The investigators conducted a retrospective study of data from Medical Expenditure Panel Survey respondents from 2006 through 2017, a period that spanned the implementation of the ACA in 2010.
The sample included 684 women younger than 65 years reporting care in the given year related to a gynecologic cancer diagnosis. The civilian, noninstitutionalized sample was weighted to represent an estimated average annual population of 533,000 persons. The population was majority White (87%) and non-Hispanic (85.5%).
The investigators found that, compared with the overall U.S. population of people under 65, gynecologic cancer patients were more likely to have incomes of 250% or less of the federal poverty line (45.1% vs. 32.2%, P < .001).
The cancer patients were more likely than was the general population to have less than full-time employment, with 15.2% and 10.5%, respectively, reporting a job change or job loss; 55.3% and 44.1%, respectively, being employed only part of a given year; and 38.6% and 32.4%, respectively, being unemployed for a full year (P < .05 for each comparison).
Gynecologic cancer patients continued to experience insurance troubles and financial hardships after the ACA went into effect, with 8.8% reporting loss of insurance, 18.7% reporting a change in insurance, 21.7% being uninsured for at least 1 month, and 8.4% being uninsured for an entire year.
In addition, 12.8% of gynecologic cancer patients reported catastrophic health expenditures in out-of-pocket costs alone, and 28.0% spent more than 10% of their income on health care when the cost of premiums was factored in.
The numbers were even worse for non-White and Hispanic patients, with 25.9% reporting an insurance change (vs. 16.3% for non-Hispanic Whites) and 30.2% reporting a period of not being insured (vs. 18.7% for non-Hispanic Whites). There were no differences in catastrophic health expenditures by race/ethnicity, however.
Not surprisingly, patients from low-income families had significantly higher probability of having catastrophic expenditures, at 22.7% vs. 3.0% for higher-income families for out-of-pocket expenses alone (P < .001), and 35.3% vs. 20.8%, respectively, when the cost of premiums was included (P = .01).
On the other hand, patients with full-year Medicaid coverage were less likely to suffer from catastrophic costs than were privately-insured patients, at 15.3% vs. 31.3% in the overall sample (P = .02), and 11.5% vs. 62.1% of low-income vs. higher-income patients (P < .001).
There was a trend toward lower catastrophic health expenditures among low-income patients after full implementation of the ACA – 2014-2017 – compared with 2006-2009, but this difference was not statistically significant.
How to change it
In a panel discussion following the presentation, comoderator Eloise Chapman-Davis, MD, of Weill Cornell Medicine in New York, said to Dr. Albright, “As we look to improve equity within our subspecialty, I would like to ask you to comment on how you believe your abstract will inform our gyn-oncology culture and speak to what changes that you believe are needed to better advocate for our patients.”
“I think that our abstract really shows the prevalence of the problems of financial toxicity and of instability in the insurance market in the U.S.,” he replied. “I think it points out that we need to be more proactive about identifying patients and seeking out patients who may be having issues related to financial toxicity, to try to refer people to resources sooner and upfront.”
The investigators did not list a funding source for the study. Dr. Albright and Dr. Chapman-Davis reported having no conflicts of interest.
FROM SGO 2021
Frail status may be better than age for predicting ovarian cancer outcomes
Baseball great Satchel Paige’s famous adage, “Age is a case of mind over matter. If you don’t mind, it don’t matter,” may also apply to candidates for ovarian cancer surgery. That’s because investigators have found that physical frailty is a better determinant of fitness for surgery than is calendar age.
Investigators conducted a retrospective analysis of 591 patients considered for primary resection of stage II to IV high-grade ovarian, fallopian tube, or peritoneal cancer. Results showed that a 10-item modified frailty index was better than patient age for predicting survival outcomes.
“Frailty does seem to correlate with age and increase with age, but it is not synonymous with age,” said investigator Katelyn F. Handley, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Frailty is a spectrum, and we can see patients of the same chronological age, but one may be a 76-year-old, ultra-distance triathlete, while another is in failing health and diminishing function,” Dr. Handley said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10463).
Dr. Handley cited a consensus definition of frailty, published in 2013, as “a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death.”
Ten-item score
To assess the effect of frailty in ovarian cancer patients on surgical procedures and outcomes, the investigators retrospectively applied a modified frailty index (mFI) to patients who were treated at MD Anderson Cancer Center from April 2013 through September 2017.
The index is a sum of 10 items: Chronic obstructive pulmonary disease or recent pneumonia, heart failure, myocardial infarction, coronary artery disease, diabetes, hypertension, peripheral vascular disease, cerebrovascular disease, cerebrovascular accident with neurologic deficit, and poor Eastern Cooperative Oncology Group performance status (3 or 4).
Of the 591 patients who met inclusion criteria, 57% had mFI scores of 0, indicating no frailty, 29% had one frailty factor, and 14% had two or more factors.
Patient age did significantly correlate with mFI scores. Patients with an mFI score of 0 had a median age of 62 years, the median age in those with a score of 1 was 69 years, and the median age for those with scores of 2 or higher was 70.5 years (P <. 001).
Charlson comorbidity index scores also significantly increased with age, with mean scores of 3.00, 3.83, and 5.14 in patients with mFI scores of 0, 1, or 2, respectively (P <. 001).
“But if you look at the age ranges in each category, you’ll notice that there are patients as young as 47 with an mFI of greater than or equal to 2, and as old as 89 with an mFI of 0,” Dr. Handley pointed out.
Higher scores, fewer assessments
The investigators found that patients with suspected ovarian cancer with frailty scores of 2 or higher were less likely to be offered laparoscopic assessment to determine primary resectability than were those with scores of 1 or 0 (28% vs. 43% and 49%, respectively, P = .004).
Among all patients who underwent laparoscopic assessment, the predictive index score (modified Fagotti score) was more likely to be 8 or higher in patients with high frailty scores (58%, 48%, and 34% for scores of 2 or greater, 1, and 0, respectively; P = .038).
Only 17% of the most frail patients went on to primary debulking surgery, compared with 26% of patients with a single frailty factor and 34% of those with none (P = .015).
Patients with higher frailty scores were less likely to undergo primary or interval tumor reductive surgery (59% vs. 74% for those with mFI scores of 1 and 85% for those with scores of 0; P <. 001). The frailest patients were significantly more likely to undergo splenectomy (20%, 3%, and 6%, respectively; P = .001) and small bowel resection (14%, 8%, and 3%, respectively; P = .006).
Two-thirds of the most frail patients (64%) had postoperative complications, primarily gastrointestinal and renal complications, compared with 56% and 44% of patients with mFI scores of 1 or 0, respectively (P = .014).
Frailty was predictive of 30-day postoperative mortality (P = .005) but not postoperative length of stay.
Frailer patients were more likely to receive neoadjuvant chemotherapy (P = .033) but less likely to receive adjuvant chemotherapy (P <. 001).
mFI scores of 2 or greater and 1 were both associated with significantly worse progression-free survival (P < .001 and P = .022, respectively), but only an mFI of 2 or greater was associated with significantly worse overall survival (P <. 001).
On multivariate analysis controlling for frailty, age, stage, BRCA status, and tumor reductive surgery status, high frailty was associated with worse progression-free survival (P = .009) and a trend toward worse overall survival (P = .079).
High frailty was better than age for predicting worse progression-free survival (hazard ratio, 1.50; P = .017) and overall survival (HR, 1.57; P = .047)
Volume counts
In a separate presentation during the same session, Morcos Nakhla, of the University of California, Los Angeles, reported finding similar associations between frailty and worse surgical outcomes for ovarian cancer patients (Abstract 11016).
Mr. Nakhla and colleagues found that frail patients had a twofold increase in the risk of postoperative complications, a threefold increase in the risk for non-home dismissal, and a threefold increased risk of death (P <. 001 for all).
The team also found, however, that mortality improved from 2005 through 2017, despite an increase in frail patients over that time period.
In addition, higher surgical volumes were associated with decreased mortality among frail patients undergoing ovarian cancer surgery.
Navigating treatment
“Frailty syndrome is a medical syndrome. It’s not a disability,” said Jamie N. Bakkum-Gamez, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant. “No patient or human wants to be frail, but at some point, we may all be at risk for frailty syndrome, and as we navigate much-needed novel ways to treat this medical syndrome, it’s imperative that we listen to the voice of the customer and that our communication and technology doesn’t add unanticipated stress.”
Dr. Bakkum-Gamez emphasized the importance of shared decision-making, screening for frailty syndrome, referral to higher volume surgical centers when practical, and surgical alternatives such as neoadjuvant chemotherapy with or without interval debulking surgery and palliative care.
Interventions for ameliorating frailty may include exercise, high-protein calorie supplementation, reduction of polypharmacy, and vitamin D supplementation.
“Sometimes, shared decision-making means deciding not to operate,” Dr. Bakkum-Gamez said. “This is sometimes amongst the hardest decisions for a surgeon. We know when we make the wrong decision in operating if our patient experiences a major, life-shortening complication, but it’s less clear to know if we make the wrong decision to not operate.”
The study by Dr. Handley and colleagues was funded by the Gulf Coast Consortia, MD Anderson, National Institutes of Health, American Cancer Society, and GOG Foundation. Mr. Nakhla and colleagues did not disclose a funding source. Dr. Handley, Mr. Nakhla, and Dr. Bakkum-Gamez all reported no relevant conflicts of interest.
Baseball great Satchel Paige’s famous adage, “Age is a case of mind over matter. If you don’t mind, it don’t matter,” may also apply to candidates for ovarian cancer surgery. That’s because investigators have found that physical frailty is a better determinant of fitness for surgery than is calendar age.
Investigators conducted a retrospective analysis of 591 patients considered for primary resection of stage II to IV high-grade ovarian, fallopian tube, or peritoneal cancer. Results showed that a 10-item modified frailty index was better than patient age for predicting survival outcomes.
“Frailty does seem to correlate with age and increase with age, but it is not synonymous with age,” said investigator Katelyn F. Handley, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Frailty is a spectrum, and we can see patients of the same chronological age, but one may be a 76-year-old, ultra-distance triathlete, while another is in failing health and diminishing function,” Dr. Handley said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10463).
Dr. Handley cited a consensus definition of frailty, published in 2013, as “a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death.”
Ten-item score
To assess the effect of frailty in ovarian cancer patients on surgical procedures and outcomes, the investigators retrospectively applied a modified frailty index (mFI) to patients who were treated at MD Anderson Cancer Center from April 2013 through September 2017.
The index is a sum of 10 items: Chronic obstructive pulmonary disease or recent pneumonia, heart failure, myocardial infarction, coronary artery disease, diabetes, hypertension, peripheral vascular disease, cerebrovascular disease, cerebrovascular accident with neurologic deficit, and poor Eastern Cooperative Oncology Group performance status (3 or 4).
Of the 591 patients who met inclusion criteria, 57% had mFI scores of 0, indicating no frailty, 29% had one frailty factor, and 14% had two or more factors.
Patient age did significantly correlate with mFI scores. Patients with an mFI score of 0 had a median age of 62 years, the median age in those with a score of 1 was 69 years, and the median age for those with scores of 2 or higher was 70.5 years (P <. 001).
Charlson comorbidity index scores also significantly increased with age, with mean scores of 3.00, 3.83, and 5.14 in patients with mFI scores of 0, 1, or 2, respectively (P <. 001).
“But if you look at the age ranges in each category, you’ll notice that there are patients as young as 47 with an mFI of greater than or equal to 2, and as old as 89 with an mFI of 0,” Dr. Handley pointed out.
Higher scores, fewer assessments
The investigators found that patients with suspected ovarian cancer with frailty scores of 2 or higher were less likely to be offered laparoscopic assessment to determine primary resectability than were those with scores of 1 or 0 (28% vs. 43% and 49%, respectively, P = .004).
Among all patients who underwent laparoscopic assessment, the predictive index score (modified Fagotti score) was more likely to be 8 or higher in patients with high frailty scores (58%, 48%, and 34% for scores of 2 or greater, 1, and 0, respectively; P = .038).
Only 17% of the most frail patients went on to primary debulking surgery, compared with 26% of patients with a single frailty factor and 34% of those with none (P = .015).
Patients with higher frailty scores were less likely to undergo primary or interval tumor reductive surgery (59% vs. 74% for those with mFI scores of 1 and 85% for those with scores of 0; P <. 001). The frailest patients were significantly more likely to undergo splenectomy (20%, 3%, and 6%, respectively; P = .001) and small bowel resection (14%, 8%, and 3%, respectively; P = .006).
Two-thirds of the most frail patients (64%) had postoperative complications, primarily gastrointestinal and renal complications, compared with 56% and 44% of patients with mFI scores of 1 or 0, respectively (P = .014).
Frailty was predictive of 30-day postoperative mortality (P = .005) but not postoperative length of stay.
Frailer patients were more likely to receive neoadjuvant chemotherapy (P = .033) but less likely to receive adjuvant chemotherapy (P <. 001).
mFI scores of 2 or greater and 1 were both associated with significantly worse progression-free survival (P < .001 and P = .022, respectively), but only an mFI of 2 or greater was associated with significantly worse overall survival (P <. 001).
On multivariate analysis controlling for frailty, age, stage, BRCA status, and tumor reductive surgery status, high frailty was associated with worse progression-free survival (P = .009) and a trend toward worse overall survival (P = .079).
High frailty was better than age for predicting worse progression-free survival (hazard ratio, 1.50; P = .017) and overall survival (HR, 1.57; P = .047)
Volume counts
In a separate presentation during the same session, Morcos Nakhla, of the University of California, Los Angeles, reported finding similar associations between frailty and worse surgical outcomes for ovarian cancer patients (Abstract 11016).
Mr. Nakhla and colleagues found that frail patients had a twofold increase in the risk of postoperative complications, a threefold increase in the risk for non-home dismissal, and a threefold increased risk of death (P <. 001 for all).
The team also found, however, that mortality improved from 2005 through 2017, despite an increase in frail patients over that time period.
In addition, higher surgical volumes were associated with decreased mortality among frail patients undergoing ovarian cancer surgery.
Navigating treatment
“Frailty syndrome is a medical syndrome. It’s not a disability,” said Jamie N. Bakkum-Gamez, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant. “No patient or human wants to be frail, but at some point, we may all be at risk for frailty syndrome, and as we navigate much-needed novel ways to treat this medical syndrome, it’s imperative that we listen to the voice of the customer and that our communication and technology doesn’t add unanticipated stress.”
Dr. Bakkum-Gamez emphasized the importance of shared decision-making, screening for frailty syndrome, referral to higher volume surgical centers when practical, and surgical alternatives such as neoadjuvant chemotherapy with or without interval debulking surgery and palliative care.
Interventions for ameliorating frailty may include exercise, high-protein calorie supplementation, reduction of polypharmacy, and vitamin D supplementation.
“Sometimes, shared decision-making means deciding not to operate,” Dr. Bakkum-Gamez said. “This is sometimes amongst the hardest decisions for a surgeon. We know when we make the wrong decision in operating if our patient experiences a major, life-shortening complication, but it’s less clear to know if we make the wrong decision to not operate.”
The study by Dr. Handley and colleagues was funded by the Gulf Coast Consortia, MD Anderson, National Institutes of Health, American Cancer Society, and GOG Foundation. Mr. Nakhla and colleagues did not disclose a funding source. Dr. Handley, Mr. Nakhla, and Dr. Bakkum-Gamez all reported no relevant conflicts of interest.
Baseball great Satchel Paige’s famous adage, “Age is a case of mind over matter. If you don’t mind, it don’t matter,” may also apply to candidates for ovarian cancer surgery. That’s because investigators have found that physical frailty is a better determinant of fitness for surgery than is calendar age.
Investigators conducted a retrospective analysis of 591 patients considered for primary resection of stage II to IV high-grade ovarian, fallopian tube, or peritoneal cancer. Results showed that a 10-item modified frailty index was better than patient age for predicting survival outcomes.
“Frailty does seem to correlate with age and increase with age, but it is not synonymous with age,” said investigator Katelyn F. Handley, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Frailty is a spectrum, and we can see patients of the same chronological age, but one may be a 76-year-old, ultra-distance triathlete, while another is in failing health and diminishing function,” Dr. Handley said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10463).
Dr. Handley cited a consensus definition of frailty, published in 2013, as “a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death.”
Ten-item score
To assess the effect of frailty in ovarian cancer patients on surgical procedures and outcomes, the investigators retrospectively applied a modified frailty index (mFI) to patients who were treated at MD Anderson Cancer Center from April 2013 through September 2017.
The index is a sum of 10 items: Chronic obstructive pulmonary disease or recent pneumonia, heart failure, myocardial infarction, coronary artery disease, diabetes, hypertension, peripheral vascular disease, cerebrovascular disease, cerebrovascular accident with neurologic deficit, and poor Eastern Cooperative Oncology Group performance status (3 or 4).
Of the 591 patients who met inclusion criteria, 57% had mFI scores of 0, indicating no frailty, 29% had one frailty factor, and 14% had two or more factors.
Patient age did significantly correlate with mFI scores. Patients with an mFI score of 0 had a median age of 62 years, the median age in those with a score of 1 was 69 years, and the median age for those with scores of 2 or higher was 70.5 years (P <. 001).
Charlson comorbidity index scores also significantly increased with age, with mean scores of 3.00, 3.83, and 5.14 in patients with mFI scores of 0, 1, or 2, respectively (P <. 001).
“But if you look at the age ranges in each category, you’ll notice that there are patients as young as 47 with an mFI of greater than or equal to 2, and as old as 89 with an mFI of 0,” Dr. Handley pointed out.
Higher scores, fewer assessments
The investigators found that patients with suspected ovarian cancer with frailty scores of 2 or higher were less likely to be offered laparoscopic assessment to determine primary resectability than were those with scores of 1 or 0 (28% vs. 43% and 49%, respectively, P = .004).
Among all patients who underwent laparoscopic assessment, the predictive index score (modified Fagotti score) was more likely to be 8 or higher in patients with high frailty scores (58%, 48%, and 34% for scores of 2 or greater, 1, and 0, respectively; P = .038).
Only 17% of the most frail patients went on to primary debulking surgery, compared with 26% of patients with a single frailty factor and 34% of those with none (P = .015).
Patients with higher frailty scores were less likely to undergo primary or interval tumor reductive surgery (59% vs. 74% for those with mFI scores of 1 and 85% for those with scores of 0; P <. 001). The frailest patients were significantly more likely to undergo splenectomy (20%, 3%, and 6%, respectively; P = .001) and small bowel resection (14%, 8%, and 3%, respectively; P = .006).
Two-thirds of the most frail patients (64%) had postoperative complications, primarily gastrointestinal and renal complications, compared with 56% and 44% of patients with mFI scores of 1 or 0, respectively (P = .014).
Frailty was predictive of 30-day postoperative mortality (P = .005) but not postoperative length of stay.
Frailer patients were more likely to receive neoadjuvant chemotherapy (P = .033) but less likely to receive adjuvant chemotherapy (P <. 001).
mFI scores of 2 or greater and 1 were both associated with significantly worse progression-free survival (P < .001 and P = .022, respectively), but only an mFI of 2 or greater was associated with significantly worse overall survival (P <. 001).
On multivariate analysis controlling for frailty, age, stage, BRCA status, and tumor reductive surgery status, high frailty was associated with worse progression-free survival (P = .009) and a trend toward worse overall survival (P = .079).
High frailty was better than age for predicting worse progression-free survival (hazard ratio, 1.50; P = .017) and overall survival (HR, 1.57; P = .047)
Volume counts
In a separate presentation during the same session, Morcos Nakhla, of the University of California, Los Angeles, reported finding similar associations between frailty and worse surgical outcomes for ovarian cancer patients (Abstract 11016).
Mr. Nakhla and colleagues found that frail patients had a twofold increase in the risk of postoperative complications, a threefold increase in the risk for non-home dismissal, and a threefold increased risk of death (P <. 001 for all).
The team also found, however, that mortality improved from 2005 through 2017, despite an increase in frail patients over that time period.
In addition, higher surgical volumes were associated with decreased mortality among frail patients undergoing ovarian cancer surgery.
Navigating treatment
“Frailty syndrome is a medical syndrome. It’s not a disability,” said Jamie N. Bakkum-Gamez, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant. “No patient or human wants to be frail, but at some point, we may all be at risk for frailty syndrome, and as we navigate much-needed novel ways to treat this medical syndrome, it’s imperative that we listen to the voice of the customer and that our communication and technology doesn’t add unanticipated stress.”
Dr. Bakkum-Gamez emphasized the importance of shared decision-making, screening for frailty syndrome, referral to higher volume surgical centers when practical, and surgical alternatives such as neoadjuvant chemotherapy with or without interval debulking surgery and palliative care.
Interventions for ameliorating frailty may include exercise, high-protein calorie supplementation, reduction of polypharmacy, and vitamin D supplementation.
“Sometimes, shared decision-making means deciding not to operate,” Dr. Bakkum-Gamez said. “This is sometimes amongst the hardest decisions for a surgeon. We know when we make the wrong decision in operating if our patient experiences a major, life-shortening complication, but it’s less clear to know if we make the wrong decision to not operate.”
The study by Dr. Handley and colleagues was funded by the Gulf Coast Consortia, MD Anderson, National Institutes of Health, American Cancer Society, and GOG Foundation. Mr. Nakhla and colleagues did not disclose a funding source. Dr. Handley, Mr. Nakhla, and Dr. Bakkum-Gamez all reported no relevant conflicts of interest.
FROM SGO 2021
Omidubicel improves on umbilical cord blood transplants
Omidubicel, an investigational enriched umbilical cord blood product being developed by Gamida Cell for transplantation in patients with blood cancers, appears to have some advantages over standard umbilical cord blood.
The results come from a global phase 3 trial (NCT02730299) presented at the annual meeting of the European Society for Blood and Bone Marrow Transplantation.
“Transplantation with omidubicel, compared to standard cord blood transplantation, results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said coinvestigator Guillermo F. Sanz, MD, PhD, from the Hospital Universitari i Politècnic la Fe in Valencia, Spain.
“Omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation,” Dr. Sanz concluded.
Zachariah DeFilipp, MD, from Mass General Cancer Center in Boston, a hematopoietic stem cell transplantation specialist who was not involved in the study, said in an interview that “omidubicel significantly improves the engraftment after transplant, as compared to standard cord blood transplant. For patients that lack an HLA-matched donor, this approach can help overcome the prolonged cytopenias that occur with standard cord blood transplants in adults.”
Gamida Cell plans to submit these data for approval of omidubicel by the Food and Drug Administration in the fourth quarter of 2021.
Omidubicel is also being evaluated in a phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937).
Expanding possibilities
Although umbilical cord blood stem cell grafts come from a readily available source and show greater tolerance across HLA barriers than other sources (such as bone marrow), the relatively low dose of stem cells in each unit results in delayed hematopoietic recovery, increased transplant-related morbidity and mortality, and longer hospitalizations, Dr. Sanz said.
Omidubicel consists of two cryopreserved fractions from a single cord blood unit. The product contains both noncultured CD133-negative cells, including T cells, and CD133-positive cells that are then expanded ex vivo for 21 days in the presence of nicotinamide.
“Nicotinamide increases stem and progenitor cells, inhibits differentiation and increases migration, bone marrow homing, and engraftment efficiency while preserving cellular functionality and phenotype,” Dr. Sanz explained during his presentation.
In an earlier phase 1/2 trial in 36 patients with high-risk hematologic malignancies, omidubicel was associated with hematopoietic engraftment lasting at least 10 years.
Details of phase 3 trial results
The global phase 3 trial was conducted in 125 patients (aged 13-65 years) with high-risk malignancies, including acute myeloid and lymphoblastic leukemias, myelodysplastic syndrome, chronic myeloid leukemia, lymphomas, and rare leukemias. These patients were all eligible for allogeneic stem cell transplantation but did not have matched donors.
Patients were randomly assigned to receive hematopoietic reconstitution with either omidubicel (n = 52) or standard cord blood (n = 58).
At 42 days of follow-up, the median time to neutrophil engraftment in the intention-to-treat (ITT) population, the primary endpoint, was 12 days with omidubicel versus 22 days with standard cord blood (P < .001).
In the as-treated population – the 108 patients who actually received omidubicel or standard cord blood – median time to engraftment was 10.0 versus 20.5 days, respectively (P < .001).
Rates of neutrophil engraftment at 42 days were 96% with omidubicel versus 89% with standard cord blood.
The secondary endpoint of time-to-platelet engraftment in the ITT population also favored omidubicel, with a cumulative day 42 incidence rate of 55%, compared with 35% with standard cord blood (P = .028).
In the as-treated population, median times to platelet engraftment were 37 days and 50 days, respectively (P = .023). The cumulative rates of platelet engraftment at 100 days of follow-up were 83% and 73%, respectively.
The incidence of grade 2 or 3 bacterial or invasive fungal infections by day 100 in the ITT population was 37% among patients who received omidubicel, compared with 57% for patients who received standard cord blood (P = .027). Viral infections occurred in 10% versus 26% of patients, respectively.
The incidence of acute graft versus host disease at day 100 was similar between treatment groups, and there was no significant difference at 1 year.
Relapse and nonrelapse mortality rates, as well as disease-free and overall survival rates also did not differ between groups.
In the first 100 days post transplant, patients who received omidubicel were alive and out of the hospital for a median of 60.5 days, compared with 48 days for patients who received standard cord blood (P = .005).
The study was funded by Gamida Cell. Dr. Sanz reported receiving research funding from the company and several others, and consulting fees, honoraria, speakers bureau activity, and travel expenses from other companies. Dr. DeFilipp reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Omidubicel, an investigational enriched umbilical cord blood product being developed by Gamida Cell for transplantation in patients with blood cancers, appears to have some advantages over standard umbilical cord blood.
The results come from a global phase 3 trial (NCT02730299) presented at the annual meeting of the European Society for Blood and Bone Marrow Transplantation.
“Transplantation with omidubicel, compared to standard cord blood transplantation, results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said coinvestigator Guillermo F. Sanz, MD, PhD, from the Hospital Universitari i Politècnic la Fe in Valencia, Spain.
“Omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation,” Dr. Sanz concluded.
Zachariah DeFilipp, MD, from Mass General Cancer Center in Boston, a hematopoietic stem cell transplantation specialist who was not involved in the study, said in an interview that “omidubicel significantly improves the engraftment after transplant, as compared to standard cord blood transplant. For patients that lack an HLA-matched donor, this approach can help overcome the prolonged cytopenias that occur with standard cord blood transplants in adults.”
Gamida Cell plans to submit these data for approval of omidubicel by the Food and Drug Administration in the fourth quarter of 2021.
Omidubicel is also being evaluated in a phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937).
Expanding possibilities
Although umbilical cord blood stem cell grafts come from a readily available source and show greater tolerance across HLA barriers than other sources (such as bone marrow), the relatively low dose of stem cells in each unit results in delayed hematopoietic recovery, increased transplant-related morbidity and mortality, and longer hospitalizations, Dr. Sanz said.
Omidubicel consists of two cryopreserved fractions from a single cord blood unit. The product contains both noncultured CD133-negative cells, including T cells, and CD133-positive cells that are then expanded ex vivo for 21 days in the presence of nicotinamide.
“Nicotinamide increases stem and progenitor cells, inhibits differentiation and increases migration, bone marrow homing, and engraftment efficiency while preserving cellular functionality and phenotype,” Dr. Sanz explained during his presentation.
In an earlier phase 1/2 trial in 36 patients with high-risk hematologic malignancies, omidubicel was associated with hematopoietic engraftment lasting at least 10 years.
Details of phase 3 trial results
The global phase 3 trial was conducted in 125 patients (aged 13-65 years) with high-risk malignancies, including acute myeloid and lymphoblastic leukemias, myelodysplastic syndrome, chronic myeloid leukemia, lymphomas, and rare leukemias. These patients were all eligible for allogeneic stem cell transplantation but did not have matched donors.
Patients were randomly assigned to receive hematopoietic reconstitution with either omidubicel (n = 52) or standard cord blood (n = 58).
At 42 days of follow-up, the median time to neutrophil engraftment in the intention-to-treat (ITT) population, the primary endpoint, was 12 days with omidubicel versus 22 days with standard cord blood (P < .001).
In the as-treated population – the 108 patients who actually received omidubicel or standard cord blood – median time to engraftment was 10.0 versus 20.5 days, respectively (P < .001).
Rates of neutrophil engraftment at 42 days were 96% with omidubicel versus 89% with standard cord blood.
The secondary endpoint of time-to-platelet engraftment in the ITT population also favored omidubicel, with a cumulative day 42 incidence rate of 55%, compared with 35% with standard cord blood (P = .028).
In the as-treated population, median times to platelet engraftment were 37 days and 50 days, respectively (P = .023). The cumulative rates of platelet engraftment at 100 days of follow-up were 83% and 73%, respectively.
The incidence of grade 2 or 3 bacterial or invasive fungal infections by day 100 in the ITT population was 37% among patients who received omidubicel, compared with 57% for patients who received standard cord blood (P = .027). Viral infections occurred in 10% versus 26% of patients, respectively.
The incidence of acute graft versus host disease at day 100 was similar between treatment groups, and there was no significant difference at 1 year.
Relapse and nonrelapse mortality rates, as well as disease-free and overall survival rates also did not differ between groups.
In the first 100 days post transplant, patients who received omidubicel were alive and out of the hospital for a median of 60.5 days, compared with 48 days for patients who received standard cord blood (P = .005).
The study was funded by Gamida Cell. Dr. Sanz reported receiving research funding from the company and several others, and consulting fees, honoraria, speakers bureau activity, and travel expenses from other companies. Dr. DeFilipp reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Omidubicel, an investigational enriched umbilical cord blood product being developed by Gamida Cell for transplantation in patients with blood cancers, appears to have some advantages over standard umbilical cord blood.
The results come from a global phase 3 trial (NCT02730299) presented at the annual meeting of the European Society for Blood and Bone Marrow Transplantation.
“Transplantation with omidubicel, compared to standard cord blood transplantation, results in faster hematopoietic recovery, fewer infections, and fewer days in hospital,” said coinvestigator Guillermo F. Sanz, MD, PhD, from the Hospital Universitari i Politècnic la Fe in Valencia, Spain.
“Omidubicel should be considered as the new standard of care for patients eligible for umbilical cord blood transplantation,” Dr. Sanz concluded.
Zachariah DeFilipp, MD, from Mass General Cancer Center in Boston, a hematopoietic stem cell transplantation specialist who was not involved in the study, said in an interview that “omidubicel significantly improves the engraftment after transplant, as compared to standard cord blood transplant. For patients that lack an HLA-matched donor, this approach can help overcome the prolonged cytopenias that occur with standard cord blood transplants in adults.”
Gamida Cell plans to submit these data for approval of omidubicel by the Food and Drug Administration in the fourth quarter of 2021.
Omidubicel is also being evaluated in a phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937).
Expanding possibilities
Although umbilical cord blood stem cell grafts come from a readily available source and show greater tolerance across HLA barriers than other sources (such as bone marrow), the relatively low dose of stem cells in each unit results in delayed hematopoietic recovery, increased transplant-related morbidity and mortality, and longer hospitalizations, Dr. Sanz said.
Omidubicel consists of two cryopreserved fractions from a single cord blood unit. The product contains both noncultured CD133-negative cells, including T cells, and CD133-positive cells that are then expanded ex vivo for 21 days in the presence of nicotinamide.
“Nicotinamide increases stem and progenitor cells, inhibits differentiation and increases migration, bone marrow homing, and engraftment efficiency while preserving cellular functionality and phenotype,” Dr. Sanz explained during his presentation.
In an earlier phase 1/2 trial in 36 patients with high-risk hematologic malignancies, omidubicel was associated with hematopoietic engraftment lasting at least 10 years.
Details of phase 3 trial results
The global phase 3 trial was conducted in 125 patients (aged 13-65 years) with high-risk malignancies, including acute myeloid and lymphoblastic leukemias, myelodysplastic syndrome, chronic myeloid leukemia, lymphomas, and rare leukemias. These patients were all eligible for allogeneic stem cell transplantation but did not have matched donors.
Patients were randomly assigned to receive hematopoietic reconstitution with either omidubicel (n = 52) or standard cord blood (n = 58).
At 42 days of follow-up, the median time to neutrophil engraftment in the intention-to-treat (ITT) population, the primary endpoint, was 12 days with omidubicel versus 22 days with standard cord blood (P < .001).
In the as-treated population – the 108 patients who actually received omidubicel or standard cord blood – median time to engraftment was 10.0 versus 20.5 days, respectively (P < .001).
Rates of neutrophil engraftment at 42 days were 96% with omidubicel versus 89% with standard cord blood.
The secondary endpoint of time-to-platelet engraftment in the ITT population also favored omidubicel, with a cumulative day 42 incidence rate of 55%, compared with 35% with standard cord blood (P = .028).
In the as-treated population, median times to platelet engraftment were 37 days and 50 days, respectively (P = .023). The cumulative rates of platelet engraftment at 100 days of follow-up were 83% and 73%, respectively.
The incidence of grade 2 or 3 bacterial or invasive fungal infections by day 100 in the ITT population was 37% among patients who received omidubicel, compared with 57% for patients who received standard cord blood (P = .027). Viral infections occurred in 10% versus 26% of patients, respectively.
The incidence of acute graft versus host disease at day 100 was similar between treatment groups, and there was no significant difference at 1 year.
Relapse and nonrelapse mortality rates, as well as disease-free and overall survival rates also did not differ between groups.
In the first 100 days post transplant, patients who received omidubicel were alive and out of the hospital for a median of 60.5 days, compared with 48 days for patients who received standard cord blood (P = .005).
The study was funded by Gamida Cell. Dr. Sanz reported receiving research funding from the company and several others, and consulting fees, honoraria, speakers bureau activity, and travel expenses from other companies. Dr. DeFilipp reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Rucaparib extends PFS in BRCA-mutated ovarian cancer, with an exception
Investigator-assessed PFS in both an intention-to-treat (ITT) analysis and an efficacy analysis that excluded patients with BRCA reversion mutations was 7.4 months in the rucaparib arm, compared with 5.7 months in patients who received either platinum-based chemotherapy or weekly paclitaxel.
Among the 23 patients with BRCA reversion mutations, however, investigator-assessed PFS was 2.9 months with rucaparib and 5.5 months with chemotherapy.
Overall survival data were not mature at the time of data cutoff in September 2020.
“Although the numbers are very small, the results suggest that presence of a BRCA reversion mutation may predict a reduced benefit from rucaparib,” said Rebecca Kristeleit, MBChB, PhD, of Guy’s and St. Thomas’ NHS Foundation Trust in London.
She presented the findings from ARIEL4 at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11479).
Invited discussant Ursula Matulonis, MD, of the Dana-Farber Cancer Institute in Boston, commented that the “BRCA reversion mutation data from ARIEL4 is intriguing. Strategies to overcome and better understand this type of resistance mechanism are needed.”
Study rationale and details
Rucaparib is approved as monotherapy for patients with BRCA-mutated, relapsed ovarian cancer who have received at least two prior lines of platinum-based chemotherapy. The approval was based on results of two phase 1/2 studies. ARIEL4 is a phase 3 confirmatory study, designed in consultation with both the U.S. Food and Drug Administration and the European Medicines Agency.
Women with relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer with deleterious germline or somatic BRCA mutations were eligible for enrollment in ARIEL4. The patients had to have received at least two lines of chemotherapy, including at least one platinum-based regimen, with no prior PARP inhibitor or single-agent paclitaxel treatment.
Overall, 95% of patients had epithelial ovarian cancer, 3% had fallopian tube cancer, and 2% had primary peritoneal cancer. About 90% of cancers were serous in histology. Most patients (84%) had germline BRCA mutations, 16% had somatic mutations, and the status was unknown in the remaining patients.
Patients were randomized on a 2:1 basis to receive rucaparib at 600 mg twice daily (n = 233) or chemotherapy (n = 116), stratified by platinum sensitivity status. Patients assigned to chemotherapy whose disease was considered platinum resistant or partially platinum sensitive were assigned to weekly paclitaxel. Patients with fully platinum-sensitive disease were assigned to platinum-based single-agent or doublet chemotherapy. Treatment cycles were 28 days.
On radiologically confirmed disease progression or unacceptable toxicity, patients assigned to chemotherapy had the option to cross over to the rucaparib arm. The follow-up portion of the study began 28 days after the last treatment dose, with visits every 8 weeks thereafter.
Baseline characteristics in the ITT population were similar between arms. There were 13 patients in the rucaparib arm and 10 in the chemotherapy arm who had BRCA reversion mutations and were excluded from the efficacy population.
Efficacy and safety
Investigator-assessed PFS in the efficacy population was a median of 7.4 months with rucaparib and 5.7 months with chemotherapy, translating to a hazard ratio (HR) of 0.64 (P = .001). In the ITT population, the respective median PFS intervals were identical, although with a slightly less favorable HR of 0.67 (P = .002). In the 23 patients with BRCA reversion mutations, the median PFS was worse with rucaparib, at 2.9 months, compared with 5.5 months for chemotherapy. This translated to a HR of 2.77, although the 95% confidence interval was wide and crossed 1, likely due to the small sample size.
Among patients who had measurable disease at baseline, the overall response rate in the efficacy population was 40.3% with rucaparib and 32.3% with chemotherapy, a difference that was not statistically significant (P = .13). The overall response data were similar in the ITT population (37.9% and 30.2%, respectively).
In the efficacy population, the duration of response was significantly longer in the rucaparib arm, at a median of 9.4 months versus 7.2 months (HR, 0.59; 95% CI, 0.36-0.98). The respective median response durations were identical in the ITT population, but the HR was 0.56 (95% CI, 0.34-0.93).
In both the efficacy and ITT populations, global health status was virtually identical and unchanged from baseline in both treatment arms through cycle 7.
Treatment-emergent adverse events (TEAEs) were more frequent with rucaparib. The most common TEAEs in the rucaparib and chemotherapy arms, respectively, were anemia/decreased hemoglobin (53.9% and 31.9%), nausea (53.4% and 31.9%), asthenia/fatigue (49.6% and 44.2%), ALT/AST increase (34.5% and 11.5%), and vomiting (34.1% and 16.8%).
In all, 8.2% of patients in the rucaparib arm and 12.4% of those in the chemotherapy arm discontinued therapy due to TEAEs.
Four patients in the rucaparib arm developed myelodysplastic syndrome or acute myeloid leukemia – one during treatment and three during follow-up. There were no cases of myelodysplastic syndrome or acute myeloid leukemia in patients who received chemotherapy.
“Data from ARIEL4 fits the paradigm that single-agent activity of PARP inhibitors in BRCA-mutated, recurrent ovarian cancer may be comparable to chemotherapy, and may, at times, be superior, depending on the study population, trial design, and treatment for control patients,” Dr. Matulonis said.
The study was funded by Clovis Oncology. Dr. Kristeleit disclosed relationships with Clovis, Roche, and Tesaro. Dr. Matulonis disclosed relationships with Novartis, Merck, and Immunogen.
Investigator-assessed PFS in both an intention-to-treat (ITT) analysis and an efficacy analysis that excluded patients with BRCA reversion mutations was 7.4 months in the rucaparib arm, compared with 5.7 months in patients who received either platinum-based chemotherapy or weekly paclitaxel.
Among the 23 patients with BRCA reversion mutations, however, investigator-assessed PFS was 2.9 months with rucaparib and 5.5 months with chemotherapy.
Overall survival data were not mature at the time of data cutoff in September 2020.
“Although the numbers are very small, the results suggest that presence of a BRCA reversion mutation may predict a reduced benefit from rucaparib,” said Rebecca Kristeleit, MBChB, PhD, of Guy’s and St. Thomas’ NHS Foundation Trust in London.
She presented the findings from ARIEL4 at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11479).
Invited discussant Ursula Matulonis, MD, of the Dana-Farber Cancer Institute in Boston, commented that the “BRCA reversion mutation data from ARIEL4 is intriguing. Strategies to overcome and better understand this type of resistance mechanism are needed.”
Study rationale and details
Rucaparib is approved as monotherapy for patients with BRCA-mutated, relapsed ovarian cancer who have received at least two prior lines of platinum-based chemotherapy. The approval was based on results of two phase 1/2 studies. ARIEL4 is a phase 3 confirmatory study, designed in consultation with both the U.S. Food and Drug Administration and the European Medicines Agency.
Women with relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer with deleterious germline or somatic BRCA mutations were eligible for enrollment in ARIEL4. The patients had to have received at least two lines of chemotherapy, including at least one platinum-based regimen, with no prior PARP inhibitor or single-agent paclitaxel treatment.
Overall, 95% of patients had epithelial ovarian cancer, 3% had fallopian tube cancer, and 2% had primary peritoneal cancer. About 90% of cancers were serous in histology. Most patients (84%) had germline BRCA mutations, 16% had somatic mutations, and the status was unknown in the remaining patients.
Patients were randomized on a 2:1 basis to receive rucaparib at 600 mg twice daily (n = 233) or chemotherapy (n = 116), stratified by platinum sensitivity status. Patients assigned to chemotherapy whose disease was considered platinum resistant or partially platinum sensitive were assigned to weekly paclitaxel. Patients with fully platinum-sensitive disease were assigned to platinum-based single-agent or doublet chemotherapy. Treatment cycles were 28 days.
On radiologically confirmed disease progression or unacceptable toxicity, patients assigned to chemotherapy had the option to cross over to the rucaparib arm. The follow-up portion of the study began 28 days after the last treatment dose, with visits every 8 weeks thereafter.
Baseline characteristics in the ITT population were similar between arms. There were 13 patients in the rucaparib arm and 10 in the chemotherapy arm who had BRCA reversion mutations and were excluded from the efficacy population.
Efficacy and safety
Investigator-assessed PFS in the efficacy population was a median of 7.4 months with rucaparib and 5.7 months with chemotherapy, translating to a hazard ratio (HR) of 0.64 (P = .001). In the ITT population, the respective median PFS intervals were identical, although with a slightly less favorable HR of 0.67 (P = .002). In the 23 patients with BRCA reversion mutations, the median PFS was worse with rucaparib, at 2.9 months, compared with 5.5 months for chemotherapy. This translated to a HR of 2.77, although the 95% confidence interval was wide and crossed 1, likely due to the small sample size.
Among patients who had measurable disease at baseline, the overall response rate in the efficacy population was 40.3% with rucaparib and 32.3% with chemotherapy, a difference that was not statistically significant (P = .13). The overall response data were similar in the ITT population (37.9% and 30.2%, respectively).
In the efficacy population, the duration of response was significantly longer in the rucaparib arm, at a median of 9.4 months versus 7.2 months (HR, 0.59; 95% CI, 0.36-0.98). The respective median response durations were identical in the ITT population, but the HR was 0.56 (95% CI, 0.34-0.93).
In both the efficacy and ITT populations, global health status was virtually identical and unchanged from baseline in both treatment arms through cycle 7.
Treatment-emergent adverse events (TEAEs) were more frequent with rucaparib. The most common TEAEs in the rucaparib and chemotherapy arms, respectively, were anemia/decreased hemoglobin (53.9% and 31.9%), nausea (53.4% and 31.9%), asthenia/fatigue (49.6% and 44.2%), ALT/AST increase (34.5% and 11.5%), and vomiting (34.1% and 16.8%).
In all, 8.2% of patients in the rucaparib arm and 12.4% of those in the chemotherapy arm discontinued therapy due to TEAEs.
Four patients in the rucaparib arm developed myelodysplastic syndrome or acute myeloid leukemia – one during treatment and three during follow-up. There were no cases of myelodysplastic syndrome or acute myeloid leukemia in patients who received chemotherapy.
“Data from ARIEL4 fits the paradigm that single-agent activity of PARP inhibitors in BRCA-mutated, recurrent ovarian cancer may be comparable to chemotherapy, and may, at times, be superior, depending on the study population, trial design, and treatment for control patients,” Dr. Matulonis said.
The study was funded by Clovis Oncology. Dr. Kristeleit disclosed relationships with Clovis, Roche, and Tesaro. Dr. Matulonis disclosed relationships with Novartis, Merck, and Immunogen.
Investigator-assessed PFS in both an intention-to-treat (ITT) analysis and an efficacy analysis that excluded patients with BRCA reversion mutations was 7.4 months in the rucaparib arm, compared with 5.7 months in patients who received either platinum-based chemotherapy or weekly paclitaxel.
Among the 23 patients with BRCA reversion mutations, however, investigator-assessed PFS was 2.9 months with rucaparib and 5.5 months with chemotherapy.
Overall survival data were not mature at the time of data cutoff in September 2020.
“Although the numbers are very small, the results suggest that presence of a BRCA reversion mutation may predict a reduced benefit from rucaparib,” said Rebecca Kristeleit, MBChB, PhD, of Guy’s and St. Thomas’ NHS Foundation Trust in London.
She presented the findings from ARIEL4 at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11479).
Invited discussant Ursula Matulonis, MD, of the Dana-Farber Cancer Institute in Boston, commented that the “BRCA reversion mutation data from ARIEL4 is intriguing. Strategies to overcome and better understand this type of resistance mechanism are needed.”
Study rationale and details
Rucaparib is approved as monotherapy for patients with BRCA-mutated, relapsed ovarian cancer who have received at least two prior lines of platinum-based chemotherapy. The approval was based on results of two phase 1/2 studies. ARIEL4 is a phase 3 confirmatory study, designed in consultation with both the U.S. Food and Drug Administration and the European Medicines Agency.
Women with relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer with deleterious germline or somatic BRCA mutations were eligible for enrollment in ARIEL4. The patients had to have received at least two lines of chemotherapy, including at least one platinum-based regimen, with no prior PARP inhibitor or single-agent paclitaxel treatment.
Overall, 95% of patients had epithelial ovarian cancer, 3% had fallopian tube cancer, and 2% had primary peritoneal cancer. About 90% of cancers were serous in histology. Most patients (84%) had germline BRCA mutations, 16% had somatic mutations, and the status was unknown in the remaining patients.
Patients were randomized on a 2:1 basis to receive rucaparib at 600 mg twice daily (n = 233) or chemotherapy (n = 116), stratified by platinum sensitivity status. Patients assigned to chemotherapy whose disease was considered platinum resistant or partially platinum sensitive were assigned to weekly paclitaxel. Patients with fully platinum-sensitive disease were assigned to platinum-based single-agent or doublet chemotherapy. Treatment cycles were 28 days.
On radiologically confirmed disease progression or unacceptable toxicity, patients assigned to chemotherapy had the option to cross over to the rucaparib arm. The follow-up portion of the study began 28 days after the last treatment dose, with visits every 8 weeks thereafter.
Baseline characteristics in the ITT population were similar between arms. There were 13 patients in the rucaparib arm and 10 in the chemotherapy arm who had BRCA reversion mutations and were excluded from the efficacy population.
Efficacy and safety
Investigator-assessed PFS in the efficacy population was a median of 7.4 months with rucaparib and 5.7 months with chemotherapy, translating to a hazard ratio (HR) of 0.64 (P = .001). In the ITT population, the respective median PFS intervals were identical, although with a slightly less favorable HR of 0.67 (P = .002). In the 23 patients with BRCA reversion mutations, the median PFS was worse with rucaparib, at 2.9 months, compared with 5.5 months for chemotherapy. This translated to a HR of 2.77, although the 95% confidence interval was wide and crossed 1, likely due to the small sample size.
Among patients who had measurable disease at baseline, the overall response rate in the efficacy population was 40.3% with rucaparib and 32.3% with chemotherapy, a difference that was not statistically significant (P = .13). The overall response data were similar in the ITT population (37.9% and 30.2%, respectively).
In the efficacy population, the duration of response was significantly longer in the rucaparib arm, at a median of 9.4 months versus 7.2 months (HR, 0.59; 95% CI, 0.36-0.98). The respective median response durations were identical in the ITT population, but the HR was 0.56 (95% CI, 0.34-0.93).
In both the efficacy and ITT populations, global health status was virtually identical and unchanged from baseline in both treatment arms through cycle 7.
Treatment-emergent adverse events (TEAEs) were more frequent with rucaparib. The most common TEAEs in the rucaparib and chemotherapy arms, respectively, were anemia/decreased hemoglobin (53.9% and 31.9%), nausea (53.4% and 31.9%), asthenia/fatigue (49.6% and 44.2%), ALT/AST increase (34.5% and 11.5%), and vomiting (34.1% and 16.8%).
In all, 8.2% of patients in the rucaparib arm and 12.4% of those in the chemotherapy arm discontinued therapy due to TEAEs.
Four patients in the rucaparib arm developed myelodysplastic syndrome or acute myeloid leukemia – one during treatment and three during follow-up. There were no cases of myelodysplastic syndrome or acute myeloid leukemia in patients who received chemotherapy.
“Data from ARIEL4 fits the paradigm that single-agent activity of PARP inhibitors in BRCA-mutated, recurrent ovarian cancer may be comparable to chemotherapy, and may, at times, be superior, depending on the study population, trial design, and treatment for control patients,” Dr. Matulonis said.
The study was funded by Clovis Oncology. Dr. Kristeleit disclosed relationships with Clovis, Roche, and Tesaro. Dr. Matulonis disclosed relationships with Novartis, Merck, and Immunogen.
FROM SGO 2021
GVHD prophylaxis: Similar outcomes with PTCy and ATG
A newer regimen was no more effective than an older regimen when both were compared for graft versus host disease (GVHD) prophylaxis in patients who underwent reduced-intensity conditioning followed by a hematopoietic stem cell transplant (HSCT) from a 10/10 HLA-matched related or unrelated donor.
These results come from a multicenter randomized trial that compared posttransplant cyclophosphamide (PTCy) to antithymocyte globulin (ATG), which has been used for decades.
There were no significant differences between the two in either disease-free or overall survival, GVHD-free relapse-free survival (GRFS), or nonrelapse mortality, reported lead investigator Eolia Brissot, MD, of Hôpital Saint-Antoine, Sorbonne University, Paris.
Her presentation was judged ‘top abstract’ at the annual meeting of the European Society for Blood and Marrow Transplantation (EBMT), held virtually because of the pandemic.
ATG has been used for more than 30 years for GVHD prophylaxis in allogeneic HSCT. In contrast, PTCy is the new kid on the block, developed to facilitate haploidentical transplants using unmanipulated bone marrow cells to act as a method for selective allodepletion in vivo.
“PTCy [has proved] to be effective in preventing both acute and chronic GVHD,” Dr. Brissot said. “However, controversial outcome data remain when comparing PTCy and ATG according to the type of donors.”
Until now, she noted, there have been no prospective randomized data available for patients with donors (related or unrelated) that have 10 of 10 matched human leukocyte antigen (HLA) alleles. Hence, these were the patients studied in this latest trial, and in this population both regimens showed similar outcomes.
A bone marrow transplant specialist who was not involved in the study said that it’s a good first step.
“This is an important study to gain preliminary data to design a larger, subsequent phase 3 study,” said Zachariah DeFilipp, MD, of Mass General Cancer Center in Boston.
“The use of ATG as part of GVHD prophylaxis is common at many centers, especially in Europe, “ he explained. “The use of posttransplant cyclophosphamide is being expanded to more settings with transplant, beyond haploidentical transplant.
“Further investigations comparing the use of PTCy to ATG will help determine whether PTCy should be more broadly adopted as a standard-of-care GVHD prophylaxis approach, given currently available regimens,” he said in an interview.
Study details
The randomized phase 2b study (NCT02876679), conducted in centers in 11 cities in France, compared PTCy with ATG in patients with hematologic malignancies for whom a reduced-intensity allogeneic HSCT was indicated. This included patients aged 50 and older, and/or heavily pretreated patients who received an autologous HSCT or more than two prior lines of chemotherapy before allogeneic HSCT, as well as patients with poor performance status due to significant medical comorbidities.
Excluded from the trial were patients with creatinine clearance less than 30 mL/min; bilirubin or liver amino transferases more than three times the upper limit of normal; cardiac ejection fraction less than 40%; or pulmonary impairment with less than 50% lung carbon monoxide diffusing capacity.
Of 90 patients enrolled, 1 experienced a relapse before randomization, and the remaining 89 patients were assigned to either PTCy (experimental arm, 45 patients) or to ATG (control group, 44 patients).
Most patients had good performance status (Eastern Cooperative Oncology Group performance status 0 or 1). Diagnoses included acute myeloid and lymphoblastic leukemia, multiple myeloma, lymphomas, and myelodysplastic syndrome. The median age was 64 years, and the male to female ratio was about 2:1 in both groups.
All patients received “FB2” reduced-intensity conditioning with fludarabine30 mg/m2 per day for 4 days, and intravenous busulfan 130 mg/m2 per day for 2 days.
Patients in the experimental arm received cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplant. Patients in the control group received ATG 2.5 mg/kg per day on days 3 and 2 prior to transplant.
All patients also received cyclosporine A, and those who had unrelated donors also received mycophenolate mofetil. In all, 39% of patients received cells from matched sibling donors, and 61% received cells from matched unrelated donors.
No significant differences seen
At 12 months of follow-up, there was no significant difference between the trial arms in the primary endpoint of GRFS, a composite of grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death. The rates of GRFS were 52.2% with PTCy vs. 45% with ATG.
Rates of disease-free survival were 68.5% with PTCy and 67.1% with ATG. The respective 12-month overall survival rates were 78.9% and 80.4%, respectively. The differences were not statistically significant.
The incidence of relapse at 1 year was 22.1% in the ATG group vs. 17.6% in the PTCy group. Respective nonrelapse mortality rates were 10.8% for the ATG group and 14% for the PTCy group. Neither difference was statistically significant.
There were also no significant between-group differences in the incidence at 12-month follow-up of either acute GVHD (34.9% PTCy arm vs. 24.3% ATG arm for grades II-IV combined, and 9.3% PTCy vs. 2.7% ATG for grades III or IV) or chronic GVHD (30.2% ATG vs. 26% PTCy).
The safety analysis showed no significant between-group differences in selected adverse events, including Epstein-Barr viral reactivation, cytomegalovirus reactivation, cardiac adverse events, or hemorrhagic cystitis.
The study was supported by Hospitals of Paris. Dr. Brissot and Dr. DeFilipp have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A newer regimen was no more effective than an older regimen when both were compared for graft versus host disease (GVHD) prophylaxis in patients who underwent reduced-intensity conditioning followed by a hematopoietic stem cell transplant (HSCT) from a 10/10 HLA-matched related or unrelated donor.
These results come from a multicenter randomized trial that compared posttransplant cyclophosphamide (PTCy) to antithymocyte globulin (ATG), which has been used for decades.
There were no significant differences between the two in either disease-free or overall survival, GVHD-free relapse-free survival (GRFS), or nonrelapse mortality, reported lead investigator Eolia Brissot, MD, of Hôpital Saint-Antoine, Sorbonne University, Paris.
Her presentation was judged ‘top abstract’ at the annual meeting of the European Society for Blood and Marrow Transplantation (EBMT), held virtually because of the pandemic.
ATG has been used for more than 30 years for GVHD prophylaxis in allogeneic HSCT. In contrast, PTCy is the new kid on the block, developed to facilitate haploidentical transplants using unmanipulated bone marrow cells to act as a method for selective allodepletion in vivo.
“PTCy [has proved] to be effective in preventing both acute and chronic GVHD,” Dr. Brissot said. “However, controversial outcome data remain when comparing PTCy and ATG according to the type of donors.”
Until now, she noted, there have been no prospective randomized data available for patients with donors (related or unrelated) that have 10 of 10 matched human leukocyte antigen (HLA) alleles. Hence, these were the patients studied in this latest trial, and in this population both regimens showed similar outcomes.
A bone marrow transplant specialist who was not involved in the study said that it’s a good first step.
“This is an important study to gain preliminary data to design a larger, subsequent phase 3 study,” said Zachariah DeFilipp, MD, of Mass General Cancer Center in Boston.
“The use of ATG as part of GVHD prophylaxis is common at many centers, especially in Europe, “ he explained. “The use of posttransplant cyclophosphamide is being expanded to more settings with transplant, beyond haploidentical transplant.
“Further investigations comparing the use of PTCy to ATG will help determine whether PTCy should be more broadly adopted as a standard-of-care GVHD prophylaxis approach, given currently available regimens,” he said in an interview.
Study details
The randomized phase 2b study (NCT02876679), conducted in centers in 11 cities in France, compared PTCy with ATG in patients with hematologic malignancies for whom a reduced-intensity allogeneic HSCT was indicated. This included patients aged 50 and older, and/or heavily pretreated patients who received an autologous HSCT or more than two prior lines of chemotherapy before allogeneic HSCT, as well as patients with poor performance status due to significant medical comorbidities.
Excluded from the trial were patients with creatinine clearance less than 30 mL/min; bilirubin or liver amino transferases more than three times the upper limit of normal; cardiac ejection fraction less than 40%; or pulmonary impairment with less than 50% lung carbon monoxide diffusing capacity.
Of 90 patients enrolled, 1 experienced a relapse before randomization, and the remaining 89 patients were assigned to either PTCy (experimental arm, 45 patients) or to ATG (control group, 44 patients).
Most patients had good performance status (Eastern Cooperative Oncology Group performance status 0 or 1). Diagnoses included acute myeloid and lymphoblastic leukemia, multiple myeloma, lymphomas, and myelodysplastic syndrome. The median age was 64 years, and the male to female ratio was about 2:1 in both groups.
All patients received “FB2” reduced-intensity conditioning with fludarabine30 mg/m2 per day for 4 days, and intravenous busulfan 130 mg/m2 per day for 2 days.
Patients in the experimental arm received cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplant. Patients in the control group received ATG 2.5 mg/kg per day on days 3 and 2 prior to transplant.
All patients also received cyclosporine A, and those who had unrelated donors also received mycophenolate mofetil. In all, 39% of patients received cells from matched sibling donors, and 61% received cells from matched unrelated donors.
No significant differences seen
At 12 months of follow-up, there was no significant difference between the trial arms in the primary endpoint of GRFS, a composite of grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death. The rates of GRFS were 52.2% with PTCy vs. 45% with ATG.
Rates of disease-free survival were 68.5% with PTCy and 67.1% with ATG. The respective 12-month overall survival rates were 78.9% and 80.4%, respectively. The differences were not statistically significant.
The incidence of relapse at 1 year was 22.1% in the ATG group vs. 17.6% in the PTCy group. Respective nonrelapse mortality rates were 10.8% for the ATG group and 14% for the PTCy group. Neither difference was statistically significant.
There were also no significant between-group differences in the incidence at 12-month follow-up of either acute GVHD (34.9% PTCy arm vs. 24.3% ATG arm for grades II-IV combined, and 9.3% PTCy vs. 2.7% ATG for grades III or IV) or chronic GVHD (30.2% ATG vs. 26% PTCy).
The safety analysis showed no significant between-group differences in selected adverse events, including Epstein-Barr viral reactivation, cytomegalovirus reactivation, cardiac adverse events, or hemorrhagic cystitis.
The study was supported by Hospitals of Paris. Dr. Brissot and Dr. DeFilipp have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A newer regimen was no more effective than an older regimen when both were compared for graft versus host disease (GVHD) prophylaxis in patients who underwent reduced-intensity conditioning followed by a hematopoietic stem cell transplant (HSCT) from a 10/10 HLA-matched related or unrelated donor.
These results come from a multicenter randomized trial that compared posttransplant cyclophosphamide (PTCy) to antithymocyte globulin (ATG), which has been used for decades.
There were no significant differences between the two in either disease-free or overall survival, GVHD-free relapse-free survival (GRFS), or nonrelapse mortality, reported lead investigator Eolia Brissot, MD, of Hôpital Saint-Antoine, Sorbonne University, Paris.
Her presentation was judged ‘top abstract’ at the annual meeting of the European Society for Blood and Marrow Transplantation (EBMT), held virtually because of the pandemic.
ATG has been used for more than 30 years for GVHD prophylaxis in allogeneic HSCT. In contrast, PTCy is the new kid on the block, developed to facilitate haploidentical transplants using unmanipulated bone marrow cells to act as a method for selective allodepletion in vivo.
“PTCy [has proved] to be effective in preventing both acute and chronic GVHD,” Dr. Brissot said. “However, controversial outcome data remain when comparing PTCy and ATG according to the type of donors.”
Until now, she noted, there have been no prospective randomized data available for patients with donors (related or unrelated) that have 10 of 10 matched human leukocyte antigen (HLA) alleles. Hence, these were the patients studied in this latest trial, and in this population both regimens showed similar outcomes.
A bone marrow transplant specialist who was not involved in the study said that it’s a good first step.
“This is an important study to gain preliminary data to design a larger, subsequent phase 3 study,” said Zachariah DeFilipp, MD, of Mass General Cancer Center in Boston.
“The use of ATG as part of GVHD prophylaxis is common at many centers, especially in Europe, “ he explained. “The use of posttransplant cyclophosphamide is being expanded to more settings with transplant, beyond haploidentical transplant.
“Further investigations comparing the use of PTCy to ATG will help determine whether PTCy should be more broadly adopted as a standard-of-care GVHD prophylaxis approach, given currently available regimens,” he said in an interview.
Study details
The randomized phase 2b study (NCT02876679), conducted in centers in 11 cities in France, compared PTCy with ATG in patients with hematologic malignancies for whom a reduced-intensity allogeneic HSCT was indicated. This included patients aged 50 and older, and/or heavily pretreated patients who received an autologous HSCT or more than two prior lines of chemotherapy before allogeneic HSCT, as well as patients with poor performance status due to significant medical comorbidities.
Excluded from the trial were patients with creatinine clearance less than 30 mL/min; bilirubin or liver amino transferases more than three times the upper limit of normal; cardiac ejection fraction less than 40%; or pulmonary impairment with less than 50% lung carbon monoxide diffusing capacity.
Of 90 patients enrolled, 1 experienced a relapse before randomization, and the remaining 89 patients were assigned to either PTCy (experimental arm, 45 patients) or to ATG (control group, 44 patients).
Most patients had good performance status (Eastern Cooperative Oncology Group performance status 0 or 1). Diagnoses included acute myeloid and lymphoblastic leukemia, multiple myeloma, lymphomas, and myelodysplastic syndrome. The median age was 64 years, and the male to female ratio was about 2:1 in both groups.
All patients received “FB2” reduced-intensity conditioning with fludarabine30 mg/m2 per day for 4 days, and intravenous busulfan 130 mg/m2 per day for 2 days.
Patients in the experimental arm received cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplant. Patients in the control group received ATG 2.5 mg/kg per day on days 3 and 2 prior to transplant.
All patients also received cyclosporine A, and those who had unrelated donors also received mycophenolate mofetil. In all, 39% of patients received cells from matched sibling donors, and 61% received cells from matched unrelated donors.
No significant differences seen
At 12 months of follow-up, there was no significant difference between the trial arms in the primary endpoint of GRFS, a composite of grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death. The rates of GRFS were 52.2% with PTCy vs. 45% with ATG.
Rates of disease-free survival were 68.5% with PTCy and 67.1% with ATG. The respective 12-month overall survival rates were 78.9% and 80.4%, respectively. The differences were not statistically significant.
The incidence of relapse at 1 year was 22.1% in the ATG group vs. 17.6% in the PTCy group. Respective nonrelapse mortality rates were 10.8% for the ATG group and 14% for the PTCy group. Neither difference was statistically significant.
There were also no significant between-group differences in the incidence at 12-month follow-up of either acute GVHD (34.9% PTCy arm vs. 24.3% ATG arm for grades II-IV combined, and 9.3% PTCy vs. 2.7% ATG for grades III or IV) or chronic GVHD (30.2% ATG vs. 26% PTCy).
The safety analysis showed no significant between-group differences in selected adverse events, including Epstein-Barr viral reactivation, cytomegalovirus reactivation, cardiac adverse events, or hemorrhagic cystitis.
The study was supported by Hospitals of Paris. Dr. Brissot and Dr. DeFilipp have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Close joint health monitoring essential with new hemophilia therapies
Novel therapies have transformed the treatment of hemophilia in recent decades, but these new approaches also raise new challenges for clinicians who monitor joint health in persons with hemophilia, a specialist said.
“Patient-reported outcomes should be combined with other, more objective outcome measures for joint health monitoring, and joint ultrasound is a promising tool for objective joint health monitoring, although, due to its relatively recent introduction in clinical practice, we lack objective data and standardization,” said Roberta Gualtierotti, MD, PhD, from the Università Degli Studi of Milan.
She reviewed the challenges and approaches to monitoring joint health in persons with hemophilia during the annual congress of the European Association for Haemophilia and Allied Disorders.
Over the last decades the target of hemophilia treatment has shifted from prolonging survival to improving joint health and quality of life, and care has improved with the introduction of novel therapies such as extended half-life replacement products, nonreplacement therapies, and gene therapy, she noted.
However, “due to different pharmacodynamics and pharmacokinetics profiles, the currently available therapies cannot be compared to each other on several levels,” Dr. Gualtierotti said.
Laboratory monitoring of replacement therapies with standard coagulation assays may be unreliable, and depending on the mechanism of action and type of administration of nonreplacement agents, patients may experience breakthrough bleeding, especially after traumatic injury, she said.
Until the specific noncoagulatory effects of factor VIII on bone and joint health is better understood, close monitoring of patients will be required, she added.
Outcome measures
Subjective measures of joint health include patient-reported bleeding rates and health-related quality of life. These are practical for home management, but patients may not be able to distinguish symptoms of acute joint bleeding from chronic arthritis pain, with the potential for either under- or overtreatment, and subjective reporting is likely to miss subclinical bleeding that can occur even when patients are on prophylaxis.
Health-related quality of life tools, whether generic or specific for hemophilia, are not sensitive to small improvements, and they are not always used in routine clinical practice.
Objective measures include physical examination with scoring according to the World Federation of Hemophilia (Gilbert Scale) score or Hemophilia Joint Health Score, but these measures have limited ability to identify early or subclinical joint abnormalities.
“Therefore, joint physical examination on its own is not a sufficient measure of treatment efficacy, and it should be used in combination with other tools more objective, such as imaging,” Dr. Gualtierotti said.
Get the picture?
Imaging with x-rays, MRI, and, recently in some centers, point-of-care ultrasound can provide clinicians with important real-time information about the joint stability and health.
Point-of-care ultrasound in particular offers promise as a practical tool, with no ionizing radiation and high sensitivity for synovial hyperplasia subclinical joint effusion. It’s relatively inexpensive, can be used to image multiple joints, and allows for ease of follow-up, she said. The technique requires specialized training, however, and there is a lack of prospective data about its utility in hemophilia.
Various ultrasound scoring systems have been proposed, and home-based ultrasound is currently being explored in several clinical trials, Dr. Gualtierotti noted.
Other avenues for remote joint health monitoring under consideration are serum or synovial biomarkers for joint bleeding and arthropathy that could be employed at bedside or at home, smartphone apps for breakthrough bleeding and patient-reported outcomes, and sensors for detecting abnormalities in gait that may signal joint dysfunction, she said.
Best practice
In the question-and-answer session following the talk, Fernando Zikan, MD, from the Federal University of Rio de Janeiro noted that, “in underdeveloped countries, we still find it very difficult to guide good practices for joint health control by the patient and family members. Which strategy do you think is fundamental for the patient to feel safe to notice changes in his body?”
“It would be useful to educate patients to come to the center whenever the patient has trauma and whenever an increase in his physical activity occurs. If this is far, a bedside ultrasound evaluation by the general practitioner could help avoid joint damage. Finally, a correct rehabilitation is fundamental,” Dr. Gualtierotti replied.
Asked by several others whether she used ultrasound in her daily practice, Dr. Gualtierotti said that “we use joint ultrasound in our clinical practice in the regular annual check-up examination and whenever the patient suspects and reports hemarthrosis.”
Dr. Gualtierotti reported participation in advisory boards for Biomarin, Pfizer, Bayer, and Takeda, and in educational seminars sponsored by Pfizer, Sobi, and Roche. She has received support for congress travel and/or attendance by Bayer and Pfizer. Dr. Zikan reported no relevant disclosures.
Novel therapies have transformed the treatment of hemophilia in recent decades, but these new approaches also raise new challenges for clinicians who monitor joint health in persons with hemophilia, a specialist said.
“Patient-reported outcomes should be combined with other, more objective outcome measures for joint health monitoring, and joint ultrasound is a promising tool for objective joint health monitoring, although, due to its relatively recent introduction in clinical practice, we lack objective data and standardization,” said Roberta Gualtierotti, MD, PhD, from the Università Degli Studi of Milan.
She reviewed the challenges and approaches to monitoring joint health in persons with hemophilia during the annual congress of the European Association for Haemophilia and Allied Disorders.
Over the last decades the target of hemophilia treatment has shifted from prolonging survival to improving joint health and quality of life, and care has improved with the introduction of novel therapies such as extended half-life replacement products, nonreplacement therapies, and gene therapy, she noted.
However, “due to different pharmacodynamics and pharmacokinetics profiles, the currently available therapies cannot be compared to each other on several levels,” Dr. Gualtierotti said.
Laboratory monitoring of replacement therapies with standard coagulation assays may be unreliable, and depending on the mechanism of action and type of administration of nonreplacement agents, patients may experience breakthrough bleeding, especially after traumatic injury, she said.
Until the specific noncoagulatory effects of factor VIII on bone and joint health is better understood, close monitoring of patients will be required, she added.
Outcome measures
Subjective measures of joint health include patient-reported bleeding rates and health-related quality of life. These are practical for home management, but patients may not be able to distinguish symptoms of acute joint bleeding from chronic arthritis pain, with the potential for either under- or overtreatment, and subjective reporting is likely to miss subclinical bleeding that can occur even when patients are on prophylaxis.
Health-related quality of life tools, whether generic or specific for hemophilia, are not sensitive to small improvements, and they are not always used in routine clinical practice.
Objective measures include physical examination with scoring according to the World Federation of Hemophilia (Gilbert Scale) score or Hemophilia Joint Health Score, but these measures have limited ability to identify early or subclinical joint abnormalities.
“Therefore, joint physical examination on its own is not a sufficient measure of treatment efficacy, and it should be used in combination with other tools more objective, such as imaging,” Dr. Gualtierotti said.
Get the picture?
Imaging with x-rays, MRI, and, recently in some centers, point-of-care ultrasound can provide clinicians with important real-time information about the joint stability and health.
Point-of-care ultrasound in particular offers promise as a practical tool, with no ionizing radiation and high sensitivity for synovial hyperplasia subclinical joint effusion. It’s relatively inexpensive, can be used to image multiple joints, and allows for ease of follow-up, she said. The technique requires specialized training, however, and there is a lack of prospective data about its utility in hemophilia.
Various ultrasound scoring systems have been proposed, and home-based ultrasound is currently being explored in several clinical trials, Dr. Gualtierotti noted.
Other avenues for remote joint health monitoring under consideration are serum or synovial biomarkers for joint bleeding and arthropathy that could be employed at bedside or at home, smartphone apps for breakthrough bleeding and patient-reported outcomes, and sensors for detecting abnormalities in gait that may signal joint dysfunction, she said.
Best practice
In the question-and-answer session following the talk, Fernando Zikan, MD, from the Federal University of Rio de Janeiro noted that, “in underdeveloped countries, we still find it very difficult to guide good practices for joint health control by the patient and family members. Which strategy do you think is fundamental for the patient to feel safe to notice changes in his body?”
“It would be useful to educate patients to come to the center whenever the patient has trauma and whenever an increase in his physical activity occurs. If this is far, a bedside ultrasound evaluation by the general practitioner could help avoid joint damage. Finally, a correct rehabilitation is fundamental,” Dr. Gualtierotti replied.
Asked by several others whether she used ultrasound in her daily practice, Dr. Gualtierotti said that “we use joint ultrasound in our clinical practice in the regular annual check-up examination and whenever the patient suspects and reports hemarthrosis.”
Dr. Gualtierotti reported participation in advisory boards for Biomarin, Pfizer, Bayer, and Takeda, and in educational seminars sponsored by Pfizer, Sobi, and Roche. She has received support for congress travel and/or attendance by Bayer and Pfizer. Dr. Zikan reported no relevant disclosures.
Novel therapies have transformed the treatment of hemophilia in recent decades, but these new approaches also raise new challenges for clinicians who monitor joint health in persons with hemophilia, a specialist said.
“Patient-reported outcomes should be combined with other, more objective outcome measures for joint health monitoring, and joint ultrasound is a promising tool for objective joint health monitoring, although, due to its relatively recent introduction in clinical practice, we lack objective data and standardization,” said Roberta Gualtierotti, MD, PhD, from the Università Degli Studi of Milan.
She reviewed the challenges and approaches to monitoring joint health in persons with hemophilia during the annual congress of the European Association for Haemophilia and Allied Disorders.
Over the last decades the target of hemophilia treatment has shifted from prolonging survival to improving joint health and quality of life, and care has improved with the introduction of novel therapies such as extended half-life replacement products, nonreplacement therapies, and gene therapy, she noted.
However, “due to different pharmacodynamics and pharmacokinetics profiles, the currently available therapies cannot be compared to each other on several levels,” Dr. Gualtierotti said.
Laboratory monitoring of replacement therapies with standard coagulation assays may be unreliable, and depending on the mechanism of action and type of administration of nonreplacement agents, patients may experience breakthrough bleeding, especially after traumatic injury, she said.
Until the specific noncoagulatory effects of factor VIII on bone and joint health is better understood, close monitoring of patients will be required, she added.
Outcome measures
Subjective measures of joint health include patient-reported bleeding rates and health-related quality of life. These are practical for home management, but patients may not be able to distinguish symptoms of acute joint bleeding from chronic arthritis pain, with the potential for either under- or overtreatment, and subjective reporting is likely to miss subclinical bleeding that can occur even when patients are on prophylaxis.
Health-related quality of life tools, whether generic or specific for hemophilia, are not sensitive to small improvements, and they are not always used in routine clinical practice.
Objective measures include physical examination with scoring according to the World Federation of Hemophilia (Gilbert Scale) score or Hemophilia Joint Health Score, but these measures have limited ability to identify early or subclinical joint abnormalities.
“Therefore, joint physical examination on its own is not a sufficient measure of treatment efficacy, and it should be used in combination with other tools more objective, such as imaging,” Dr. Gualtierotti said.
Get the picture?
Imaging with x-rays, MRI, and, recently in some centers, point-of-care ultrasound can provide clinicians with important real-time information about the joint stability and health.
Point-of-care ultrasound in particular offers promise as a practical tool, with no ionizing radiation and high sensitivity for synovial hyperplasia subclinical joint effusion. It’s relatively inexpensive, can be used to image multiple joints, and allows for ease of follow-up, she said. The technique requires specialized training, however, and there is a lack of prospective data about its utility in hemophilia.
Various ultrasound scoring systems have been proposed, and home-based ultrasound is currently being explored in several clinical trials, Dr. Gualtierotti noted.
Other avenues for remote joint health monitoring under consideration are serum or synovial biomarkers for joint bleeding and arthropathy that could be employed at bedside or at home, smartphone apps for breakthrough bleeding and patient-reported outcomes, and sensors for detecting abnormalities in gait that may signal joint dysfunction, she said.
Best practice
In the question-and-answer session following the talk, Fernando Zikan, MD, from the Federal University of Rio de Janeiro noted that, “in underdeveloped countries, we still find it very difficult to guide good practices for joint health control by the patient and family members. Which strategy do you think is fundamental for the patient to feel safe to notice changes in his body?”
“It would be useful to educate patients to come to the center whenever the patient has trauma and whenever an increase in his physical activity occurs. If this is far, a bedside ultrasound evaluation by the general practitioner could help avoid joint damage. Finally, a correct rehabilitation is fundamental,” Dr. Gualtierotti replied.
Asked by several others whether she used ultrasound in her daily practice, Dr. Gualtierotti said that “we use joint ultrasound in our clinical practice in the regular annual check-up examination and whenever the patient suspects and reports hemarthrosis.”
Dr. Gualtierotti reported participation in advisory boards for Biomarin, Pfizer, Bayer, and Takeda, and in educational seminars sponsored by Pfizer, Sobi, and Roche. She has received support for congress travel and/or attendance by Bayer and Pfizer. Dr. Zikan reported no relevant disclosures.
FROM EAHAD 2021
Joint pain in patients with hemophilia may be neuropathic
Nearly one-third of persons with hemophilia had neuropathic pain or altered central pain mechanisms, investigators in a small study found.
Among 30 patients with hemophilia, 9 (30%) had scores of 4 or greater on the 10-point Diabetic Neuropathy 4 (DN4) scale, indicating significant neuropathic pain, reported Nathalie Roussel, PhD, from the University of Antwerp (Belgium), at the annual congress of the European Association for Haemophilia and Allied Disorders.
“The results of this study show us that a large difference exists in pain assessments when we have consecutive sample of patients with hemophilia. These results also show that there are subgroups of patients with altered central pain mechanisms and other subgroups with neuropathic pain, and patients with neuropathic pain have a significantly worse quality of life that is not associated with joint structure and joint function,” she said.
“This is a very good abstract in my opinion, and it deserves more study,” commented hemophilia specialist Rajiv K. Pruthi, MBBS, from the Mayo Clinic in Rochester, Minn., who was not involved in the study.
Structural and functional tests
To get a better understanding of the complexities of ankle pain in persons with hemophilia, Dr. Roussel and colleagues recruited 30 adults followed at their center for moderate or severe hemophilia A or B who were on replacement therapy with factor VIII or factor IX concentrate.
They used MRI without contrast to look for structural alterations in both the talocrural and subtalar joints of both ankles in all patients using the International Prophylaxis Study Group Score, adapted for subtalar joint assessment.
The investigators also used the hemophilia joint health score to assess joint funding, and tests for limits on physical activity, including the Timed Up and Go Test, 2-minute walk test, and Hemophilia Activities Lists.
In addition, they assessed pain with Quantitative Sensory Testing, a noninvasive method for evaluating patient responses to heat, cold, and mechanical pressure. Other measures included questionnaires regarding neuropathic pain and quality of life.
The participants included 23 patients with severe and 3 with moderate hemophilia A, and 1 patient with severe and 3 with moderate hemophilia B. The mean patient age was 39.4 years.
In all, 24 of the 30 patients (80%) were on prophylaxis, and 9 (30%) reported using pain medications; 25 patients reported having some degree of pain.
On MRI, 48/60 (80%) of talocrural joints imaged had pathological findings, as did 41 of 60 (68%) subtalar joints.
“Despite the fact that these patients do not all suffer from ankle joint pain, a lot of them have signs of joint pathology,” Dr. Roussel said.
On the Brief Pain Inventory, only 5 patients had no reported pain, but 14 patients reported either three, five, or six painful locations, and 20 out of 30 patients reported that their ankles were the most affected joints.
Although the sample size was not large enough for statistical comparisons, there were also large variations in pain perception across hemophilia severity.
“This is an important finding, that also patients with moderate hemophilia can have intense pain,” Dr. Roussel said.
On the DN4 questionnaire, nine patients had scores of 4 or greater, indicating that their pain was neuropathic in origin.
When they compared the patients with neuropathic pain with those suffering from nonneuropathic pain, the investigators observed similar structural and joint function between the groups, but significantly worse reported quality of life for patients with neuropathic pain.
“This is a finding that merits further attention,” she commented.
In correlation analyses, the investigators also found that MRI scores did not correlate significantly with either hemophilia joint health score, physical function, participation in activities, or pressure pain thresholds.
Why the discrepancies?
Dr. Pruthi said in an interview that he has seen evidence from other studies showing that some patients with hemophilia who were on prophylaxis had MRI evidence of joint damage, while others who used on-demand therapy had none.
“That opens up a whole can of worms as to what are we dealing with here. Why do some patients end up with damage and others don’t?” he asked.
He said that the finding that the origin of pain in a large proportion of patients was neuropathic rather than arthritic in origin was new to him.
“It raises a lot of good questions: maybe we need to be managing pain in these patients with nonnarcotic approaches, and in this day and age with the opioid crisis it’s even more important to do that,” he said.
He hypothesized that degenerative arthritis may irritate nearby nerves, resulting in neuropathic pain.
The study was funded by EAHAD, with support from participating institutions. Dr. Roussel and Dr. Pruthi reported no conflicts of interest to declare.
Nearly one-third of persons with hemophilia had neuropathic pain or altered central pain mechanisms, investigators in a small study found.
Among 30 patients with hemophilia, 9 (30%) had scores of 4 or greater on the 10-point Diabetic Neuropathy 4 (DN4) scale, indicating significant neuropathic pain, reported Nathalie Roussel, PhD, from the University of Antwerp (Belgium), at the annual congress of the European Association for Haemophilia and Allied Disorders.
“The results of this study show us that a large difference exists in pain assessments when we have consecutive sample of patients with hemophilia. These results also show that there are subgroups of patients with altered central pain mechanisms and other subgroups with neuropathic pain, and patients with neuropathic pain have a significantly worse quality of life that is not associated with joint structure and joint function,” she said.
“This is a very good abstract in my opinion, and it deserves more study,” commented hemophilia specialist Rajiv K. Pruthi, MBBS, from the Mayo Clinic in Rochester, Minn., who was not involved in the study.
Structural and functional tests
To get a better understanding of the complexities of ankle pain in persons with hemophilia, Dr. Roussel and colleagues recruited 30 adults followed at their center for moderate or severe hemophilia A or B who were on replacement therapy with factor VIII or factor IX concentrate.
They used MRI without contrast to look for structural alterations in both the talocrural and subtalar joints of both ankles in all patients using the International Prophylaxis Study Group Score, adapted for subtalar joint assessment.
The investigators also used the hemophilia joint health score to assess joint funding, and tests for limits on physical activity, including the Timed Up and Go Test, 2-minute walk test, and Hemophilia Activities Lists.
In addition, they assessed pain with Quantitative Sensory Testing, a noninvasive method for evaluating patient responses to heat, cold, and mechanical pressure. Other measures included questionnaires regarding neuropathic pain and quality of life.
The participants included 23 patients with severe and 3 with moderate hemophilia A, and 1 patient with severe and 3 with moderate hemophilia B. The mean patient age was 39.4 years.
In all, 24 of the 30 patients (80%) were on prophylaxis, and 9 (30%) reported using pain medications; 25 patients reported having some degree of pain.
On MRI, 48/60 (80%) of talocrural joints imaged had pathological findings, as did 41 of 60 (68%) subtalar joints.
“Despite the fact that these patients do not all suffer from ankle joint pain, a lot of them have signs of joint pathology,” Dr. Roussel said.
On the Brief Pain Inventory, only 5 patients had no reported pain, but 14 patients reported either three, five, or six painful locations, and 20 out of 30 patients reported that their ankles were the most affected joints.
Although the sample size was not large enough for statistical comparisons, there were also large variations in pain perception across hemophilia severity.
“This is an important finding, that also patients with moderate hemophilia can have intense pain,” Dr. Roussel said.
On the DN4 questionnaire, nine patients had scores of 4 or greater, indicating that their pain was neuropathic in origin.
When they compared the patients with neuropathic pain with those suffering from nonneuropathic pain, the investigators observed similar structural and joint function between the groups, but significantly worse reported quality of life for patients with neuropathic pain.
“This is a finding that merits further attention,” she commented.
In correlation analyses, the investigators also found that MRI scores did not correlate significantly with either hemophilia joint health score, physical function, participation in activities, or pressure pain thresholds.
Why the discrepancies?
Dr. Pruthi said in an interview that he has seen evidence from other studies showing that some patients with hemophilia who were on prophylaxis had MRI evidence of joint damage, while others who used on-demand therapy had none.
“That opens up a whole can of worms as to what are we dealing with here. Why do some patients end up with damage and others don’t?” he asked.
He said that the finding that the origin of pain in a large proportion of patients was neuropathic rather than arthritic in origin was new to him.
“It raises a lot of good questions: maybe we need to be managing pain in these patients with nonnarcotic approaches, and in this day and age with the opioid crisis it’s even more important to do that,” he said.
He hypothesized that degenerative arthritis may irritate nearby nerves, resulting in neuropathic pain.
The study was funded by EAHAD, with support from participating institutions. Dr. Roussel and Dr. Pruthi reported no conflicts of interest to declare.
Nearly one-third of persons with hemophilia had neuropathic pain or altered central pain mechanisms, investigators in a small study found.
Among 30 patients with hemophilia, 9 (30%) had scores of 4 or greater on the 10-point Diabetic Neuropathy 4 (DN4) scale, indicating significant neuropathic pain, reported Nathalie Roussel, PhD, from the University of Antwerp (Belgium), at the annual congress of the European Association for Haemophilia and Allied Disorders.
“The results of this study show us that a large difference exists in pain assessments when we have consecutive sample of patients with hemophilia. These results also show that there are subgroups of patients with altered central pain mechanisms and other subgroups with neuropathic pain, and patients with neuropathic pain have a significantly worse quality of life that is not associated with joint structure and joint function,” she said.
“This is a very good abstract in my opinion, and it deserves more study,” commented hemophilia specialist Rajiv K. Pruthi, MBBS, from the Mayo Clinic in Rochester, Minn., who was not involved in the study.
Structural and functional tests
To get a better understanding of the complexities of ankle pain in persons with hemophilia, Dr. Roussel and colleagues recruited 30 adults followed at their center for moderate or severe hemophilia A or B who were on replacement therapy with factor VIII or factor IX concentrate.
They used MRI without contrast to look for structural alterations in both the talocrural and subtalar joints of both ankles in all patients using the International Prophylaxis Study Group Score, adapted for subtalar joint assessment.
The investigators also used the hemophilia joint health score to assess joint funding, and tests for limits on physical activity, including the Timed Up and Go Test, 2-minute walk test, and Hemophilia Activities Lists.
In addition, they assessed pain with Quantitative Sensory Testing, a noninvasive method for evaluating patient responses to heat, cold, and mechanical pressure. Other measures included questionnaires regarding neuropathic pain and quality of life.
The participants included 23 patients with severe and 3 with moderate hemophilia A, and 1 patient with severe and 3 with moderate hemophilia B. The mean patient age was 39.4 years.
In all, 24 of the 30 patients (80%) were on prophylaxis, and 9 (30%) reported using pain medications; 25 patients reported having some degree of pain.
On MRI, 48/60 (80%) of talocrural joints imaged had pathological findings, as did 41 of 60 (68%) subtalar joints.
“Despite the fact that these patients do not all suffer from ankle joint pain, a lot of them have signs of joint pathology,” Dr. Roussel said.
On the Brief Pain Inventory, only 5 patients had no reported pain, but 14 patients reported either three, five, or six painful locations, and 20 out of 30 patients reported that their ankles were the most affected joints.
Although the sample size was not large enough for statistical comparisons, there were also large variations in pain perception across hemophilia severity.
“This is an important finding, that also patients with moderate hemophilia can have intense pain,” Dr. Roussel said.
On the DN4 questionnaire, nine patients had scores of 4 or greater, indicating that their pain was neuropathic in origin.
When they compared the patients with neuropathic pain with those suffering from nonneuropathic pain, the investigators observed similar structural and joint function between the groups, but significantly worse reported quality of life for patients with neuropathic pain.
“This is a finding that merits further attention,” she commented.
In correlation analyses, the investigators also found that MRI scores did not correlate significantly with either hemophilia joint health score, physical function, participation in activities, or pressure pain thresholds.
Why the discrepancies?
Dr. Pruthi said in an interview that he has seen evidence from other studies showing that some patients with hemophilia who were on prophylaxis had MRI evidence of joint damage, while others who used on-demand therapy had none.
“That opens up a whole can of worms as to what are we dealing with here. Why do some patients end up with damage and others don’t?” he asked.
He said that the finding that the origin of pain in a large proportion of patients was neuropathic rather than arthritic in origin was new to him.
“It raises a lot of good questions: maybe we need to be managing pain in these patients with nonnarcotic approaches, and in this day and age with the opioid crisis it’s even more important to do that,” he said.
He hypothesized that degenerative arthritis may irritate nearby nerves, resulting in neuropathic pain.
The study was funded by EAHAD, with support from participating institutions. Dr. Roussel and Dr. Pruthi reported no conflicts of interest to declare.
FROM EAHAD 2021
Type 3 von Willebrand a rare but serious bleeding disorder
Type 3 von Willebrand disease (VWD) is rare, but this form of the disease is associated with severe bleeding, particularly in muscles and joints, a bleeding disorders expert said.
“There’s a virtually complete deficiency in von Willebrand factor [in type 3 disease], so usually it’s defined as below 5 or in some studies below 3 IU/dL, but also due to the very low levels of von Willebrand factor, there’s also a very low level of factor VIII,” said Jeroen Eikenboom, MD, PhD, from Leiden (the Netherlands) University Medical Center.
“The inheritance pattern is autosomal recessive, and the prevalence is about 1 in a million,” he said during the annual congress of the European Association for Haemophilia and Allied Disorders.
Erik Adolf von Willenbrand, MD, PhD, first described this form of VWD in a family from the Åland Islands, an autonomous region of Finland. The disease, later discovered to be caused in this family by a cytosine deletion in exon 18 of the von Willebrand factor (VWF) gene, was associated with fatal bleeding events in several family members.
“As VWF is the carrier protein of factor VIII, the very low VWF level leads to a strongly reduced factor VIII level, comparable to the levels seen in mild to moderate hemophilia A. As a consequence, VWD type 3 has the combined characteristics of a primary as well as a secondary hemostasis defect,” Dr. Eikenboom explained in an abstract accompanying his talk.
Compared with VWD type 1 or 2, type 3 VWD is associated with bleeding episodes more commonly seen in patients with hemophilia A, notably mucocutaneous bleeding, bleeding after trauma or during surgery, and bleeding into joints and/or muscles.
Treatment
The goals of treatment for patients with type 3 VWD are to correct the dual hemostasis defects of impaired platelet adhesion because of low VWF levels, and the intrinsic coagulation defect because of levels of factor VIII.
Desmopressin is not effective in type 3 VWD, Dr. Eikenboom said, so treatment requires the use of either plasma-derived VWF, with or without factor VIII, or recombinant VWF.
In the United States, the only standalone VWF concentrate approved by the Food and Drug Administration is a recombinant product (Vonvendi), Three other human plasma–derived concentrates containing both VWF and factor VIII are also licensed (Alpanate, Humate-P, Wilate).
Clinicians prescribing the combined factor concentrates need to be aware of differences in pharmacokinetics between the products.
For example, following infusion of Wilate, which has equal amounts of von Willebrand factor and factor VIII, there is an increase in circulation of both von Willebrand factor and factor VIII and a similar decline in each factor over time.
In contrast, following an infusion of Humate-P, which contains lower levels of factor VIII, “interestingly, you see a secondary rise of factor VIII in Humate-P–infused patients, whereas the secondary rise is not visible in the Wilate patients,” he said.
Approximately 22% of patients with type 3 VWD also receive prophylaxis with VWF concentrate, which has been shown to decrease the median annualized bleeding rate from 25% to 6.1%.
Dr. Eikenboom cautioned that 5%-10% of patients with type 3 VWD may develop allo-antibodies against VWF concentrates, which can complicate treatment and carries risk of anaphylactic shock.
“It’s also been mentioned in literature that there may be an association with partial or complete von Willebrand factor gene deletions or nonsense mutations and the development of allo-antibodies,” he said.
Prophylaxis burdensome but helpful
Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee, who specializes in the treatment of patients with von Willebrand disease, follows a number of both girls and boys with type 3 VWD.
“Those are the people who will have bleeding into their joints, and for the girls, worse periods than some of those with other types of von Willebrand disease, and it is true that if you want to stop their bleeding, you cannot use desmopressin like we use in most other von Willebrand patients. They will need factor, although for the heavy menstrual bleeding you can use hormones or tranexamic acid – there are some other options for that,” she said in an interview.
She also noted that type 3 von Willebrand disease can be highly variable. For patients with especially frequent joint bleeding, her center recommends prophylaxis.
“Prophylaxis can be very burdensome for patients. You’re talking about IV therapy several times a week, but it’s very helpful for the joint bleeds. Episodic prophylaxis can be very helpful for heavy menstrual bleeding, and we actually have type 2, type 3, and some type 1 patients with bad enough nose bleeds that they end up on prophylaxis,” she said.
Patients with gastrointestinal bleeding are the most challenging to care for, she noted.
“You can put them on factor prophylaxis, but even that isn’t always enough to help some adults with bad GI bleeding, and we’re investigating other options for that,” she said.
Dr. Eikenboom disclosed research support from CSL Behring and honoraria (directed to his institution) for educational activities sponsored by Roche and Celgene. Dr. Flood reported having no conflicts of interest to disclose.
Type 3 von Willebrand disease (VWD) is rare, but this form of the disease is associated with severe bleeding, particularly in muscles and joints, a bleeding disorders expert said.
“There’s a virtually complete deficiency in von Willebrand factor [in type 3 disease], so usually it’s defined as below 5 or in some studies below 3 IU/dL, but also due to the very low levels of von Willebrand factor, there’s also a very low level of factor VIII,” said Jeroen Eikenboom, MD, PhD, from Leiden (the Netherlands) University Medical Center.
“The inheritance pattern is autosomal recessive, and the prevalence is about 1 in a million,” he said during the annual congress of the European Association for Haemophilia and Allied Disorders.
Erik Adolf von Willenbrand, MD, PhD, first described this form of VWD in a family from the Åland Islands, an autonomous region of Finland. The disease, later discovered to be caused in this family by a cytosine deletion in exon 18 of the von Willebrand factor (VWF) gene, was associated with fatal bleeding events in several family members.
“As VWF is the carrier protein of factor VIII, the very low VWF level leads to a strongly reduced factor VIII level, comparable to the levels seen in mild to moderate hemophilia A. As a consequence, VWD type 3 has the combined characteristics of a primary as well as a secondary hemostasis defect,” Dr. Eikenboom explained in an abstract accompanying his talk.
Compared with VWD type 1 or 2, type 3 VWD is associated with bleeding episodes more commonly seen in patients with hemophilia A, notably mucocutaneous bleeding, bleeding after trauma or during surgery, and bleeding into joints and/or muscles.
Treatment
The goals of treatment for patients with type 3 VWD are to correct the dual hemostasis defects of impaired platelet adhesion because of low VWF levels, and the intrinsic coagulation defect because of levels of factor VIII.
Desmopressin is not effective in type 3 VWD, Dr. Eikenboom said, so treatment requires the use of either plasma-derived VWF, with or without factor VIII, or recombinant VWF.
In the United States, the only standalone VWF concentrate approved by the Food and Drug Administration is a recombinant product (Vonvendi), Three other human plasma–derived concentrates containing both VWF and factor VIII are also licensed (Alpanate, Humate-P, Wilate).
Clinicians prescribing the combined factor concentrates need to be aware of differences in pharmacokinetics between the products.
For example, following infusion of Wilate, which has equal amounts of von Willebrand factor and factor VIII, there is an increase in circulation of both von Willebrand factor and factor VIII and a similar decline in each factor over time.
In contrast, following an infusion of Humate-P, which contains lower levels of factor VIII, “interestingly, you see a secondary rise of factor VIII in Humate-P–infused patients, whereas the secondary rise is not visible in the Wilate patients,” he said.
Approximately 22% of patients with type 3 VWD also receive prophylaxis with VWF concentrate, which has been shown to decrease the median annualized bleeding rate from 25% to 6.1%.
Dr. Eikenboom cautioned that 5%-10% of patients with type 3 VWD may develop allo-antibodies against VWF concentrates, which can complicate treatment and carries risk of anaphylactic shock.
“It’s also been mentioned in literature that there may be an association with partial or complete von Willebrand factor gene deletions or nonsense mutations and the development of allo-antibodies,” he said.
Prophylaxis burdensome but helpful
Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee, who specializes in the treatment of patients with von Willebrand disease, follows a number of both girls and boys with type 3 VWD.
“Those are the people who will have bleeding into their joints, and for the girls, worse periods than some of those with other types of von Willebrand disease, and it is true that if you want to stop their bleeding, you cannot use desmopressin like we use in most other von Willebrand patients. They will need factor, although for the heavy menstrual bleeding you can use hormones or tranexamic acid – there are some other options for that,” she said in an interview.
She also noted that type 3 von Willebrand disease can be highly variable. For patients with especially frequent joint bleeding, her center recommends prophylaxis.
“Prophylaxis can be very burdensome for patients. You’re talking about IV therapy several times a week, but it’s very helpful for the joint bleeds. Episodic prophylaxis can be very helpful for heavy menstrual bleeding, and we actually have type 2, type 3, and some type 1 patients with bad enough nose bleeds that they end up on prophylaxis,” she said.
Patients with gastrointestinal bleeding are the most challenging to care for, she noted.
“You can put them on factor prophylaxis, but even that isn’t always enough to help some adults with bad GI bleeding, and we’re investigating other options for that,” she said.
Dr. Eikenboom disclosed research support from CSL Behring and honoraria (directed to his institution) for educational activities sponsored by Roche and Celgene. Dr. Flood reported having no conflicts of interest to disclose.
Type 3 von Willebrand disease (VWD) is rare, but this form of the disease is associated with severe bleeding, particularly in muscles and joints, a bleeding disorders expert said.
“There’s a virtually complete deficiency in von Willebrand factor [in type 3 disease], so usually it’s defined as below 5 or in some studies below 3 IU/dL, but also due to the very low levels of von Willebrand factor, there’s also a very low level of factor VIII,” said Jeroen Eikenboom, MD, PhD, from Leiden (the Netherlands) University Medical Center.
“The inheritance pattern is autosomal recessive, and the prevalence is about 1 in a million,” he said during the annual congress of the European Association for Haemophilia and Allied Disorders.
Erik Adolf von Willenbrand, MD, PhD, first described this form of VWD in a family from the Åland Islands, an autonomous region of Finland. The disease, later discovered to be caused in this family by a cytosine deletion in exon 18 of the von Willebrand factor (VWF) gene, was associated with fatal bleeding events in several family members.
“As VWF is the carrier protein of factor VIII, the very low VWF level leads to a strongly reduced factor VIII level, comparable to the levels seen in mild to moderate hemophilia A. As a consequence, VWD type 3 has the combined characteristics of a primary as well as a secondary hemostasis defect,” Dr. Eikenboom explained in an abstract accompanying his talk.
Compared with VWD type 1 or 2, type 3 VWD is associated with bleeding episodes more commonly seen in patients with hemophilia A, notably mucocutaneous bleeding, bleeding after trauma or during surgery, and bleeding into joints and/or muscles.
Treatment
The goals of treatment for patients with type 3 VWD are to correct the dual hemostasis defects of impaired platelet adhesion because of low VWF levels, and the intrinsic coagulation defect because of levels of factor VIII.
Desmopressin is not effective in type 3 VWD, Dr. Eikenboom said, so treatment requires the use of either plasma-derived VWF, with or without factor VIII, or recombinant VWF.
In the United States, the only standalone VWF concentrate approved by the Food and Drug Administration is a recombinant product (Vonvendi), Three other human plasma–derived concentrates containing both VWF and factor VIII are also licensed (Alpanate, Humate-P, Wilate).
Clinicians prescribing the combined factor concentrates need to be aware of differences in pharmacokinetics between the products.
For example, following infusion of Wilate, which has equal amounts of von Willebrand factor and factor VIII, there is an increase in circulation of both von Willebrand factor and factor VIII and a similar decline in each factor over time.
In contrast, following an infusion of Humate-P, which contains lower levels of factor VIII, “interestingly, you see a secondary rise of factor VIII in Humate-P–infused patients, whereas the secondary rise is not visible in the Wilate patients,” he said.
Approximately 22% of patients with type 3 VWD also receive prophylaxis with VWF concentrate, which has been shown to decrease the median annualized bleeding rate from 25% to 6.1%.
Dr. Eikenboom cautioned that 5%-10% of patients with type 3 VWD may develop allo-antibodies against VWF concentrates, which can complicate treatment and carries risk of anaphylactic shock.
“It’s also been mentioned in literature that there may be an association with partial or complete von Willebrand factor gene deletions or nonsense mutations and the development of allo-antibodies,” he said.
Prophylaxis burdensome but helpful
Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee, who specializes in the treatment of patients with von Willebrand disease, follows a number of both girls and boys with type 3 VWD.
“Those are the people who will have bleeding into their joints, and for the girls, worse periods than some of those with other types of von Willebrand disease, and it is true that if you want to stop their bleeding, you cannot use desmopressin like we use in most other von Willebrand patients. They will need factor, although for the heavy menstrual bleeding you can use hormones or tranexamic acid – there are some other options for that,” she said in an interview.
She also noted that type 3 von Willebrand disease can be highly variable. For patients with especially frequent joint bleeding, her center recommends prophylaxis.
“Prophylaxis can be very burdensome for patients. You’re talking about IV therapy several times a week, but it’s very helpful for the joint bleeds. Episodic prophylaxis can be very helpful for heavy menstrual bleeding, and we actually have type 2, type 3, and some type 1 patients with bad enough nose bleeds that they end up on prophylaxis,” she said.
Patients with gastrointestinal bleeding are the most challenging to care for, she noted.
“You can put them on factor prophylaxis, but even that isn’t always enough to help some adults with bad GI bleeding, and we’re investigating other options for that,” she said.
Dr. Eikenboom disclosed research support from CSL Behring and honoraria (directed to his institution) for educational activities sponsored by Roche and Celgene. Dr. Flood reported having no conflicts of interest to disclose.
FROM EAHAD 2021