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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Study highlights importance of genotyping in von Willebrand disease
Patients with genetically confirmed von Willebrand disease (VWD) type 2M have a relatively mild clinical phenotype, according to findings from a retrospective cross-sectional study.
In fact, three of 31 patients included in the study had a near normal laboratory phenotype. Additionally, patients with the p.Val1360Ala mutation had significantly higher values of all von Willebrand factor (VWF)-related laboratory parameters, compared with those with the p.Arg1374Cys or p.Phe1293Leu mutation, Dominique Maas reported at the European Association for Haemophilia and Allied Disorders annual meeting.
The findings underscore the importance of genotyping for making a correct diagnosis of VWD type 2M, said Ms. Maas of Radboud University Medical Center, Nijmegen, The Netherlands.
The study subjects, who had a least one VWD type 2M mutation, had a median age of 34 years and a median bleeding score of 6. Most suffered from mucocutaneous bleeding, but with low frequency compared with other VWD subtypes. The incidence of muscle hematomas, postpartum hemorrhage, and postsurgery bleeding were relatively high, however. Age and bleeding score were strongly positively correlated.
Subjects had a median VWF antigen level of 24 IU dL-1, median VWF ristocetin cofactor activity of 6 IU dL-1, and median VSF:RCo/VWF:Ag ratio of 0.29. The VSF collagen binding activity and VWF:Ag ratio was normal, she said.
Genotyping is a powerful diagnostic tool for making an appropriate diagnosis and classification of VWD. The current findings are important because understanding the correlation between genotype and phenotype improves the understanding of VWD pathogenesis and has important implications for treatment, follow-up, and genetic counseling, but has not been throughly investigated in fully genotyped patients with VWD type 2M, she said.
Ms. Maas reported having no disclosures.
Patients with genetically confirmed von Willebrand disease (VWD) type 2M have a relatively mild clinical phenotype, according to findings from a retrospective cross-sectional study.
In fact, three of 31 patients included in the study had a near normal laboratory phenotype. Additionally, patients with the p.Val1360Ala mutation had significantly higher values of all von Willebrand factor (VWF)-related laboratory parameters, compared with those with the p.Arg1374Cys or p.Phe1293Leu mutation, Dominique Maas reported at the European Association for Haemophilia and Allied Disorders annual meeting.
The findings underscore the importance of genotyping for making a correct diagnosis of VWD type 2M, said Ms. Maas of Radboud University Medical Center, Nijmegen, The Netherlands.
The study subjects, who had a least one VWD type 2M mutation, had a median age of 34 years and a median bleeding score of 6. Most suffered from mucocutaneous bleeding, but with low frequency compared with other VWD subtypes. The incidence of muscle hematomas, postpartum hemorrhage, and postsurgery bleeding were relatively high, however. Age and bleeding score were strongly positively correlated.
Subjects had a median VWF antigen level of 24 IU dL-1, median VWF ristocetin cofactor activity of 6 IU dL-1, and median VSF:RCo/VWF:Ag ratio of 0.29. The VSF collagen binding activity and VWF:Ag ratio was normal, she said.
Genotyping is a powerful diagnostic tool for making an appropriate diagnosis and classification of VWD. The current findings are important because understanding the correlation between genotype and phenotype improves the understanding of VWD pathogenesis and has important implications for treatment, follow-up, and genetic counseling, but has not been throughly investigated in fully genotyped patients with VWD type 2M, she said.
Ms. Maas reported having no disclosures.
Patients with genetically confirmed von Willebrand disease (VWD) type 2M have a relatively mild clinical phenotype, according to findings from a retrospective cross-sectional study.
In fact, three of 31 patients included in the study had a near normal laboratory phenotype. Additionally, patients with the p.Val1360Ala mutation had significantly higher values of all von Willebrand factor (VWF)-related laboratory parameters, compared with those with the p.Arg1374Cys or p.Phe1293Leu mutation, Dominique Maas reported at the European Association for Haemophilia and Allied Disorders annual meeting.
The findings underscore the importance of genotyping for making a correct diagnosis of VWD type 2M, said Ms. Maas of Radboud University Medical Center, Nijmegen, The Netherlands.
The study subjects, who had a least one VWD type 2M mutation, had a median age of 34 years and a median bleeding score of 6. Most suffered from mucocutaneous bleeding, but with low frequency compared with other VWD subtypes. The incidence of muscle hematomas, postpartum hemorrhage, and postsurgery bleeding were relatively high, however. Age and bleeding score were strongly positively correlated.
Subjects had a median VWF antigen level of 24 IU dL-1, median VWF ristocetin cofactor activity of 6 IU dL-1, and median VSF:RCo/VWF:Ag ratio of 0.29. The VSF collagen binding activity and VWF:Ag ratio was normal, she said.
Genotyping is a powerful diagnostic tool for making an appropriate diagnosis and classification of VWD. The current findings are important because understanding the correlation between genotype and phenotype improves the understanding of VWD pathogenesis and has important implications for treatment, follow-up, and genetic counseling, but has not been throughly investigated in fully genotyped patients with VWD type 2M, she said.
Ms. Maas reported having no disclosures.
FROM EAHAD 2017
Key clinical point:
Major finding: Three of 31 patients included in the study had a near normal laboratory phenotype.
Data source: A retrospective cross-sectional study of 31 patients.
Disclosures: Ms. Maas reported having no disclosures.
Solulin variants activate TAFI in vitro
A new generation of solulin variants is showing promise for the treatment of severe hemophilia A.
The in vitro production and characterization of these solulin variants – F376A-, M388A-, and F376A/M388A-solulin – showed that while they lost their abilities to activate protein C (an inhibitor of thrombin generation), they were still capable of activating thrombin activatable fibrinolysis inhibitor (TAFI), Yohann Repesse, PhD reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Additionally, the double mutant F376A/M388A-solulin, which was tested ex vivo using blood samples from hemophilic A patients, was found on thromboelastography to increase clot firmness and stability. As opposed to wild type solulin, the effects were maintained even at high concentrations of F376A/M388A-solulin, said Dr. Repesse of the National Institute of Health and Medical Research, Caen, France.
An important aggravating factor when it comes to treating hemophilia involves premature fibrinolysis, which means that antifibrinolytics are of interest, he explained. Thrombomodulin is a key player in the coagulation cascade, because it activates protein C, and also in the fibrinolytic cascade, as it activates TAFI. Solulin, a soluble form of thrombomodulin, has both capabilities.
The findings with respect to the new generation of solulin variants tested in this study open new opportunities for the development of specific medications for hemophilia patients, he concluded.
Dr. Repesse reported having no disclosures.
A new generation of solulin variants is showing promise for the treatment of severe hemophilia A.
The in vitro production and characterization of these solulin variants – F376A-, M388A-, and F376A/M388A-solulin – showed that while they lost their abilities to activate protein C (an inhibitor of thrombin generation), they were still capable of activating thrombin activatable fibrinolysis inhibitor (TAFI), Yohann Repesse, PhD reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Additionally, the double mutant F376A/M388A-solulin, which was tested ex vivo using blood samples from hemophilic A patients, was found on thromboelastography to increase clot firmness and stability. As opposed to wild type solulin, the effects were maintained even at high concentrations of F376A/M388A-solulin, said Dr. Repesse of the National Institute of Health and Medical Research, Caen, France.
An important aggravating factor when it comes to treating hemophilia involves premature fibrinolysis, which means that antifibrinolytics are of interest, he explained. Thrombomodulin is a key player in the coagulation cascade, because it activates protein C, and also in the fibrinolytic cascade, as it activates TAFI. Solulin, a soluble form of thrombomodulin, has both capabilities.
The findings with respect to the new generation of solulin variants tested in this study open new opportunities for the development of specific medications for hemophilia patients, he concluded.
Dr. Repesse reported having no disclosures.
A new generation of solulin variants is showing promise for the treatment of severe hemophilia A.
The in vitro production and characterization of these solulin variants – F376A-, M388A-, and F376A/M388A-solulin – showed that while they lost their abilities to activate protein C (an inhibitor of thrombin generation), they were still capable of activating thrombin activatable fibrinolysis inhibitor (TAFI), Yohann Repesse, PhD reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Additionally, the double mutant F376A/M388A-solulin, which was tested ex vivo using blood samples from hemophilic A patients, was found on thromboelastography to increase clot firmness and stability. As opposed to wild type solulin, the effects were maintained even at high concentrations of F376A/M388A-solulin, said Dr. Repesse of the National Institute of Health and Medical Research, Caen, France.
An important aggravating factor when it comes to treating hemophilia involves premature fibrinolysis, which means that antifibrinolytics are of interest, he explained. Thrombomodulin is a key player in the coagulation cascade, because it activates protein C, and also in the fibrinolytic cascade, as it activates TAFI. Solulin, a soluble form of thrombomodulin, has both capabilities.
The findings with respect to the new generation of solulin variants tested in this study open new opportunities for the development of specific medications for hemophilia patients, he concluded.
Dr. Repesse reported having no disclosures.
FROM EAHAD 2017
Key clinical point:
Major finding: F376A-, M388A-, and F376A/M388A-solulin lost their abilities to activate protein C but were still capable of activating TAFI.
Data source: An in vitro and ex vivo evaluation of solulin variants.
Disclosures: Dr. Repesse reported having no disclosures.
Boys with severe hemophilia have good physical function
Children with severe hemophilia in a U.K. study had generally good self-reported health-related quality of life and physical functioning, but impairment on both measures was greater in those who reported pain.
Of 123 boys with a mean age of 12 years who were included in the multicenter SO-FIT study, 110 had hemophilia A, 25 had a past inhibitor, and 9 had a current inhibitor. Prophylactic treatment was given in 120 of the boys, Kate Khair, PhD of Great Ormond Street Hospital for Children, London, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
In the preceding 6 months, participants experienced a median of 0 joint bleeds (range of 0-8), and a median Hemophilia Joint Health Score (HJHS) of 1 (range, 0-37). Physical function scores were good; the Haemophilia & Exercise Project questionnaire (HEP-Test-Q) mean score was 80.82, with the highest impairments seen in the domain of “endurance” (mean, 72.21), and the Paediatric Haemophilia Activities List (PedHAL) mean score was 85.13, with the highest impairments seen in the domains of “leisure activities and sports” and “lying/sitting/kneeling/standing” (mean, 82.04 and 82.97, respectively).
Health-related quality of life as assessed by the Haemo-QoL Short Form was also generally good (mean, 23.07), with the highest impairments seen in the domains of “friends” and “family” (mean, 27.08 and 26.59, respectively).
In the 27% of participants with pain, a high correlation was seen between the HEP-Test-Q and Haemo-QoL, and moderate correlation was seen between the PedHAL and Haemo-QoL, which implies that good physical functioning is related to good health-related quality of life, Dr. Khair explained.
In fact, patients who said they often or always had pain reported significantly worse subjective physical functioning in all HEP-Test-Q and PedHAL domains, as well as higher impairments in their HRQoL vs. those who said they sometimes, rarely, or never experienced pain, she said.
Interestingly, data completion by study participants was improved with use of an iPad vs. “paper and pencil” for questionnaire completion, Dr. Khair said in an interview.
“They preferred this method – it was more in keeping with how they communicate and learn at school,” she said, noting that the iPad database was set up to give real time scores, which could then be used to tailor assessments.
This is an approach that could be undertaken at home pre-clinic visits, she said.
“Gaining the views of children and young adults in patient-reported outcomes is complex, but reveals their views of their care and their lives – an area we should address more,” she added.
Dr. Khair received grant or research support from Pfizer ASPIRE.
Children with severe hemophilia in a U.K. study had generally good self-reported health-related quality of life and physical functioning, but impairment on both measures was greater in those who reported pain.
Of 123 boys with a mean age of 12 years who were included in the multicenter SO-FIT study, 110 had hemophilia A, 25 had a past inhibitor, and 9 had a current inhibitor. Prophylactic treatment was given in 120 of the boys, Kate Khair, PhD of Great Ormond Street Hospital for Children, London, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
In the preceding 6 months, participants experienced a median of 0 joint bleeds (range of 0-8), and a median Hemophilia Joint Health Score (HJHS) of 1 (range, 0-37). Physical function scores were good; the Haemophilia & Exercise Project questionnaire (HEP-Test-Q) mean score was 80.82, with the highest impairments seen in the domain of “endurance” (mean, 72.21), and the Paediatric Haemophilia Activities List (PedHAL) mean score was 85.13, with the highest impairments seen in the domains of “leisure activities and sports” and “lying/sitting/kneeling/standing” (mean, 82.04 and 82.97, respectively).
Health-related quality of life as assessed by the Haemo-QoL Short Form was also generally good (mean, 23.07), with the highest impairments seen in the domains of “friends” and “family” (mean, 27.08 and 26.59, respectively).
In the 27% of participants with pain, a high correlation was seen between the HEP-Test-Q and Haemo-QoL, and moderate correlation was seen between the PedHAL and Haemo-QoL, which implies that good physical functioning is related to good health-related quality of life, Dr. Khair explained.
In fact, patients who said they often or always had pain reported significantly worse subjective physical functioning in all HEP-Test-Q and PedHAL domains, as well as higher impairments in their HRQoL vs. those who said they sometimes, rarely, or never experienced pain, she said.
Interestingly, data completion by study participants was improved with use of an iPad vs. “paper and pencil” for questionnaire completion, Dr. Khair said in an interview.
“They preferred this method – it was more in keeping with how they communicate and learn at school,” she said, noting that the iPad database was set up to give real time scores, which could then be used to tailor assessments.
This is an approach that could be undertaken at home pre-clinic visits, she said.
“Gaining the views of children and young adults in patient-reported outcomes is complex, but reveals their views of their care and their lives – an area we should address more,” she added.
Dr. Khair received grant or research support from Pfizer ASPIRE.
Children with severe hemophilia in a U.K. study had generally good self-reported health-related quality of life and physical functioning, but impairment on both measures was greater in those who reported pain.
Of 123 boys with a mean age of 12 years who were included in the multicenter SO-FIT study, 110 had hemophilia A, 25 had a past inhibitor, and 9 had a current inhibitor. Prophylactic treatment was given in 120 of the boys, Kate Khair, PhD of Great Ormond Street Hospital for Children, London, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
In the preceding 6 months, participants experienced a median of 0 joint bleeds (range of 0-8), and a median Hemophilia Joint Health Score (HJHS) of 1 (range, 0-37). Physical function scores were good; the Haemophilia & Exercise Project questionnaire (HEP-Test-Q) mean score was 80.82, with the highest impairments seen in the domain of “endurance” (mean, 72.21), and the Paediatric Haemophilia Activities List (PedHAL) mean score was 85.13, with the highest impairments seen in the domains of “leisure activities and sports” and “lying/sitting/kneeling/standing” (mean, 82.04 and 82.97, respectively).
Health-related quality of life as assessed by the Haemo-QoL Short Form was also generally good (mean, 23.07), with the highest impairments seen in the domains of “friends” and “family” (mean, 27.08 and 26.59, respectively).
In the 27% of participants with pain, a high correlation was seen between the HEP-Test-Q and Haemo-QoL, and moderate correlation was seen between the PedHAL and Haemo-QoL, which implies that good physical functioning is related to good health-related quality of life, Dr. Khair explained.
In fact, patients who said they often or always had pain reported significantly worse subjective physical functioning in all HEP-Test-Q and PedHAL domains, as well as higher impairments in their HRQoL vs. those who said they sometimes, rarely, or never experienced pain, she said.
Interestingly, data completion by study participants was improved with use of an iPad vs. “paper and pencil” for questionnaire completion, Dr. Khair said in an interview.
“They preferred this method – it was more in keeping with how they communicate and learn at school,” she said, noting that the iPad database was set up to give real time scores, which could then be used to tailor assessments.
This is an approach that could be undertaken at home pre-clinic visits, she said.
“Gaining the views of children and young adults in patient-reported outcomes is complex, but reveals their views of their care and their lives – an area we should address more,” she added.
Dr. Khair received grant or research support from Pfizer ASPIRE.
FROM EAHAD 2017
Key clinical point:
Major finding: Physical function score (HEP-Test-Q) was a mean of 80.82, with the highest impairments seen in the domain of “endurance” (mean, 72.21).
Data source: The SO-FIT study of 123 boys with severe hemophilia.
Disclosures: Dr. Khair received grant or research support from Pfizer ASPIRE.
ITI protects against bleeding in hemophilia A with factor VIII inhibitors
Immune tolerance induction, or ITI, in hemophilia A patients with inhibitor development against factor VIII (FVIII) appears to provide some protection against bleeding, as bleeding during ITI in patients from the PedNet registry was dependent on inhibitor titer and ITI regimen, according to Kathelijn Fischer, MD.
Of 218 registry patients who were born during 1990-2009 and who had clinically relevant inhibitors and available data on joint bleeding, 157 had bleeding for at least 3 months. They were followed for a median of 26 months starting at age 16 months, and most had high titer inhibitors (52% had titers of 5-199 BU, and 32% had titers greater than 200 BU).
The bleeding rates in 12 patients without ITI who were on prophylaxis were similar to those in 89 such patients without prophylaxis (0.3 and 0.4 bleeds/month, respectively); no significant difference was seen between the groups based on inhibitor titer, Dr. Fischer of University Medical Center Utrecht, The Netherlands reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Similarly, the bleeding rate during ITI among those on prophylaxis did not differ significantly from the rate in those without prophylaxis (0.4 vs. 0.3/month, respectively), but the rate did increase significantly according to inhibitor titer: The rate increased from 0.05/month in the group with less than 5 BU, to 0.2/month in those with 5-199 BU, and to 0.5/month in the group with greater than 200 BU.
Further, while ITI dose did not affect bleeding, dosing frequency had a strong effect. The median rate with nondaily dosing in 36 patients vs. daily dosing in 63 patients was 0.4/month vs. 0.2/month, respectively, Dr. Fischer said.
She reported having no disclosures.
Immune tolerance induction, or ITI, in hemophilia A patients with inhibitor development against factor VIII (FVIII) appears to provide some protection against bleeding, as bleeding during ITI in patients from the PedNet registry was dependent on inhibitor titer and ITI regimen, according to Kathelijn Fischer, MD.
Of 218 registry patients who were born during 1990-2009 and who had clinically relevant inhibitors and available data on joint bleeding, 157 had bleeding for at least 3 months. They were followed for a median of 26 months starting at age 16 months, and most had high titer inhibitors (52% had titers of 5-199 BU, and 32% had titers greater than 200 BU).
The bleeding rates in 12 patients without ITI who were on prophylaxis were similar to those in 89 such patients without prophylaxis (0.3 and 0.4 bleeds/month, respectively); no significant difference was seen between the groups based on inhibitor titer, Dr. Fischer of University Medical Center Utrecht, The Netherlands reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Similarly, the bleeding rate during ITI among those on prophylaxis did not differ significantly from the rate in those without prophylaxis (0.4 vs. 0.3/month, respectively), but the rate did increase significantly according to inhibitor titer: The rate increased from 0.05/month in the group with less than 5 BU, to 0.2/month in those with 5-199 BU, and to 0.5/month in the group with greater than 200 BU.
Further, while ITI dose did not affect bleeding, dosing frequency had a strong effect. The median rate with nondaily dosing in 36 patients vs. daily dosing in 63 patients was 0.4/month vs. 0.2/month, respectively, Dr. Fischer said.
She reported having no disclosures.
Immune tolerance induction, or ITI, in hemophilia A patients with inhibitor development against factor VIII (FVIII) appears to provide some protection against bleeding, as bleeding during ITI in patients from the PedNet registry was dependent on inhibitor titer and ITI regimen, according to Kathelijn Fischer, MD.
Of 218 registry patients who were born during 1990-2009 and who had clinically relevant inhibitors and available data on joint bleeding, 157 had bleeding for at least 3 months. They were followed for a median of 26 months starting at age 16 months, and most had high titer inhibitors (52% had titers of 5-199 BU, and 32% had titers greater than 200 BU).
The bleeding rates in 12 patients without ITI who were on prophylaxis were similar to those in 89 such patients without prophylaxis (0.3 and 0.4 bleeds/month, respectively); no significant difference was seen between the groups based on inhibitor titer, Dr. Fischer of University Medical Center Utrecht, The Netherlands reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Similarly, the bleeding rate during ITI among those on prophylaxis did not differ significantly from the rate in those without prophylaxis (0.4 vs. 0.3/month, respectively), but the rate did increase significantly according to inhibitor titer: The rate increased from 0.05/month in the group with less than 5 BU, to 0.2/month in those with 5-199 BU, and to 0.5/month in the group with greater than 200 BU.
Further, while ITI dose did not affect bleeding, dosing frequency had a strong effect. The median rate with nondaily dosing in 36 patients vs. daily dosing in 63 patients was 0.4/month vs. 0.2/month, respectively, Dr. Fischer said.
She reported having no disclosures.
FROM EAHAD 2017
Key clinical point:
Major finding: Median bleeding rate with nondaily vs. daily ITI dosing was 0.4/month vs. 0.2/month, respectively.
Data source: An analysis of 218 patients from the PedNet registry.
Disclosures: Dr. Fischer reported having no disclosures.
Study: No link between vaccines, inhibitor development
The administration of pediatric vaccinations in close proximity to factor VIII (FVIII) exposure was not associated with inhibitor development in previously untreated patients with severe hemophilia A in the PedNet Registry.
Similarly, no association was seen between recurrent vaccinations and inhibitor development, Dr. van den Berg reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Inhibitor development in this patient population is a multifactorial event, but these findings show no association between vaccinations administered early in life and increased inhibitor risk, she concluded.
Dr. van den Berg received grant/research support from Bayer, Baxalta, Pfizer, CSI, and Grifols.
The administration of pediatric vaccinations in close proximity to factor VIII (FVIII) exposure was not associated with inhibitor development in previously untreated patients with severe hemophilia A in the PedNet Registry.
Similarly, no association was seen between recurrent vaccinations and inhibitor development, Dr. van den Berg reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Inhibitor development in this patient population is a multifactorial event, but these findings show no association between vaccinations administered early in life and increased inhibitor risk, she concluded.
Dr. van den Berg received grant/research support from Bayer, Baxalta, Pfizer, CSI, and Grifols.
The administration of pediatric vaccinations in close proximity to factor VIII (FVIII) exposure was not associated with inhibitor development in previously untreated patients with severe hemophilia A in the PedNet Registry.
Similarly, no association was seen between recurrent vaccinations and inhibitor development, Dr. van den Berg reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Inhibitor development in this patient population is a multifactorial event, but these findings show no association between vaccinations administered early in life and increased inhibitor risk, she concluded.
Dr. van den Berg received grant/research support from Bayer, Baxalta, Pfizer, CSI, and Grifols.
FROM EAHAD 2017
Key clinical point:
Major finding: The adjusted hazard ratio for any inhibitor development related to vaccinations in close proximity to FVIII was 0.65.
Data source: A review of data from 375 children in the PedNet Registry.
Disclosures: Dr. van den Berg received grant/research support from Bayer, Baxalta, Pfizer, CSI, and Grifols.
AHEAD studies establish bleed rate benchmarks
The findings from a large cohort study of patients with moderate and severe hemophilia A have supplied benchmarks that can be used in developing new treatments, Alessandro Gringeri, MD, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.*
More than 37% of 869 patients with moderate or severe hemophilia A who were on prophylaxis and who were enrolled in the noninterventional, prospective, long-term AHEAD international and German cohort studies experienced less than one bleed per year on average, and 50% had an annual bleed rate of less than two.
Furthermore, a median of 56% of those on prophylaxis had an annual joint bleed rate (AJBR) of less than one, and nearly 70% had an AJBR of less than two. Study subjects were enrolled from 22 countries at a mean age at screening of 23.4 years. Most (67%) had severe hemophilia A, and 79% were on prophylaxis, said Dr. Gringeri of Global Medical Affairs Hematology, Shire, Austria.
Among patients in the international arm and the German arm of the study, the median annual bleed rates, respectively, were 1.2 and 2.5 in year 1, 1.2 and 2.2 in year 2, and 1.9 in each arm in year 3. Median AJBRs were 0.9 in each arm in year 1, 0.9 and 0 in year 2, and 1.0 and 0.8 in year 3.
The data provide a valid benchmark for new products and therapeutic approaches, Dr. Gringeri concluded.
Dr. Gringeri is an employee of Shire.
CORRECTION 2/11/17: An earlier version of this article misstated the presenting author's name.
The findings from a large cohort study of patients with moderate and severe hemophilia A have supplied benchmarks that can be used in developing new treatments, Alessandro Gringeri, MD, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.*
More than 37% of 869 patients with moderate or severe hemophilia A who were on prophylaxis and who were enrolled in the noninterventional, prospective, long-term AHEAD international and German cohort studies experienced less than one bleed per year on average, and 50% had an annual bleed rate of less than two.
Furthermore, a median of 56% of those on prophylaxis had an annual joint bleed rate (AJBR) of less than one, and nearly 70% had an AJBR of less than two. Study subjects were enrolled from 22 countries at a mean age at screening of 23.4 years. Most (67%) had severe hemophilia A, and 79% were on prophylaxis, said Dr. Gringeri of Global Medical Affairs Hematology, Shire, Austria.
Among patients in the international arm and the German arm of the study, the median annual bleed rates, respectively, were 1.2 and 2.5 in year 1, 1.2 and 2.2 in year 2, and 1.9 in each arm in year 3. Median AJBRs were 0.9 in each arm in year 1, 0.9 and 0 in year 2, and 1.0 and 0.8 in year 3.
The data provide a valid benchmark for new products and therapeutic approaches, Dr. Gringeri concluded.
Dr. Gringeri is an employee of Shire.
CORRECTION 2/11/17: An earlier version of this article misstated the presenting author's name.
The findings from a large cohort study of patients with moderate and severe hemophilia A have supplied benchmarks that can be used in developing new treatments, Alessandro Gringeri, MD, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.*
More than 37% of 869 patients with moderate or severe hemophilia A who were on prophylaxis and who were enrolled in the noninterventional, prospective, long-term AHEAD international and German cohort studies experienced less than one bleed per year on average, and 50% had an annual bleed rate of less than two.
Furthermore, a median of 56% of those on prophylaxis had an annual joint bleed rate (AJBR) of less than one, and nearly 70% had an AJBR of less than two. Study subjects were enrolled from 22 countries at a mean age at screening of 23.4 years. Most (67%) had severe hemophilia A, and 79% were on prophylaxis, said Dr. Gringeri of Global Medical Affairs Hematology, Shire, Austria.
Among patients in the international arm and the German arm of the study, the median annual bleed rates, respectively, were 1.2 and 2.5 in year 1, 1.2 and 2.2 in year 2, and 1.9 in each arm in year 3. Median AJBRs were 0.9 in each arm in year 1, 0.9 and 0 in year 2, and 1.0 and 0.8 in year 3.
The data provide a valid benchmark for new products and therapeutic approaches, Dr. Gringeri concluded.
Dr. Gringeri is an employee of Shire.
CORRECTION 2/11/17: An earlier version of this article misstated the presenting author's name.
FROM EAHAD 2017
Key clinical point:
Major finding: 37% of hemophilia A patients on prophylaxis experienced less than one bleed per year on average.
Data source: The prospective long-term AHEAD cohort studies, including 869 patients.
Disclosures: Dr. Gringeri is an employee of Shire.
In active CLL with deletion 17p, consider trial enrollment
NEW YORK – Outside of clinical trials, therapy for early stage chronic lymphocytic leukemia in patients with deletion of the short arm of chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 requires the presence of active disease, according to Neil E. Kay, MD.
“Right now, we would propose that patients with del[17]p should have additional prognostic work-up. It’s very important to know if they are unmutated or mutated for the IgVH gene,” he said, adding that stimulated karyotype is also important to perform in those with del[17]p.
“The median overall survivorship in many phase II and phase III trials appears to be around 2 to 3 years,” he said.
Those with a chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 who receive chemoimmunotherapy very rarely achieve a complete response, or if they do they have a short duration of response, he added.
In treated patients, 17p deletion and p53 mutation are the most common abnormalities acquired during the course of the disease.
“Unfortunately there appears to be a selection pressure, and [in treated patients] the incidence of 17p and the p53 mutation has been reported up to 23%-44%. No one understands completely the biology of this, but it may be that subclones are present and expand, or that new mutations occur due to selection pressure of [chemoimmunotherapy] and the overgrowth of these subclones,” he said.
Importantly, not all patients with del[17]p or p53 mutation have bad outcomes; there are patients with indolent disease, he noted, adding that various criteria have been shown to help identify which patients are at risk for poor outcomes and to classify them according to risk. In general, lower-risk patients have mutated immunoglobulin heavy chain variable gene status, early stage disease, younger age, good performance status, and normal serum lactate dehydrogenase. These criteria could be used to identify low-risk patients who can be followed, he said.
Fluorescence in situ hybridization (FISH) evaluation of patients is a useful tool when there is no access to sequencing and other tests, Dr. Kay said, describing a recent multinational CLL Research Consortium study of nearly 1,600 patients (Br J Haematol. 2016 Apr;173[1]:105-13).
In that study, he and his colleagues found that patients with less than 50% 17p did not have such poor outcomes, but at 50%-plus they did much worse in terms of time to first treatment.
Based on the available data, Dr. Kay said that treatment is unnecessary in asymptomatic patients, except, perhaps, in high-risk patients identified using recently published risk models, for whom clinical trial enrollment may be considered.
“We do advocate having a discussion about allogeneic stem cell transplant since this may still be the only curative approach,” he added.
In patients with del[17]p and/or p53 mutation who have progressive disease, Dr. Kay said his take on the available data is that patients should first be categorized by age, then by whether they are fit or frail, and finally by whether or not they have del[17]p. Those under age 70 years without del[17]p and who have a mutated IgVH status should be considered for a clinical trial, and are also good candidates for chemoimmunotherapy. If they do have del[17]p or p53 mutation, consider clinical trial enrollment or treatment with ibrutinib, he said.
Fit patients in a complete response can be referred for transplant evaluation, but while the other treatments can be considered in frail patients or those aged 70 years or older, transplant is not advised, he added.
For relapsed or refractory patients, FISH testing should be performed or repeated, because such patients are at high risk of progression to develop del[17]p or mutation, he noted.
Those who are asymptomatic can be observed or enrolled in a clinical trial, and those who are symptomatic can be enrolled in a clinical trial or treated with various novel agents, including ibrutinib, idelalisib/rituximab, venetoclax, or combination therapies with methylpred–anti-CD20, or alemtuzumab with or without rituximab. Referral for transplant may be warranted in these patients if they are fit.
“Progressive CLL patients with 17p deletion/p53 mutations are much less likely to do well with chemoimmunotherapy, and novel inhibitors are effective, but we still need to enhance complete response rates and minimal residual disease-negative status for these high-risk patients,” he said.
Dr. Kay reported consulting for or receiving grant/research support from Acerta, Celgene, Gilead, Infinity, MorphoSys, Pharmacyclics, and Tolero.
NEW YORK – Outside of clinical trials, therapy for early stage chronic lymphocytic leukemia in patients with deletion of the short arm of chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 requires the presence of active disease, according to Neil E. Kay, MD.
“Right now, we would propose that patients with del[17]p should have additional prognostic work-up. It’s very important to know if they are unmutated or mutated for the IgVH gene,” he said, adding that stimulated karyotype is also important to perform in those with del[17]p.
“The median overall survivorship in many phase II and phase III trials appears to be around 2 to 3 years,” he said.
Those with a chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 who receive chemoimmunotherapy very rarely achieve a complete response, or if they do they have a short duration of response, he added.
In treated patients, 17p deletion and p53 mutation are the most common abnormalities acquired during the course of the disease.
“Unfortunately there appears to be a selection pressure, and [in treated patients] the incidence of 17p and the p53 mutation has been reported up to 23%-44%. No one understands completely the biology of this, but it may be that subclones are present and expand, or that new mutations occur due to selection pressure of [chemoimmunotherapy] and the overgrowth of these subclones,” he said.
Importantly, not all patients with del[17]p or p53 mutation have bad outcomes; there are patients with indolent disease, he noted, adding that various criteria have been shown to help identify which patients are at risk for poor outcomes and to classify them according to risk. In general, lower-risk patients have mutated immunoglobulin heavy chain variable gene status, early stage disease, younger age, good performance status, and normal serum lactate dehydrogenase. These criteria could be used to identify low-risk patients who can be followed, he said.
Fluorescence in situ hybridization (FISH) evaluation of patients is a useful tool when there is no access to sequencing and other tests, Dr. Kay said, describing a recent multinational CLL Research Consortium study of nearly 1,600 patients (Br J Haematol. 2016 Apr;173[1]:105-13).
In that study, he and his colleagues found that patients with less than 50% 17p did not have such poor outcomes, but at 50%-plus they did much worse in terms of time to first treatment.
Based on the available data, Dr. Kay said that treatment is unnecessary in asymptomatic patients, except, perhaps, in high-risk patients identified using recently published risk models, for whom clinical trial enrollment may be considered.
“We do advocate having a discussion about allogeneic stem cell transplant since this may still be the only curative approach,” he added.
In patients with del[17]p and/or p53 mutation who have progressive disease, Dr. Kay said his take on the available data is that patients should first be categorized by age, then by whether they are fit or frail, and finally by whether or not they have del[17]p. Those under age 70 years without del[17]p and who have a mutated IgVH status should be considered for a clinical trial, and are also good candidates for chemoimmunotherapy. If they do have del[17]p or p53 mutation, consider clinical trial enrollment or treatment with ibrutinib, he said.
Fit patients in a complete response can be referred for transplant evaluation, but while the other treatments can be considered in frail patients or those aged 70 years or older, transplant is not advised, he added.
For relapsed or refractory patients, FISH testing should be performed or repeated, because such patients are at high risk of progression to develop del[17]p or mutation, he noted.
Those who are asymptomatic can be observed or enrolled in a clinical trial, and those who are symptomatic can be enrolled in a clinical trial or treated with various novel agents, including ibrutinib, idelalisib/rituximab, venetoclax, or combination therapies with methylpred–anti-CD20, or alemtuzumab with or without rituximab. Referral for transplant may be warranted in these patients if they are fit.
“Progressive CLL patients with 17p deletion/p53 mutations are much less likely to do well with chemoimmunotherapy, and novel inhibitors are effective, but we still need to enhance complete response rates and minimal residual disease-negative status for these high-risk patients,” he said.
Dr. Kay reported consulting for or receiving grant/research support from Acerta, Celgene, Gilead, Infinity, MorphoSys, Pharmacyclics, and Tolero.
NEW YORK – Outside of clinical trials, therapy for early stage chronic lymphocytic leukemia in patients with deletion of the short arm of chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 requires the presence of active disease, according to Neil E. Kay, MD.
“Right now, we would propose that patients with del[17]p should have additional prognostic work-up. It’s very important to know if they are unmutated or mutated for the IgVH gene,” he said, adding that stimulated karyotype is also important to perform in those with del[17]p.
“The median overall survivorship in many phase II and phase III trials appears to be around 2 to 3 years,” he said.
Those with a chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 who receive chemoimmunotherapy very rarely achieve a complete response, or if they do they have a short duration of response, he added.
In treated patients, 17p deletion and p53 mutation are the most common abnormalities acquired during the course of the disease.
“Unfortunately there appears to be a selection pressure, and [in treated patients] the incidence of 17p and the p53 mutation has been reported up to 23%-44%. No one understands completely the biology of this, but it may be that subclones are present and expand, or that new mutations occur due to selection pressure of [chemoimmunotherapy] and the overgrowth of these subclones,” he said.
Importantly, not all patients with del[17]p or p53 mutation have bad outcomes; there are patients with indolent disease, he noted, adding that various criteria have been shown to help identify which patients are at risk for poor outcomes and to classify them according to risk. In general, lower-risk patients have mutated immunoglobulin heavy chain variable gene status, early stage disease, younger age, good performance status, and normal serum lactate dehydrogenase. These criteria could be used to identify low-risk patients who can be followed, he said.
Fluorescence in situ hybridization (FISH) evaluation of patients is a useful tool when there is no access to sequencing and other tests, Dr. Kay said, describing a recent multinational CLL Research Consortium study of nearly 1,600 patients (Br J Haematol. 2016 Apr;173[1]:105-13).
In that study, he and his colleagues found that patients with less than 50% 17p did not have such poor outcomes, but at 50%-plus they did much worse in terms of time to first treatment.
Based on the available data, Dr. Kay said that treatment is unnecessary in asymptomatic patients, except, perhaps, in high-risk patients identified using recently published risk models, for whom clinical trial enrollment may be considered.
“We do advocate having a discussion about allogeneic stem cell transplant since this may still be the only curative approach,” he added.
In patients with del[17]p and/or p53 mutation who have progressive disease, Dr. Kay said his take on the available data is that patients should first be categorized by age, then by whether they are fit or frail, and finally by whether or not they have del[17]p. Those under age 70 years without del[17]p and who have a mutated IgVH status should be considered for a clinical trial, and are also good candidates for chemoimmunotherapy. If they do have del[17]p or p53 mutation, consider clinical trial enrollment or treatment with ibrutinib, he said.
Fit patients in a complete response can be referred for transplant evaluation, but while the other treatments can be considered in frail patients or those aged 70 years or older, transplant is not advised, he added.
For relapsed or refractory patients, FISH testing should be performed or repeated, because such patients are at high risk of progression to develop del[17]p or mutation, he noted.
Those who are asymptomatic can be observed or enrolled in a clinical trial, and those who are symptomatic can be enrolled in a clinical trial or treated with various novel agents, including ibrutinib, idelalisib/rituximab, venetoclax, or combination therapies with methylpred–anti-CD20, or alemtuzumab with or without rituximab. Referral for transplant may be warranted in these patients if they are fit.
“Progressive CLL patients with 17p deletion/p53 mutations are much less likely to do well with chemoimmunotherapy, and novel inhibitors are effective, but we still need to enhance complete response rates and minimal residual disease-negative status for these high-risk patients,” he said.
Dr. Kay reported consulting for or receiving grant/research support from Acerta, Celgene, Gilead, Infinity, MorphoSys, Pharmacyclics, and Tolero.
EXPERT ANALYSIS FROM LYMPHOMA & MYELOMA
In high-risk myeloma, look beyond VRD for induction
NEW YORK – There’s more to induction therapy for transplant-eligible multiple myeloma patients than the go-to combination of bortezomib, lenalidomide, and dexamethasone, commonly known as VRD, according to Joseph R. Mikhael, MD.
“Outstanding evidence” has emerged that demonstrates the value of combining multiple mechanisms of action, but there are numerous options available – there is a trend toward increasing use of carfilzomib, for example – and VRD isn’t necessarily the best option for all patients, nor is it available in all cases, Dr. Mikhael of Mayo Clinic Arizona, Scottsdale, said at an international congress on hematologic malignancies.
Further, choosing the treatment method shown to give the most powerful or deepest response as a default isn’t necessarily the best option, either, he said, noting data showing that the regimen most often associated with at least very good partial response (VGPR) after four cycles in newly diagnosed multiple myeloma (carfilzomib, lenalidomide, dexamethasone, or KRD, about a 90% response rate) costs 2.5 times more than does the regimen (lenalidomide, dexamethasone, or RD) that provided about a 50% response rate ($250,000 vs. $100,000 per year).“But it’s also the toxicity cost ... do we need that many [drugs]?” he said, adding that “just because a clinical trial shows that three drugs work better than two, it doesn’t mean that every time I have a patient who is eligible I’m going to go with all three.”
It may be that a patient can start on two, with a third added if needed, he added.
“That being said, we want to maximize the synergy of those three, especially in high-risk patients,” he said.
Prior to 2016, popular regimens included CyBorD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone), which were commonly used worldwide. CTD (cyclophosphamide, thalidomide, dexamethasone) was used in Brazil and other countries where it was difficult to obtain bortezomib; VRD was “king of the hill” in the United States, and transplant was routinely recommended, Dr. Mikhael said.
A number of recent studies are changing that paradigm, he said.
One such study, the prospective randomized Intergroupe Francophone du Myélome (IFM) 2013-04 trial, showed that VTD is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) for induction in patients with de novo multiple myeloma. VGPR and PR rates were significantly superior in the VTD arm.
Of note, hematologic toxicity increased in the VCD arm, and the peripheral neuropathy rate was higher in the VTD arm. However, the study was conducted at a time when bortezomib was generally used twice weekly; now it is standard to use it once weekly and subcutaneously, which significantly reduces the risk of peripheral neuropathy.
The authors advocated the preferential use of VTD over VCD for induction, based on the synergistic effect of a proteasome inhibitor and immunomodulatory drug, Dr. Mikhael said.
“Meanwhile, back in the United States, many trials were starting to be built with VRD,” he said, noting that “really extraordinary” responses were seen in phase I and phase II studies.
Perhaps the VRD study (called RVD in this case) that is most cited is the phase III IFM 2009 study comparing RVD with and without autologous stem cell transplant in newly diagnosed younger multiple myeloma patients. Although final results are still pending, interim results reported at the American Society of Hematology 2015 meeting (abstract 391) have been very helpful, Dr. Mikhael said.
The authors reported a 31% reduction in the risk of progression or death with autologous stem cell transplant versus RVD alone in patients with newly diagnosed multiple myeloma, as well as improved rates of thrombotic thrombocytopenic purpura (TTP) and minimal residual disease negativity (MRD). Mortality rates were similar.
The findings show that transplantation is feasible (93%), and associated with acceptable mortality (1.4%), an increased rate of negative MRD versus with RVD alone (80% vs. 65%), an improved 4-year progression-free survival (47% vs. 35%), and improved 4-year TTP (49% vs. 35%).
“Here the question was not so much is RVD the standard ... but is RVD plus transplant superior to RVD alone,” he said.
Surprising to many, especially the “dissenters in the crowd” who thought perhaps RVD would be the death knell to autologous stem cell transplant, transplant actually significantly improved the depth of response, he added.
Median progression-free survival at 10 months was 43% with versus 34% without transplantation.
“So there was definitely an argument here that transplant remains the standard of care,” he said, noting that transplant should be considered as decisions are made about up-front therapy.
As for the trend of bringing carfilzomib in earlier on in treatment, a number of studies, including the phase II CYKLONE study by Dr. Mikhael and his colleagues, suggest it improves the rates of deep response; some show that is especially true when used with transplant.
One study looking at KRD showed that the regimen provides high rates of deep and durable responses with acceptable tolerability – a finding that needs confirmation in a randomized setting.
Other studies are comparing KRD and VRD, and KRD and KCyd (carfilzomib, cyclophosphamide), as well as adding monoclonal antibodies such as daratumumab to treatment regimens, and results are very much anticipated, Dr. Mikhael said.
Currently, however, VRD remains the standard of care in standard risk and intermediate risk patients.
“But consideration in the highest-risk patients should be given to something like KRD,” he said. “We still recommend transplant across the board, we still recommend some form of maintenance therapy, be it with lenalidomide for most patients, but potentially bortezomib combined with carfilzomib in the highest risk patients.”
Dr. Mikhael reported consulting for Abbvie, Celgene, Onyx, and Sanofi.
NEW YORK – There’s more to induction therapy for transplant-eligible multiple myeloma patients than the go-to combination of bortezomib, lenalidomide, and dexamethasone, commonly known as VRD, according to Joseph R. Mikhael, MD.
“Outstanding evidence” has emerged that demonstrates the value of combining multiple mechanisms of action, but there are numerous options available – there is a trend toward increasing use of carfilzomib, for example – and VRD isn’t necessarily the best option for all patients, nor is it available in all cases, Dr. Mikhael of Mayo Clinic Arizona, Scottsdale, said at an international congress on hematologic malignancies.
Further, choosing the treatment method shown to give the most powerful or deepest response as a default isn’t necessarily the best option, either, he said, noting data showing that the regimen most often associated with at least very good partial response (VGPR) after four cycles in newly diagnosed multiple myeloma (carfilzomib, lenalidomide, dexamethasone, or KRD, about a 90% response rate) costs 2.5 times more than does the regimen (lenalidomide, dexamethasone, or RD) that provided about a 50% response rate ($250,000 vs. $100,000 per year).“But it’s also the toxicity cost ... do we need that many [drugs]?” he said, adding that “just because a clinical trial shows that three drugs work better than two, it doesn’t mean that every time I have a patient who is eligible I’m going to go with all three.”
It may be that a patient can start on two, with a third added if needed, he added.
“That being said, we want to maximize the synergy of those three, especially in high-risk patients,” he said.
Prior to 2016, popular regimens included CyBorD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone), which were commonly used worldwide. CTD (cyclophosphamide, thalidomide, dexamethasone) was used in Brazil and other countries where it was difficult to obtain bortezomib; VRD was “king of the hill” in the United States, and transplant was routinely recommended, Dr. Mikhael said.
A number of recent studies are changing that paradigm, he said.
One such study, the prospective randomized Intergroupe Francophone du Myélome (IFM) 2013-04 trial, showed that VTD is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) for induction in patients with de novo multiple myeloma. VGPR and PR rates were significantly superior in the VTD arm.
Of note, hematologic toxicity increased in the VCD arm, and the peripheral neuropathy rate was higher in the VTD arm. However, the study was conducted at a time when bortezomib was generally used twice weekly; now it is standard to use it once weekly and subcutaneously, which significantly reduces the risk of peripheral neuropathy.
The authors advocated the preferential use of VTD over VCD for induction, based on the synergistic effect of a proteasome inhibitor and immunomodulatory drug, Dr. Mikhael said.
“Meanwhile, back in the United States, many trials were starting to be built with VRD,” he said, noting that “really extraordinary” responses were seen in phase I and phase II studies.
Perhaps the VRD study (called RVD in this case) that is most cited is the phase III IFM 2009 study comparing RVD with and without autologous stem cell transplant in newly diagnosed younger multiple myeloma patients. Although final results are still pending, interim results reported at the American Society of Hematology 2015 meeting (abstract 391) have been very helpful, Dr. Mikhael said.
The authors reported a 31% reduction in the risk of progression or death with autologous stem cell transplant versus RVD alone in patients with newly diagnosed multiple myeloma, as well as improved rates of thrombotic thrombocytopenic purpura (TTP) and minimal residual disease negativity (MRD). Mortality rates were similar.
The findings show that transplantation is feasible (93%), and associated with acceptable mortality (1.4%), an increased rate of negative MRD versus with RVD alone (80% vs. 65%), an improved 4-year progression-free survival (47% vs. 35%), and improved 4-year TTP (49% vs. 35%).
“Here the question was not so much is RVD the standard ... but is RVD plus transplant superior to RVD alone,” he said.
Surprising to many, especially the “dissenters in the crowd” who thought perhaps RVD would be the death knell to autologous stem cell transplant, transplant actually significantly improved the depth of response, he added.
Median progression-free survival at 10 months was 43% with versus 34% without transplantation.
“So there was definitely an argument here that transplant remains the standard of care,” he said, noting that transplant should be considered as decisions are made about up-front therapy.
As for the trend of bringing carfilzomib in earlier on in treatment, a number of studies, including the phase II CYKLONE study by Dr. Mikhael and his colleagues, suggest it improves the rates of deep response; some show that is especially true when used with transplant.
One study looking at KRD showed that the regimen provides high rates of deep and durable responses with acceptable tolerability – a finding that needs confirmation in a randomized setting.
Other studies are comparing KRD and VRD, and KRD and KCyd (carfilzomib, cyclophosphamide), as well as adding monoclonal antibodies such as daratumumab to treatment regimens, and results are very much anticipated, Dr. Mikhael said.
Currently, however, VRD remains the standard of care in standard risk and intermediate risk patients.
“But consideration in the highest-risk patients should be given to something like KRD,” he said. “We still recommend transplant across the board, we still recommend some form of maintenance therapy, be it with lenalidomide for most patients, but potentially bortezomib combined with carfilzomib in the highest risk patients.”
Dr. Mikhael reported consulting for Abbvie, Celgene, Onyx, and Sanofi.
NEW YORK – There’s more to induction therapy for transplant-eligible multiple myeloma patients than the go-to combination of bortezomib, lenalidomide, and dexamethasone, commonly known as VRD, according to Joseph R. Mikhael, MD.
“Outstanding evidence” has emerged that demonstrates the value of combining multiple mechanisms of action, but there are numerous options available – there is a trend toward increasing use of carfilzomib, for example – and VRD isn’t necessarily the best option for all patients, nor is it available in all cases, Dr. Mikhael of Mayo Clinic Arizona, Scottsdale, said at an international congress on hematologic malignancies.
Further, choosing the treatment method shown to give the most powerful or deepest response as a default isn’t necessarily the best option, either, he said, noting data showing that the regimen most often associated with at least very good partial response (VGPR) after four cycles in newly diagnosed multiple myeloma (carfilzomib, lenalidomide, dexamethasone, or KRD, about a 90% response rate) costs 2.5 times more than does the regimen (lenalidomide, dexamethasone, or RD) that provided about a 50% response rate ($250,000 vs. $100,000 per year).“But it’s also the toxicity cost ... do we need that many [drugs]?” he said, adding that “just because a clinical trial shows that three drugs work better than two, it doesn’t mean that every time I have a patient who is eligible I’m going to go with all three.”
It may be that a patient can start on two, with a third added if needed, he added.
“That being said, we want to maximize the synergy of those three, especially in high-risk patients,” he said.
Prior to 2016, popular regimens included CyBorD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone), which were commonly used worldwide. CTD (cyclophosphamide, thalidomide, dexamethasone) was used in Brazil and other countries where it was difficult to obtain bortezomib; VRD was “king of the hill” in the United States, and transplant was routinely recommended, Dr. Mikhael said.
A number of recent studies are changing that paradigm, he said.
One such study, the prospective randomized Intergroupe Francophone du Myélome (IFM) 2013-04 trial, showed that VTD is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) for induction in patients with de novo multiple myeloma. VGPR and PR rates were significantly superior in the VTD arm.
Of note, hematologic toxicity increased in the VCD arm, and the peripheral neuropathy rate was higher in the VTD arm. However, the study was conducted at a time when bortezomib was generally used twice weekly; now it is standard to use it once weekly and subcutaneously, which significantly reduces the risk of peripheral neuropathy.
The authors advocated the preferential use of VTD over VCD for induction, based on the synergistic effect of a proteasome inhibitor and immunomodulatory drug, Dr. Mikhael said.
“Meanwhile, back in the United States, many trials were starting to be built with VRD,” he said, noting that “really extraordinary” responses were seen in phase I and phase II studies.
Perhaps the VRD study (called RVD in this case) that is most cited is the phase III IFM 2009 study comparing RVD with and without autologous stem cell transplant in newly diagnosed younger multiple myeloma patients. Although final results are still pending, interim results reported at the American Society of Hematology 2015 meeting (abstract 391) have been very helpful, Dr. Mikhael said.
The authors reported a 31% reduction in the risk of progression or death with autologous stem cell transplant versus RVD alone in patients with newly diagnosed multiple myeloma, as well as improved rates of thrombotic thrombocytopenic purpura (TTP) and minimal residual disease negativity (MRD). Mortality rates were similar.
The findings show that transplantation is feasible (93%), and associated with acceptable mortality (1.4%), an increased rate of negative MRD versus with RVD alone (80% vs. 65%), an improved 4-year progression-free survival (47% vs. 35%), and improved 4-year TTP (49% vs. 35%).
“Here the question was not so much is RVD the standard ... but is RVD plus transplant superior to RVD alone,” he said.
Surprising to many, especially the “dissenters in the crowd” who thought perhaps RVD would be the death knell to autologous stem cell transplant, transplant actually significantly improved the depth of response, he added.
Median progression-free survival at 10 months was 43% with versus 34% without transplantation.
“So there was definitely an argument here that transplant remains the standard of care,” he said, noting that transplant should be considered as decisions are made about up-front therapy.
As for the trend of bringing carfilzomib in earlier on in treatment, a number of studies, including the phase II CYKLONE study by Dr. Mikhael and his colleagues, suggest it improves the rates of deep response; some show that is especially true when used with transplant.
One study looking at KRD showed that the regimen provides high rates of deep and durable responses with acceptable tolerability – a finding that needs confirmation in a randomized setting.
Other studies are comparing KRD and VRD, and KRD and KCyd (carfilzomib, cyclophosphamide), as well as adding monoclonal antibodies such as daratumumab to treatment regimens, and results are very much anticipated, Dr. Mikhael said.
Currently, however, VRD remains the standard of care in standard risk and intermediate risk patients.
“But consideration in the highest-risk patients should be given to something like KRD,” he said. “We still recommend transplant across the board, we still recommend some form of maintenance therapy, be it with lenalidomide for most patients, but potentially bortezomib combined with carfilzomib in the highest risk patients.”
Dr. Mikhael reported consulting for Abbvie, Celgene, Onyx, and Sanofi.
EXPERT ANALYSIS FROM LYMPHOMA & MYELOMA
Why CLL may go chemo free
NEW YORK – The approach to treating chronic lymphocytic leukemia (CLL) is evolving, and while chemoimmunotherapy remains a reasonable initial option in some cases, a “chemo-free” approach is also a very real possibility, according to Bruce D. Cheson, MD.
A number of studies showing survival benefits with targeted therapies vs. chemoimmunotherapy (CIT) regimens have been completed, including studies that look specifically at outcomes by mutation status and other factors. One example – a likely game changer – is the ALLIANCE trial, a randomized phase III study of bendamustine plus rituximab vs. ibrutinib plus rituximab vs. ibrutinib alone in untreated CLL patients aged 65 years or older, Dr. Cheson of Georgetown University Hospital, Washington, said at an international congress on hematologic malignancies.
“I think [the ALLIANCE] trial has the possibility of totally changing how we treat patients with CLL, even though it was done in older patients,” he said, noting that the study is completed, but final results are pending adequate follow-up.
Based on the available data, he suggests a treatment paradigm for untreated CLL patients who require therapy that begins with consideration of patient age, comorbidities, functional status, and fluorescence in situ hybridization (FISH).
While clinical trial enrollment is preferable, those who are CIT eligible based on age and comorbidities can be treated with bendamustine/rituximab (BR), fludarabine/cyclophosphamide/rituximab (FCR), or ibrutinib.
“I think BR and FCR are both reasonable options, although the latter primarily for young, IGHV-mutated patients, and certainly ibrutinib remains an option for this patient population,” he said.
For those not eligible for CIT, options include ibrutinib and chlorambucil/obinutuzumab. For those with deletion 17p, ibrutinib is the standard for frontline therapy. And for those who are frail, ibrutinib is a good option.
“Some might use an anti-CD20, but as a single agent, it’s not what I would prefer,” Dr. Cheson said, explaining that response rates with such agents are low and tend to lack durability.
CIT remains a reasonable initial option for those patients who are mutated, but with the prolonged progression-free survival seen with ibrutinib in several trials, he predicted that will change over time.
“The role of targeted approaches is a subject of discussion. It takes the most time in my clinic of any discussion I have. [Patients ask] ‘Should I get ibrutinib? Should I get chemoimmunotherapy?’ ” he said. “One needs to take into account patient age and comorbidities, the fact that with CIT you are six [treatments] and done vs. indefinite therapy [with ibrutinib]. There is cost and there is compliance that one needs to consider.”
As for relapsed/refractory CLL, the role of CIT is particularly diminished in the wake of trials such as HELIOS and RESONATE, showing survival benefits with ibrutinib, others showing survival benefits with rituximab/idelalisib (R-idelalisib), and trials showing better results with venetoclax non-CIT regimens than would be expected with CIT regimens. As with treatment-naive CLL patients, age, comorbidities, functional status, and FISH should be considered in those with previously treated CLL who require therapy, and if clinical trial enrollment is not possible, treatment options depend on certain patient characteristics.
“For patients who had a long first response to chemoimmunotherapy, I would still use ibrutinib, and in select patients, R-idelalisib,” he said.
If they had a long response with BR, or FCR, retreatment with those can be considered as well, he noted, adding, “But I don’t see the point when the results with kinase inhibitors are at least as good as, if not better than one would expect with CIT in this context.”
In patients who had short first response, ibrutinib and R-idelalisib are the best options. For those with deletion 17p, the best options are ibrutinib or venetoclax, and possibly R-idelalisib. For frail patients, options include ibrutinib, R-idelalisib, or anti-CD20, although, as with untreated patients, the latter is his least favorite option because of the increased risk of toxicity in this population, he said.
“I think the role of chemoimmunotherapy in CLL is vanishing, and a chemo-free world for CLL patients is a reality,” he said.
Dr. Cheson reported consulting for Acerta, Celgene Pharmacyclics, and Roche-Genentech.
NEW YORK – The approach to treating chronic lymphocytic leukemia (CLL) is evolving, and while chemoimmunotherapy remains a reasonable initial option in some cases, a “chemo-free” approach is also a very real possibility, according to Bruce D. Cheson, MD.
A number of studies showing survival benefits with targeted therapies vs. chemoimmunotherapy (CIT) regimens have been completed, including studies that look specifically at outcomes by mutation status and other factors. One example – a likely game changer – is the ALLIANCE trial, a randomized phase III study of bendamustine plus rituximab vs. ibrutinib plus rituximab vs. ibrutinib alone in untreated CLL patients aged 65 years or older, Dr. Cheson of Georgetown University Hospital, Washington, said at an international congress on hematologic malignancies.
“I think [the ALLIANCE] trial has the possibility of totally changing how we treat patients with CLL, even though it was done in older patients,” he said, noting that the study is completed, but final results are pending adequate follow-up.
Based on the available data, he suggests a treatment paradigm for untreated CLL patients who require therapy that begins with consideration of patient age, comorbidities, functional status, and fluorescence in situ hybridization (FISH).
While clinical trial enrollment is preferable, those who are CIT eligible based on age and comorbidities can be treated with bendamustine/rituximab (BR), fludarabine/cyclophosphamide/rituximab (FCR), or ibrutinib.
“I think BR and FCR are both reasonable options, although the latter primarily for young, IGHV-mutated patients, and certainly ibrutinib remains an option for this patient population,” he said.
For those not eligible for CIT, options include ibrutinib and chlorambucil/obinutuzumab. For those with deletion 17p, ibrutinib is the standard for frontline therapy. And for those who are frail, ibrutinib is a good option.
“Some might use an anti-CD20, but as a single agent, it’s not what I would prefer,” Dr. Cheson said, explaining that response rates with such agents are low and tend to lack durability.
CIT remains a reasonable initial option for those patients who are mutated, but with the prolonged progression-free survival seen with ibrutinib in several trials, he predicted that will change over time.
“The role of targeted approaches is a subject of discussion. It takes the most time in my clinic of any discussion I have. [Patients ask] ‘Should I get ibrutinib? Should I get chemoimmunotherapy?’ ” he said. “One needs to take into account patient age and comorbidities, the fact that with CIT you are six [treatments] and done vs. indefinite therapy [with ibrutinib]. There is cost and there is compliance that one needs to consider.”
As for relapsed/refractory CLL, the role of CIT is particularly diminished in the wake of trials such as HELIOS and RESONATE, showing survival benefits with ibrutinib, others showing survival benefits with rituximab/idelalisib (R-idelalisib), and trials showing better results with venetoclax non-CIT regimens than would be expected with CIT regimens. As with treatment-naive CLL patients, age, comorbidities, functional status, and FISH should be considered in those with previously treated CLL who require therapy, and if clinical trial enrollment is not possible, treatment options depend on certain patient characteristics.
“For patients who had a long first response to chemoimmunotherapy, I would still use ibrutinib, and in select patients, R-idelalisib,” he said.
If they had a long response with BR, or FCR, retreatment with those can be considered as well, he noted, adding, “But I don’t see the point when the results with kinase inhibitors are at least as good as, if not better than one would expect with CIT in this context.”
In patients who had short first response, ibrutinib and R-idelalisib are the best options. For those with deletion 17p, the best options are ibrutinib or venetoclax, and possibly R-idelalisib. For frail patients, options include ibrutinib, R-idelalisib, or anti-CD20, although, as with untreated patients, the latter is his least favorite option because of the increased risk of toxicity in this population, he said.
“I think the role of chemoimmunotherapy in CLL is vanishing, and a chemo-free world for CLL patients is a reality,” he said.
Dr. Cheson reported consulting for Acerta, Celgene Pharmacyclics, and Roche-Genentech.
NEW YORK – The approach to treating chronic lymphocytic leukemia (CLL) is evolving, and while chemoimmunotherapy remains a reasonable initial option in some cases, a “chemo-free” approach is also a very real possibility, according to Bruce D. Cheson, MD.
A number of studies showing survival benefits with targeted therapies vs. chemoimmunotherapy (CIT) regimens have been completed, including studies that look specifically at outcomes by mutation status and other factors. One example – a likely game changer – is the ALLIANCE trial, a randomized phase III study of bendamustine plus rituximab vs. ibrutinib plus rituximab vs. ibrutinib alone in untreated CLL patients aged 65 years or older, Dr. Cheson of Georgetown University Hospital, Washington, said at an international congress on hematologic malignancies.
“I think [the ALLIANCE] trial has the possibility of totally changing how we treat patients with CLL, even though it was done in older patients,” he said, noting that the study is completed, but final results are pending adequate follow-up.
Based on the available data, he suggests a treatment paradigm for untreated CLL patients who require therapy that begins with consideration of patient age, comorbidities, functional status, and fluorescence in situ hybridization (FISH).
While clinical trial enrollment is preferable, those who are CIT eligible based on age and comorbidities can be treated with bendamustine/rituximab (BR), fludarabine/cyclophosphamide/rituximab (FCR), or ibrutinib.
“I think BR and FCR are both reasonable options, although the latter primarily for young, IGHV-mutated patients, and certainly ibrutinib remains an option for this patient population,” he said.
For those not eligible for CIT, options include ibrutinib and chlorambucil/obinutuzumab. For those with deletion 17p, ibrutinib is the standard for frontline therapy. And for those who are frail, ibrutinib is a good option.
“Some might use an anti-CD20, but as a single agent, it’s not what I would prefer,” Dr. Cheson said, explaining that response rates with such agents are low and tend to lack durability.
CIT remains a reasonable initial option for those patients who are mutated, but with the prolonged progression-free survival seen with ibrutinib in several trials, he predicted that will change over time.
“The role of targeted approaches is a subject of discussion. It takes the most time in my clinic of any discussion I have. [Patients ask] ‘Should I get ibrutinib? Should I get chemoimmunotherapy?’ ” he said. “One needs to take into account patient age and comorbidities, the fact that with CIT you are six [treatments] and done vs. indefinite therapy [with ibrutinib]. There is cost and there is compliance that one needs to consider.”
As for relapsed/refractory CLL, the role of CIT is particularly diminished in the wake of trials such as HELIOS and RESONATE, showing survival benefits with ibrutinib, others showing survival benefits with rituximab/idelalisib (R-idelalisib), and trials showing better results with venetoclax non-CIT regimens than would be expected with CIT regimens. As with treatment-naive CLL patients, age, comorbidities, functional status, and FISH should be considered in those with previously treated CLL who require therapy, and if clinical trial enrollment is not possible, treatment options depend on certain patient characteristics.
“For patients who had a long first response to chemoimmunotherapy, I would still use ibrutinib, and in select patients, R-idelalisib,” he said.
If they had a long response with BR, or FCR, retreatment with those can be considered as well, he noted, adding, “But I don’t see the point when the results with kinase inhibitors are at least as good as, if not better than one would expect with CIT in this context.”
In patients who had short first response, ibrutinib and R-idelalisib are the best options. For those with deletion 17p, the best options are ibrutinib or venetoclax, and possibly R-idelalisib. For frail patients, options include ibrutinib, R-idelalisib, or anti-CD20, although, as with untreated patients, the latter is his least favorite option because of the increased risk of toxicity in this population, he said.
“I think the role of chemoimmunotherapy in CLL is vanishing, and a chemo-free world for CLL patients is a reality,” he said.
Dr. Cheson reported consulting for Acerta, Celgene Pharmacyclics, and Roche-Genentech.
Review offers reassurance on prenatal Tdap vaccination safety
Combined tetanus, diphtheria, and pertussis (Tdap) vaccination during the second or third trimester of pregnancy does not appear to be associated with clinically significant harm to the fetus or neonate, according to findings from a systematic review of the literature.
However, the findings are limited by a dearth of randomized, placebo-controlled trials.
Point estimates for all anomalies after Tdap vaccination ranged from 1.20 to 1.60, Mark McMillan of the University of Adelaide, North Adelaide, Australia and his colleagues reported (Obstet Gynecol. 2017;129:560-73).
“Statistical imprecision for combined ‘all anomalies’ outcomes meant that upper 95% [confidence intervals] were 2.0 or above,” the researchers wrote. “Statistical imprecision was even greater in the individual congenital anomaly outcomes and little confidence can be placed in these estimates.”
Additionally, one of three studies assessing chorioamnionitis showed a small but significant increase in risk (relative risk, 1.19) after vaccination.
Among the studies examining medically attended adverse events, no association was seen between vaccination and such events or reactions, including neurologic events, gestational diabetes, preeclampsia or eclampsia, and cardiac events. Maternal effects included fever in 1%-3% of subjects, and headache, malaise, and myalgia, which were more common.
“Overall, despite the limitations described, the review offers reassurance for antenatal Tdap or Tdap-IPV [diphtheria, tetanus, pertussis, and polio] vaccination administered during the second or third trimester of pregnancy,” the researchers wrote. “These findings need to be interpreted in the context of the evidence of effectiveness of antenatal vaccination programs at preventing serious morbidity and mortality from pertussis in young infants.”
Mr. McMillan received travel support from GlaxoSmithKline, and institutional research grants from GSK and Sanofi Pasteur. Other researchers also reported receiving research funding and/or travel support from these companies.
Combined tetanus, diphtheria, and pertussis (Tdap) vaccination during the second or third trimester of pregnancy does not appear to be associated with clinically significant harm to the fetus or neonate, according to findings from a systematic review of the literature.
However, the findings are limited by a dearth of randomized, placebo-controlled trials.
Point estimates for all anomalies after Tdap vaccination ranged from 1.20 to 1.60, Mark McMillan of the University of Adelaide, North Adelaide, Australia and his colleagues reported (Obstet Gynecol. 2017;129:560-73).
“Statistical imprecision for combined ‘all anomalies’ outcomes meant that upper 95% [confidence intervals] were 2.0 or above,” the researchers wrote. “Statistical imprecision was even greater in the individual congenital anomaly outcomes and little confidence can be placed in these estimates.”
Additionally, one of three studies assessing chorioamnionitis showed a small but significant increase in risk (relative risk, 1.19) after vaccination.
Among the studies examining medically attended adverse events, no association was seen between vaccination and such events or reactions, including neurologic events, gestational diabetes, preeclampsia or eclampsia, and cardiac events. Maternal effects included fever in 1%-3% of subjects, and headache, malaise, and myalgia, which were more common.
“Overall, despite the limitations described, the review offers reassurance for antenatal Tdap or Tdap-IPV [diphtheria, tetanus, pertussis, and polio] vaccination administered during the second or third trimester of pregnancy,” the researchers wrote. “These findings need to be interpreted in the context of the evidence of effectiveness of antenatal vaccination programs at preventing serious morbidity and mortality from pertussis in young infants.”
Mr. McMillan received travel support from GlaxoSmithKline, and institutional research grants from GSK and Sanofi Pasteur. Other researchers also reported receiving research funding and/or travel support from these companies.
Combined tetanus, diphtheria, and pertussis (Tdap) vaccination during the second or third trimester of pregnancy does not appear to be associated with clinically significant harm to the fetus or neonate, according to findings from a systematic review of the literature.
However, the findings are limited by a dearth of randomized, placebo-controlled trials.
Point estimates for all anomalies after Tdap vaccination ranged from 1.20 to 1.60, Mark McMillan of the University of Adelaide, North Adelaide, Australia and his colleagues reported (Obstet Gynecol. 2017;129:560-73).
“Statistical imprecision for combined ‘all anomalies’ outcomes meant that upper 95% [confidence intervals] were 2.0 or above,” the researchers wrote. “Statistical imprecision was even greater in the individual congenital anomaly outcomes and little confidence can be placed in these estimates.”
Additionally, one of three studies assessing chorioamnionitis showed a small but significant increase in risk (relative risk, 1.19) after vaccination.
Among the studies examining medically attended adverse events, no association was seen between vaccination and such events or reactions, including neurologic events, gestational diabetes, preeclampsia or eclampsia, and cardiac events. Maternal effects included fever in 1%-3% of subjects, and headache, malaise, and myalgia, which were more common.
“Overall, despite the limitations described, the review offers reassurance for antenatal Tdap or Tdap-IPV [diphtheria, tetanus, pertussis, and polio] vaccination administered during the second or third trimester of pregnancy,” the researchers wrote. “These findings need to be interpreted in the context of the evidence of effectiveness of antenatal vaccination programs at preventing serious morbidity and mortality from pertussis in young infants.”
Mr. McMillan received travel support from GlaxoSmithKline, and institutional research grants from GSK and Sanofi Pasteur. Other researchers also reported receiving research funding and/or travel support from these companies.
FROM OBSTETRICS & GYNECOLOGY
Key clinical point:
Major finding: Point estimates for all anomalies after Tdap vaccination ranged from 1.20 to 1.60.
Data source: A systematic review of 21 studies.
Disclosures: Mr. McMillan received travel support from GlaxoSmithKline, and institutional research grants from GSK and Sanofi Pasteur. Other researchers also reported receiving research funding and/or travel support from these companies.