Will Pass

Women with invasive, well-differentiated mucinous ovarian cancer are more likely to die from their disease within 10 years of diagnosis than women with mucinous borderline ovarian tumors, according to a retrospective study of more than 2,700 cases.

The analysis also revealed different clinical characteristics, reported lead author Koji Matsuo, MD, PhD of the University of Southern California, Los Angeles, and his colleagues. For example, compared with borderline ovarian tumors (BOT), patients with ovarian cancer (OC) were usually older and had undergone hysterectomy.

“Our study endorses the importance of making the proper diagnosis for invasive cancer when the ovarian tumor is of mucinous histology,” the investigators wrote in Gynecologic Oncology.

Using Surveillance, Epidemiology, and End Results data from 1988-2000, the analysis included 581 cases of stage I, invasive, well-differentiated mucinous OC and 2,130 cases of stage I mucinous BOT. The investigators noted “histological misclassification of BOT as OC or OC as BOT is not uncommon,” because of similar histopathologic characteristics.

Multivariable analysis showed that, compared with cases of BOT, women with OC were more often from the eastern United States (22.0% vs. 13.6%), older (51.9 vs. 48.0 years), and had a history of lymphadenectomy (47.0% vs. 23.2%) or hysterectomy (64.4% vs. 35.8%). Women with OC were also more likely to have tumors smaller than 4 cm (12.9% vs. 8.9%) and stage T1c disease (15.7% vs. 7.3%). Rates of OC declined over time, from 34.7% during 1988-1991 to 22.0% during 1997-2000. Following propensity score matching, multivariable analysis showed that 10-year cause-specific survival rates for OC and BOT were 92.7% and 97.5%, respectively, giving OC a hazard ratio of 2.03 (P = .007). Overall survival showed a similar disparity, of 76.1% for OC, compared with 83.6% for BOT. The investigators concluded that “survival of these two diseases is completely different.”

Regarding histopathologic misclassification, the investigators proposed “a standardized specimen sectioning protocol and diagnostic criteria for mucinous ovarian tumors.”

The study was funded by Ensign Endowment for Gynecologic Cancer Research. The investigators reported financial relationships with KIYATEC, BioPath, M-Trap, and Chugai.

SOURCE: Matsuo K et al. Gynecol Oncol. 2019 Feb 20. doi: 10.1016/j.ygyno.2019.02.003.

Women with invasive, well-differentiated mucinous ovarian cancer are more likely to die from their disease within 10 years of diagnosis than women with mucinous borderline ovarian tumors, according to a retrospective study of more than 2,700 cases.

The analysis also revealed different clinical characteristics, reported lead author Koji Matsuo, MD, PhD of the University of Southern California, Los Angeles, and his colleagues. For example, compared with borderline ovarian tumors (BOT), patients with ovarian cancer (OC) were usually older and had undergone hysterectomy.

“Our study endorses the importance of making the proper diagnosis for invasive cancer when the ovarian tumor is of mucinous histology,” the investigators wrote in Gynecologic Oncology.

Using Surveillance, Epidemiology, and End Results data from 1988-2000, the analysis included 581 cases of stage I, invasive, well-differentiated mucinous OC and 2,130 cases of stage I mucinous BOT. The investigators noted “histological misclassification of BOT as OC or OC as BOT is not uncommon,” because of similar histopathologic characteristics.

Multivariable analysis showed that, compared with cases of BOT, women with OC were more often from the eastern United States (22.0% vs. 13.6%), older (51.9 vs. 48.0 years), and had a history of lymphadenectomy (47.0% vs. 23.2%) or hysterectomy (64.4% vs. 35.8%). Women with OC were also more likely to have tumors smaller than 4 cm (12.9% vs. 8.9%) and stage T1c disease (15.7% vs. 7.3%). Rates of OC declined over time, from 34.7% during 1988-1991 to 22.0% during 1997-2000. Following propensity score matching, multivariable analysis showed that 10-year cause-specific survival rates for OC and BOT were 92.7% and 97.5%, respectively, giving OC a hazard ratio of 2.03 (P = .007). Overall survival showed a similar disparity, of 76.1% for OC, compared with 83.6% for BOT. The investigators concluded that “survival of these two diseases is completely different.”

Regarding histopathologic misclassification, the investigators proposed “a standardized specimen sectioning protocol and diagnostic criteria for mucinous ovarian tumors.”

The study was funded by Ensign Endowment for Gynecologic Cancer Research. The investigators reported financial relationships with KIYATEC, BioPath, M-Trap, and Chugai.

SOURCE: Matsuo K et al. Gynecol Oncol. 2019 Feb 20. doi: 10.1016/j.ygyno.2019.02.003.

Women with invasive, well-differentiated mucinous ovarian cancer are more likely to die from their disease within 10 years of diagnosis than women with mucinous borderline ovarian tumors, according to a retrospective study of more than 2,700 cases.

The analysis also revealed different clinical characteristics, reported lead author Koji Matsuo, MD, PhD of the University of Southern California, Los Angeles, and his colleagues. For example, compared with borderline ovarian tumors (BOT), patients with ovarian cancer (OC) were usually older and had undergone hysterectomy.

“Our study endorses the importance of making the proper diagnosis for invasive cancer when the ovarian tumor is of mucinous histology,” the investigators wrote in Gynecologic Oncology.

Using Surveillance, Epidemiology, and End Results data from 1988-2000, the analysis included 581 cases of stage I, invasive, well-differentiated mucinous OC and 2,130 cases of stage I mucinous BOT. The investigators noted “histological misclassification of BOT as OC or OC as BOT is not uncommon,” because of similar histopathologic characteristics.

Multivariable analysis showed that, compared with cases of BOT, women with OC were more often from the eastern United States (22.0% vs. 13.6%), older (51.9 vs. 48.0 years), and had a history of lymphadenectomy (47.0% vs. 23.2%) or hysterectomy (64.4% vs. 35.8%). Women with OC were also more likely to have tumors smaller than 4 cm (12.9% vs. 8.9%) and stage T1c disease (15.7% vs. 7.3%). Rates of OC declined over time, from 34.7% during 1988-1991 to 22.0% during 1997-2000. Following propensity score matching, multivariable analysis showed that 10-year cause-specific survival rates for OC and BOT were 92.7% and 97.5%, respectively, giving OC a hazard ratio of 2.03 (P = .007). Overall survival showed a similar disparity, of 76.1% for OC, compared with 83.6% for BOT. The investigators concluded that “survival of these two diseases is completely different.”

Regarding histopathologic misclassification, the investigators proposed “a standardized specimen sectioning protocol and diagnostic criteria for mucinous ovarian tumors.”

The study was funded by Ensign Endowment for Gynecologic Cancer Research. The investigators reported financial relationships with KIYATEC, BioPath, M-Trap, and Chugai.

SOURCE: Matsuo K et al. Gynecol Oncol. 2019 Feb 20. doi: 10.1016/j.ygyno.2019.02.003.

PRAGUE – Patients with hemophilia A or B and inhibitors may have reduced bleeding days when given subcutaneous factor VIIa (FVIIa) marzeptacog alfa, according to early results from a phase 2/3 trial.

Will Pass/MDedge News

The ongoing study is evaluating pharmacokinetics, pharmacodynamics, efficacy, and safety of marzeptacog alfa, which has four engineered amino acid substitutions within the FVIIa protein to increase catalytic activity, reported lead author Howard Levy, MBBCh, PhD, chief medical officer of Catalyst Biosciences in San Francisco, and his colleagues.

“[Marzeptacog alfa] is about nine times as potent as NovoSeven [RT],” Dr. Levy said, referring to the FVIIa product from Novo Nordisk. “This allows for subcutaneous dosing. One of the advantages of subcutaneous dosing is that it further prolongs the half-life.”

Dr. Levy presented the findings at the annual congress of the European Association for Haemophilia and Allied Disorders.

The study involved 12 patients with hemophilia A or B and inhibitors, all of whom began with an annualized bleeding rate (ABR) of more than 12 days per year; of these, 7 have completed dosing.

Following pharmacokinetic analysis, subcutaneous dosing began at an initial dose of 30 mcg/kg daily. As-needed dose escalations were allowed at regular intervals. Specifically, if spontaneous bleeding occurred, then at the next 50-day interval, an individual patient’s dose would be increased to the next level. Dose levels were 30 mcg/kg, 60 mcg/kg, 90 mcg/kg, and 120 mcg/kg.

Any patient completing a 50-day interval without bleeding was finished with the study and proceeded to a 30-day follow-up period, during which time resumption of bleeding was monitored. The primary endpoint was a reduction in the ABR at the final dose level. Secondary endpoints were safety, tolerability, and a lack of inhibitor formation.

As Dr. Levy discussed results, he expressed concern that ABR is an inadequate measure of efficacy. “There is a significant amount hidden by the raw statistic of an annualized bleed rate.” He elaborated further by describing two trial participants who each had an ABR of about 23 days per year but had very different proportions of days with bleeding in the 6-month lead-in period (22% vs. 9%), suggesting that this proportion may provide a clearer impression of efficacy.

Prior to treatment, the mean ABR among all patients was 19 days per year and the median proportion of days with bleeding was 11%. This latter value dropped from 11% to 1% with treatment. The former value, ABR, was reduced in a “clinically significant” fashion, although exact values were not provided (P = .009).

Two patients required dose escalation to 60 mcg/kg, and five out of seven patients had no bleeding (traumatic or spontaneous), at their final dose levels.

Subcutaneous half-life was 13.1 hours, compared with intravenous half-life of 3.9 hours. After more than 260 cumulative days of subcutaneous injections, no thromboses or antidrug antibodies were detected. Two subjects had a total of six injection site reactions, with mild to moderate redness and moderate swelling that resolved without sequelae.

One patient died on day 11 of the trial because of fatal hemorrhagic stroke, but this patient had uncontrolled hypertension and the death was not considered drug related.

More clinical data from this trial will be reported in July 2019 at the annual congress of the International Society on Thrombosis and Haemostasis in Melbourne.

The study was funded by Catalyst Biosciences. Dr. Levy and multiple coauthors are employees, shareholders, or consultants for Catalyst Biosciences.

SOURCE: Levy H et al. EAHAD 2019, Abstract OR11.

PRAGUE – Patients with hemophilia A or B and inhibitors may have reduced bleeding days when given subcutaneous factor VIIa (FVIIa) marzeptacog alfa, according to early results from a phase 2/3 trial.

Will Pass/MDedge News

The ongoing study is evaluating pharmacokinetics, pharmacodynamics, efficacy, and safety of marzeptacog alfa, which has four engineered amino acid substitutions within the FVIIa protein to increase catalytic activity, reported lead author Howard Levy, MBBCh, PhD, chief medical officer of Catalyst Biosciences in San Francisco, and his colleagues.

“[Marzeptacog alfa] is about nine times as potent as NovoSeven [RT],” Dr. Levy said, referring to the FVIIa product from Novo Nordisk. “This allows for subcutaneous dosing. One of the advantages of subcutaneous dosing is that it further prolongs the half-life.”

Dr. Levy presented the findings at the annual congress of the European Association for Haemophilia and Allied Disorders.

The study involved 12 patients with hemophilia A or B and inhibitors, all of whom began with an annualized bleeding rate (ABR) of more than 12 days per year; of these, 7 have completed dosing.

Following pharmacokinetic analysis, subcutaneous dosing began at an initial dose of 30 mcg/kg daily. As-needed dose escalations were allowed at regular intervals. Specifically, if spontaneous bleeding occurred, then at the next 50-day interval, an individual patient’s dose would be increased to the next level. Dose levels were 30 mcg/kg, 60 mcg/kg, 90 mcg/kg, and 120 mcg/kg.

Any patient completing a 50-day interval without bleeding was finished with the study and proceeded to a 30-day follow-up period, during which time resumption of bleeding was monitored. The primary endpoint was a reduction in the ABR at the final dose level. Secondary endpoints were safety, tolerability, and a lack of inhibitor formation.

As Dr. Levy discussed results, he expressed concern that ABR is an inadequate measure of efficacy. “There is a significant amount hidden by the raw statistic of an annualized bleed rate.” He elaborated further by describing two trial participants who each had an ABR of about 23 days per year but had very different proportions of days with bleeding in the 6-month lead-in period (22% vs. 9%), suggesting that this proportion may provide a clearer impression of efficacy.

Prior to treatment, the mean ABR among all patients was 19 days per year and the median proportion of days with bleeding was 11%. This latter value dropped from 11% to 1% with treatment. The former value, ABR, was reduced in a “clinically significant” fashion, although exact values were not provided (P = .009).

Two patients required dose escalation to 60 mcg/kg, and five out of seven patients had no bleeding (traumatic or spontaneous), at their final dose levels.

Subcutaneous half-life was 13.1 hours, compared with intravenous half-life of 3.9 hours. After more than 260 cumulative days of subcutaneous injections, no thromboses or antidrug antibodies were detected. Two subjects had a total of six injection site reactions, with mild to moderate redness and moderate swelling that resolved without sequelae.

One patient died on day 11 of the trial because of fatal hemorrhagic stroke, but this patient had uncontrolled hypertension and the death was not considered drug related.

More clinical data from this trial will be reported in July 2019 at the annual congress of the International Society on Thrombosis and Haemostasis in Melbourne.

The study was funded by Catalyst Biosciences. Dr. Levy and multiple coauthors are employees, shareholders, or consultants for Catalyst Biosciences.

SOURCE: Levy H et al. EAHAD 2019, Abstract OR11.

PRAGUE – Patients with hemophilia A or B and inhibitors may have reduced bleeding days when given subcutaneous factor VIIa (FVIIa) marzeptacog alfa, according to early results from a phase 2/3 trial.

Will Pass/MDedge News

The ongoing study is evaluating pharmacokinetics, pharmacodynamics, efficacy, and safety of marzeptacog alfa, which has four engineered amino acid substitutions within the FVIIa protein to increase catalytic activity, reported lead author Howard Levy, MBBCh, PhD, chief medical officer of Catalyst Biosciences in San Francisco, and his colleagues.

“[Marzeptacog alfa] is about nine times as potent as NovoSeven [RT],” Dr. Levy said, referring to the FVIIa product from Novo Nordisk. “This allows for subcutaneous dosing. One of the advantages of subcutaneous dosing is that it further prolongs the half-life.”

Dr. Levy presented the findings at the annual congress of the European Association for Haemophilia and Allied Disorders.

The study involved 12 patients with hemophilia A or B and inhibitors, all of whom began with an annualized bleeding rate (ABR) of more than 12 days per year; of these, 7 have completed dosing.

Following pharmacokinetic analysis, subcutaneous dosing began at an initial dose of 30 mcg/kg daily. As-needed dose escalations were allowed at regular intervals. Specifically, if spontaneous bleeding occurred, then at the next 50-day interval, an individual patient’s dose would be increased to the next level. Dose levels were 30 mcg/kg, 60 mcg/kg, 90 mcg/kg, and 120 mcg/kg.

Any patient completing a 50-day interval without bleeding was finished with the study and proceeded to a 30-day follow-up period, during which time resumption of bleeding was monitored. The primary endpoint was a reduction in the ABR at the final dose level. Secondary endpoints were safety, tolerability, and a lack of inhibitor formation.

As Dr. Levy discussed results, he expressed concern that ABR is an inadequate measure of efficacy. “There is a significant amount hidden by the raw statistic of an annualized bleed rate.” He elaborated further by describing two trial participants who each had an ABR of about 23 days per year but had very different proportions of days with bleeding in the 6-month lead-in period (22% vs. 9%), suggesting that this proportion may provide a clearer impression of efficacy.

Prior to treatment, the mean ABR among all patients was 19 days per year and the median proportion of days with bleeding was 11%. This latter value dropped from 11% to 1% with treatment. The former value, ABR, was reduced in a “clinically significant” fashion, although exact values were not provided (P = .009).

Two patients required dose escalation to 60 mcg/kg, and five out of seven patients had no bleeding (traumatic or spontaneous), at their final dose levels.

Subcutaneous half-life was 13.1 hours, compared with intravenous half-life of 3.9 hours. After more than 260 cumulative days of subcutaneous injections, no thromboses or antidrug antibodies were detected. Two subjects had a total of six injection site reactions, with mild to moderate redness and moderate swelling that resolved without sequelae.

One patient died on day 11 of the trial because of fatal hemorrhagic stroke, but this patient had uncontrolled hypertension and the death was not considered drug related.

More clinical data from this trial will be reported in July 2019 at the annual congress of the International Society on Thrombosis and Haemostasis in Melbourne.

The study was funded by Catalyst Biosciences. Dr. Levy and multiple coauthors are employees, shareholders, or consultants for Catalyst Biosciences.

SOURCE: Levy H et al. EAHAD 2019, Abstract OR11.

PRAGUE – AMT-061, a gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector and a Padua variant human factor IX (hFIX) gene, provides clinically meaningful FIX activity, based on early results from an ongoing, phase 2b study.

Will Pass/ MDedge News

The findings provide traction for a phase 3 trial (HOPE-B; NCT03569891) which is currently enrolling, according to lead author Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California, San Diego.

Dr. Von Drygalski said that the results also demonstrate the positive impact of switching from a wild-type hFIX gene in AMT-060 to a Padua hFIX variant in AMT-061, achieved by replacing arginine with leucine at R338L.

Speaking at the annual congress of the European Association for Haemophilia and Allied Disorders, Dr. Von Drygalski referred to AMT-061 as the “enhanced version” of AMT-060. Prior to human trials, nonhuman primate studies comparing AMT-060 with AMT-061 demonstrated a 550% increase in factor IX activity, similar to previous reports of 600%-800% boosts from the Padua variant.

The current findings revealed early outcomes for three men with severe hemophilia B who were given AMT-061. The patients were between 43 years and 50 years of age and had been taking clotting factors prophylactically. Among them, annualized bleed rates ranged from one to five events per year. Two of the three men were HIV-positive, one had IgM antibodies against AAV5, and all three had neutralizing antibodies against AAV5.

“Of note,” Dr. Von Drygalski said, “two of the participants had previously been excluded from participation in gene therapy due to preexisting antibodies against AAV.”

Each man was given a single dose of 2 x 10¹³ gene copies/kg of AMT-061 intravenously. The primary endpoint was efficacy at 6 weeks after administration. Ongoing secondary endpoints include patient-reported bleeding and FIX concentrate use, joint health, patient-reported quality of life, and laboratory parameters. Patients will be followed for 1 year.

Within 2 weeks, all three men achieved meaningful levels of FIX. Two of three patients demonstrated an upward trend of FIX activity that peaked at about 50% of normal. The third patient’s levels plateaued sooner, with the most recent reading at week 14 showing 25%. Mean factor IX activity level was 38% of normal 12 weeks after gene therapy.

“These clotting factor activity levels translated into complete control [of bleeding] with no requirement for factor IX replacement after infusion,” Dr. Von Drygalski said. For comparison, AMT-060, the wild-type version, only achieved levels of 3%-13%, which are less clinically meaningful.

Along with demonstrating efficacy, AMT-061 was well tolerated. One patient had two adverse events that resolved without treatment: very mild C-reactive protein elevation and transient headache. One patient had a very mild and transient AST elevation (week 2, 43 U/L; week 4, 48 U/L) that resolved without treatment. No patients had ALT elevations and immunosuppression was not needed.

These findings provide a strong foundation for the phase 3 HOPE-B trial, which will include about 50 patients with FIX activity no greater than 2%. Dr. Von Drygalski noted that patients with AAV5-neutralizing antibodies will not be excluded.

The investigators reported financial relationships with Bayer, UniQure, Pfizer, Novo Nordisk, Shire, and others.

SOURCE: Von Drygalski A et al. EAHAD 2019, Abstract OR10.

PRAGUE – AMT-061, a gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector and a Padua variant human factor IX (hFIX) gene, provides clinically meaningful FIX activity, based on early results from an ongoing, phase 2b study.

Will Pass/ MDedge News

The findings provide traction for a phase 3 trial (HOPE-B; NCT03569891) which is currently enrolling, according to lead author Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California, San Diego.

Dr. Von Drygalski said that the results also demonstrate the positive impact of switching from a wild-type hFIX gene in AMT-060 to a Padua hFIX variant in AMT-061, achieved by replacing arginine with leucine at R338L.

Speaking at the annual congress of the European Association for Haemophilia and Allied Disorders, Dr. Von Drygalski referred to AMT-061 as the “enhanced version” of AMT-060. Prior to human trials, nonhuman primate studies comparing AMT-060 with AMT-061 demonstrated a 550% increase in factor IX activity, similar to previous reports of 600%-800% boosts from the Padua variant.

The current findings revealed early outcomes for three men with severe hemophilia B who were given AMT-061. The patients were between 43 years and 50 years of age and had been taking clotting factors prophylactically. Among them, annualized bleed rates ranged from one to five events per year. Two of the three men were HIV-positive, one had IgM antibodies against AAV5, and all three had neutralizing antibodies against AAV5.

“Of note,” Dr. Von Drygalski said, “two of the participants had previously been excluded from participation in gene therapy due to preexisting antibodies against AAV.”

Each man was given a single dose of 2 x 10¹³ gene copies/kg of AMT-061 intravenously. The primary endpoint was efficacy at 6 weeks after administration. Ongoing secondary endpoints include patient-reported bleeding and FIX concentrate use, joint health, patient-reported quality of life, and laboratory parameters. Patients will be followed for 1 year.

Within 2 weeks, all three men achieved meaningful levels of FIX. Two of three patients demonstrated an upward trend of FIX activity that peaked at about 50% of normal. The third patient’s levels plateaued sooner, with the most recent reading at week 14 showing 25%. Mean factor IX activity level was 38% of normal 12 weeks after gene therapy.

“These clotting factor activity levels translated into complete control [of bleeding] with no requirement for factor IX replacement after infusion,” Dr. Von Drygalski said. For comparison, AMT-060, the wild-type version, only achieved levels of 3%-13%, which are less clinically meaningful.

Along with demonstrating efficacy, AMT-061 was well tolerated. One patient had two adverse events that resolved without treatment: very mild C-reactive protein elevation and transient headache. One patient had a very mild and transient AST elevation (week 2, 43 U/L; week 4, 48 U/L) that resolved without treatment. No patients had ALT elevations and immunosuppression was not needed.

These findings provide a strong foundation for the phase 3 HOPE-B trial, which will include about 50 patients with FIX activity no greater than 2%. Dr. Von Drygalski noted that patients with AAV5-neutralizing antibodies will not be excluded.

The investigators reported financial relationships with Bayer, UniQure, Pfizer, Novo Nordisk, Shire, and others.

SOURCE: Von Drygalski A et al. EAHAD 2019, Abstract OR10.

PRAGUE – AMT-061, a gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector and a Padua variant human factor IX (hFIX) gene, provides clinically meaningful FIX activity, based on early results from an ongoing, phase 2b study.

Will Pass/ MDedge News

The findings provide traction for a phase 3 trial (HOPE-B; NCT03569891) which is currently enrolling, according to lead author Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California, San Diego.

Dr. Von Drygalski said that the results also demonstrate the positive impact of switching from a wild-type hFIX gene in AMT-060 to a Padua hFIX variant in AMT-061, achieved by replacing arginine with leucine at R338L.

Speaking at the annual congress of the European Association for Haemophilia and Allied Disorders, Dr. Von Drygalski referred to AMT-061 as the “enhanced version” of AMT-060. Prior to human trials, nonhuman primate studies comparing AMT-060 with AMT-061 demonstrated a 550% increase in factor IX activity, similar to previous reports of 600%-800% boosts from the Padua variant.

The current findings revealed early outcomes for three men with severe hemophilia B who were given AMT-061. The patients were between 43 years and 50 years of age and had been taking clotting factors prophylactically. Among them, annualized bleed rates ranged from one to five events per year. Two of the three men were HIV-positive, one had IgM antibodies against AAV5, and all three had neutralizing antibodies against AAV5.

“Of note,” Dr. Von Drygalski said, “two of the participants had previously been excluded from participation in gene therapy due to preexisting antibodies against AAV.”

Each man was given a single dose of 2 x 10¹³ gene copies/kg of AMT-061 intravenously. The primary endpoint was efficacy at 6 weeks after administration. Ongoing secondary endpoints include patient-reported bleeding and FIX concentrate use, joint health, patient-reported quality of life, and laboratory parameters. Patients will be followed for 1 year.

Within 2 weeks, all three men achieved meaningful levels of FIX. Two of three patients demonstrated an upward trend of FIX activity that peaked at about 50% of normal. The third patient’s levels plateaued sooner, with the most recent reading at week 14 showing 25%. Mean factor IX activity level was 38% of normal 12 weeks after gene therapy.

“These clotting factor activity levels translated into complete control [of bleeding] with no requirement for factor IX replacement after infusion,” Dr. Von Drygalski said. For comparison, AMT-060, the wild-type version, only achieved levels of 3%-13%, which are less clinically meaningful.

Along with demonstrating efficacy, AMT-061 was well tolerated. One patient had two adverse events that resolved without treatment: very mild C-reactive protein elevation and transient headache. One patient had a very mild and transient AST elevation (week 2, 43 U/L; week 4, 48 U/L) that resolved without treatment. No patients had ALT elevations and immunosuppression was not needed.

These findings provide a strong foundation for the phase 3 HOPE-B trial, which will include about 50 patients with FIX activity no greater than 2%. Dr. Von Drygalski noted that patients with AAV5-neutralizing antibodies will not be excluded.

The investigators reported financial relationships with Bayer, UniQure, Pfizer, Novo Nordisk, Shire, and others.

SOURCE: Von Drygalski A et al. EAHAD 2019, Abstract OR10.

For patients with resectable stage I non–small cell lung cancer (NSCLC), stereotactic ablative radiotherapy (SABR) may lack the efficacy needed to replace surgical intervention, according to a recent phase II trial.

SABR provided a pathologic complete response rate (pCR) of 60%, which was “lower than hypothesized,” reported lead author David A. Palma, MD, PhD, of London (Ont.) Health Sciences Centre, and his colleagues.

“In patients with cancer who are fit for resection ... the role of SABR is controversial,” the investigators wrote in JAMA Oncology. “Although some recent studies suggest that SABR may achieve outcomes similar to surgery, others do not, and randomized clinical trials are currently under way to compare these 2 modalities.”

The present trial involved 40 adult patients with stage I NSCLC, good pulmonary function, and good performance status. Of these, 35 were evaluable for the primary endpoint, which was tumor pCR rate after SABR. Secondary endpoints were toxic effects, quality of life, distant control, regional control, and local control. Patients with tumors no larger than 3 cm in diameter were given 54 Gy in 3 fractions, while bigger tumors received 55 Gy in 5 fractions. Patients with tumors 2 cm or closer to the brachial plexus or mediastinum were given 60 Gy in 8 fractions. Ten weeks after SABR, sublobar resection or lobectomy was performed, via an open approach or with video-assisted thoracoscopic surgery (VATS).

Analysis revealed a pCR rate of 60%, which was lower than anticipated. One-month and 3-month survival rates were both 100%. After a median follow-up of 19 months, local control rate was 100%, but only three out of four patients (76%) had distant control, and half (53%) had regional control. After 2 years, three out of four patients were still alive (77%). Eighteen percent of patients experienced grade 3 or higher toxic effects.

“[T]he pCR rate of 60% at 10 weeks suggests that practitioners should be cautious in the use of SABR in patients with cancers who are fit for resection,” the investigators concluded.

The Ontario Institute for Cancer Research funded the study. Dr. Palma and Dr. Ward are patent holders for a computed tomography technology that assesses responses after radiotherapy. Dr. Louie reported honoraria from AstraZeneca and Varian Medical Systems Inc.

SOURCE: Palma et al. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.6993.

For patients with resectable stage I non–small cell lung cancer (NSCLC), stereotactic ablative radiotherapy (SABR) may lack the efficacy needed to replace surgical intervention, according to a recent phase II trial.

SABR provided a pathologic complete response rate (pCR) of 60%, which was “lower than hypothesized,” reported lead author David A. Palma, MD, PhD, of London (Ont.) Health Sciences Centre, and his colleagues.

“In patients with cancer who are fit for resection ... the role of SABR is controversial,” the investigators wrote in JAMA Oncology. “Although some recent studies suggest that SABR may achieve outcomes similar to surgery, others do not, and randomized clinical trials are currently under way to compare these 2 modalities.”

The present trial involved 40 adult patients with stage I NSCLC, good pulmonary function, and good performance status. Of these, 35 were evaluable for the primary endpoint, which was tumor pCR rate after SABR. Secondary endpoints were toxic effects, quality of life, distant control, regional control, and local control. Patients with tumors no larger than 3 cm in diameter were given 54 Gy in 3 fractions, while bigger tumors received 55 Gy in 5 fractions. Patients with tumors 2 cm or closer to the brachial plexus or mediastinum were given 60 Gy in 8 fractions. Ten weeks after SABR, sublobar resection or lobectomy was performed, via an open approach or with video-assisted thoracoscopic surgery (VATS).

Analysis revealed a pCR rate of 60%, which was lower than anticipated. One-month and 3-month survival rates were both 100%. After a median follow-up of 19 months, local control rate was 100%, but only three out of four patients (76%) had distant control, and half (53%) had regional control. After 2 years, three out of four patients were still alive (77%). Eighteen percent of patients experienced grade 3 or higher toxic effects.

“[T]he pCR rate of 60% at 10 weeks suggests that practitioners should be cautious in the use of SABR in patients with cancers who are fit for resection,” the investigators concluded.

The Ontario Institute for Cancer Research funded the study. Dr. Palma and Dr. Ward are patent holders for a computed tomography technology that assesses responses after radiotherapy. Dr. Louie reported honoraria from AstraZeneca and Varian Medical Systems Inc.

SOURCE: Palma et al. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.6993.

For patients with resectable stage I non–small cell lung cancer (NSCLC), stereotactic ablative radiotherapy (SABR) may lack the efficacy needed to replace surgical intervention, according to a recent phase II trial.

SABR provided a pathologic complete response rate (pCR) of 60%, which was “lower than hypothesized,” reported lead author David A. Palma, MD, PhD, of London (Ont.) Health Sciences Centre, and his colleagues.

“In patients with cancer who are fit for resection ... the role of SABR is controversial,” the investigators wrote in JAMA Oncology. “Although some recent studies suggest that SABR may achieve outcomes similar to surgery, others do not, and randomized clinical trials are currently under way to compare these 2 modalities.”

The present trial involved 40 adult patients with stage I NSCLC, good pulmonary function, and good performance status. Of these, 35 were evaluable for the primary endpoint, which was tumor pCR rate after SABR. Secondary endpoints were toxic effects, quality of life, distant control, regional control, and local control. Patients with tumors no larger than 3 cm in diameter were given 54 Gy in 3 fractions, while bigger tumors received 55 Gy in 5 fractions. Patients with tumors 2 cm or closer to the brachial plexus or mediastinum were given 60 Gy in 8 fractions. Ten weeks after SABR, sublobar resection or lobectomy was performed, via an open approach or with video-assisted thoracoscopic surgery (VATS).

Analysis revealed a pCR rate of 60%, which was lower than anticipated. One-month and 3-month survival rates were both 100%. After a median follow-up of 19 months, local control rate was 100%, but only three out of four patients (76%) had distant control, and half (53%) had regional control. After 2 years, three out of four patients were still alive (77%). Eighteen percent of patients experienced grade 3 or higher toxic effects.

“[T]he pCR rate of 60% at 10 weeks suggests that practitioners should be cautious in the use of SABR in patients with cancers who are fit for resection,” the investigators concluded.

The Ontario Institute for Cancer Research funded the study. Dr. Palma and Dr. Ward are patent holders for a computed tomography technology that assesses responses after radiotherapy. Dr. Louie reported honoraria from AstraZeneca and Varian Medical Systems Inc.

SOURCE: Palma et al. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.6993.

For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.

Nephron/Wikimedia Commons/CC BY-SA 3.0

When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.

“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”

But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.

The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).

After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.

In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.

Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.

The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.

Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”

The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.

SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.

For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.

Nephron/Wikimedia Commons/CC BY-SA 3.0

When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.

“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”

But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.

The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).

After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.

In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.

Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.

The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.

Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”

The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.

SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.

For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.

Nephron/Wikimedia Commons/CC BY-SA 3.0

When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.

“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”

But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.

The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).

After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.

In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.

Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.

The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.

Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”

The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.

SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.

An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.

Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).

These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.

The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.

Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.

The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.

Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.

The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).

“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.

The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.

SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.

An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.

Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).

These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.

The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.

Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.

The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.

Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.

The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).

“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.

The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.

SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.

An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.

Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).

These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.

The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.

Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.

The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.

Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.

The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).

“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.

The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.

SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.

PRAGUE – Fitusiran, a novel small interfering RNA therapeutic that decreases antithrombin (AT) synthesis and bleeding in patients with hemophilia A or B, with or without inhibitors, is reversible upon dosing cessation and becomes effective again with resumption of dosing. That finding is based on data obtained before, during, and after a phase 2 study dosing suspension.

Will Pass/MDedge News

In September 2017, the fitusiran open-label extension study was suspended to investigate a fatal thrombotic event. The suspension was lifted 3 months later, and the trial continued with reduced doses of replacement factors or bypassing agents for breakthrough bleeds.

The pause in the study was used to gather data about the effects of dosing cessation and resumption, which were reported by coauthor Craig Benson, MD, of Sanofi Genzyme in Cambridge, Mass. Dr. Benson presented findings at the annual congress of the European Association for Haemophilia and Allied Disorders on behalf of lead author John Pasi, MD, PhD, of the Haemophilia Centre at the Royal London Hospital and colleagues.

Prior to the suspension, 28 patients with hemophilia A or B, with or without inhibitors, were given 50-80 mg of fitusiran for up to 20 months with a median dose duration of 11 months. During dosing suspension, the investigators measured AT levels, thrombin generation, and annualized bleeding rates (ABR).

“We can see that the antithrombin knockdown effect of fitusiran is reversible with dosing hold,” Dr. Benson said, referring to an upward trend of median AT level.

Within 4 months of stopping fitusiran, median AT level was 60% of normal. This level continued to rise to about 90% by month 7, before returning to normal at month 11.

“This is an AT recovery we had previously seen by a few subjects that had discontinued [fitusiran] prior to the clinical hold,” Dr. Benson said, “but here, with a much larger sample size, we see a fairly consistent AT recovery.”

As expected, while AT levels rose, thrombin generation showed an inverse trend. “We see a similar temporal pattern,” Dr. Benson said. “The bulk of thrombin generation decrease is seen by the 4th month off fitusiran.”

When patients restarted fitusiran after the suspension was lifted, AT levels dropped to about 30% of normal by month 1 and about 20% of normal from month 2 onward. Again, in an inverse manner, thrombin generation increased.

Clinically, changes in AT and thrombin generation before, during, and after study suspension were reflected in median ABR, which rose from 1.43 events per year prior to cessation to 6.47 events per year during treatment hold before falling to 1.25 events per year after restarting fitusiran.

Overall, the results support the efficacy and reversibility of fitusiran. The agent is continuing to be studied in the phase 3 ATLAS trials.

The study was funded by Sanofi Genzyme and Alnylam. Dr. Benson is an employee of Sanofi Genzyme. Other investigators reported financial ties to Sanofi Genzyme, Alnylam, Baxalta, Octapharma, Pfizer, Shire, and others.

SOURCE: Pasi J et al. EAHAD 2019, Abstract OR16.

PRAGUE – Fitusiran, a novel small interfering RNA therapeutic that decreases antithrombin (AT) synthesis and bleeding in patients with hemophilia A or B, with or without inhibitors, is reversible upon dosing cessation and becomes effective again with resumption of dosing. That finding is based on data obtained before, during, and after a phase 2 study dosing suspension.

Will Pass/MDedge News

In September 2017, the fitusiran open-label extension study was suspended to investigate a fatal thrombotic event. The suspension was lifted 3 months later, and the trial continued with reduced doses of replacement factors or bypassing agents for breakthrough bleeds.

The pause in the study was used to gather data about the effects of dosing cessation and resumption, which were reported by coauthor Craig Benson, MD, of Sanofi Genzyme in Cambridge, Mass. Dr. Benson presented findings at the annual congress of the European Association for Haemophilia and Allied Disorders on behalf of lead author John Pasi, MD, PhD, of the Haemophilia Centre at the Royal London Hospital and colleagues.

Prior to the suspension, 28 patients with hemophilia A or B, with or without inhibitors, were given 50-80 mg of fitusiran for up to 20 months with a median dose duration of 11 months. During dosing suspension, the investigators measured AT levels, thrombin generation, and annualized bleeding rates (ABR).

“We can see that the antithrombin knockdown effect of fitusiran is reversible with dosing hold,” Dr. Benson said, referring to an upward trend of median AT level.

Within 4 months of stopping fitusiran, median AT level was 60% of normal. This level continued to rise to about 90% by month 7, before returning to normal at month 11.

“This is an AT recovery we had previously seen by a few subjects that had discontinued [fitusiran] prior to the clinical hold,” Dr. Benson said, “but here, with a much larger sample size, we see a fairly consistent AT recovery.”

As expected, while AT levels rose, thrombin generation showed an inverse trend. “We see a similar temporal pattern,” Dr. Benson said. “The bulk of thrombin generation decrease is seen by the 4th month off fitusiran.”

When patients restarted fitusiran after the suspension was lifted, AT levels dropped to about 30% of normal by month 1 and about 20% of normal from month 2 onward. Again, in an inverse manner, thrombin generation increased.

Clinically, changes in AT and thrombin generation before, during, and after study suspension were reflected in median ABR, which rose from 1.43 events per year prior to cessation to 6.47 events per year during treatment hold before falling to 1.25 events per year after restarting fitusiran.

Overall, the results support the efficacy and reversibility of fitusiran. The agent is continuing to be studied in the phase 3 ATLAS trials.

The study was funded by Sanofi Genzyme and Alnylam. Dr. Benson is an employee of Sanofi Genzyme. Other investigators reported financial ties to Sanofi Genzyme, Alnylam, Baxalta, Octapharma, Pfizer, Shire, and others.

SOURCE: Pasi J et al. EAHAD 2019, Abstract OR16.

PRAGUE – Fitusiran, a novel small interfering RNA therapeutic that decreases antithrombin (AT) synthesis and bleeding in patients with hemophilia A or B, with or without inhibitors, is reversible upon dosing cessation and becomes effective again with resumption of dosing. That finding is based on data obtained before, during, and after a phase 2 study dosing suspension.

Will Pass/MDedge News

In September 2017, the fitusiran open-label extension study was suspended to investigate a fatal thrombotic event. The suspension was lifted 3 months later, and the trial continued with reduced doses of replacement factors or bypassing agents for breakthrough bleeds.

The pause in the study was used to gather data about the effects of dosing cessation and resumption, which were reported by coauthor Craig Benson, MD, of Sanofi Genzyme in Cambridge, Mass. Dr. Benson presented findings at the annual congress of the European Association for Haemophilia and Allied Disorders on behalf of lead author John Pasi, MD, PhD, of the Haemophilia Centre at the Royal London Hospital and colleagues.

Prior to the suspension, 28 patients with hemophilia A or B, with or without inhibitors, were given 50-80 mg of fitusiran for up to 20 months with a median dose duration of 11 months. During dosing suspension, the investigators measured AT levels, thrombin generation, and annualized bleeding rates (ABR).

“We can see that the antithrombin knockdown effect of fitusiran is reversible with dosing hold,” Dr. Benson said, referring to an upward trend of median AT level.

Within 4 months of stopping fitusiran, median AT level was 60% of normal. This level continued to rise to about 90% by month 7, before returning to normal at month 11.

“This is an AT recovery we had previously seen by a few subjects that had discontinued [fitusiran] prior to the clinical hold,” Dr. Benson said, “but here, with a much larger sample size, we see a fairly consistent AT recovery.”

As expected, while AT levels rose, thrombin generation showed an inverse trend. “We see a similar temporal pattern,” Dr. Benson said. “The bulk of thrombin generation decrease is seen by the 4th month off fitusiran.”

When patients restarted fitusiran after the suspension was lifted, AT levels dropped to about 30% of normal by month 1 and about 20% of normal from month 2 onward. Again, in an inverse manner, thrombin generation increased.

Clinically, changes in AT and thrombin generation before, during, and after study suspension were reflected in median ABR, which rose from 1.43 events per year prior to cessation to 6.47 events per year during treatment hold before falling to 1.25 events per year after restarting fitusiran.

Overall, the results support the efficacy and reversibility of fitusiran. The agent is continuing to be studied in the phase 3 ATLAS trials.

The study was funded by Sanofi Genzyme and Alnylam. Dr. Benson is an employee of Sanofi Genzyme. Other investigators reported financial ties to Sanofi Genzyme, Alnylam, Baxalta, Octapharma, Pfizer, Shire, and others.

SOURCE: Pasi J et al. EAHAD 2019, Abstract OR16.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

PRAGUE—For previously untreated patients (PUPs) with severe hemophilia A, the risk of developing factor VIII (FVIII) alloantibodies (inhibitors) becomes negligible after 75 exposure days, according to a recent study involving more than 1,000 infants.

Will Pass/ MDedge News

This finding answers a long-standing and important question in the management of hemophilia A, reported lead author H. Marijke van den Berg, MD, PhD, of University Medical Centre in Utrecht, The Netherlands.

Inhibitor development is the biggest safety concern facing infants with severe hemophilia A because it affects 25%-35% of the patient population, but no previous studies have adequately described the associated risk profile, she noted.

“Most studies until now collected data until about 50 [exposure days] and not that far beyond,” Dr. van den Berg said at the annual congress of the European Association for Haemophilia and Allied Disorders. “So we were interested to see the serum plateau in our large cohort.”

Such a plateau would represent the time point at which risk of inhibitor development approaches zero.

Dr. van den Berg and her colleagues followed 1,038 PUPs with severe hemophilia A from first exposure to FVIII onward. Data were from drawn from the PedNet Registry. From the initial group, 943 patients (91%) were followed until 50 exposure days, and 899 (87%) were followed until 75 exposure days.

Inhibitor development was defined by a minimum of two positive inhibitor titers. In addition to determining the point in time of inhibitor development, the investigators performed a survival analysis for inhibitor incidence and reported median ages at first exposure and at exposure day 75.

The results showed that 298 out of 300 instances of inhibitor development occurred within 75 exposure days, and no inhibitors developed between exposure day 75 and 150. The final two instances occurred at exposure day 249 and 262, both with a low titer.

Median age at first exposure was 1.1 years, compared with 2.3 years at exposure day 75.

These findings suggest that risk of inhibitors is “near zero” after 75 days and that risk is approaching zero just 1 year after first exposure to FVIII, she said.

The results from this study could affect the design of future clinical trials for PUPs.

“Our recommendation will be to continue frequent [inhibitor] testing until 75 exposure days,” Dr. van den Berg said.

The time frame involved is very short, so close monitoring should be feasible for investigators, she noted.

Dr. van den Berg said that additional data, including Kaplan-Meier curves, would “hopefully” be published in a journal soon.

Dr. van den Berg reported having no relevant financial disclosures.

SOURCE: van den Berg HM et al. EAHAD 2019, Abstract OR05.

PRAGUE—For previously untreated patients (PUPs) with severe hemophilia A, the risk of developing factor VIII (FVIII) alloantibodies (inhibitors) becomes negligible after 75 exposure days, according to a recent study involving more than 1,000 infants.

Will Pass/ MDedge News

This finding answers a long-standing and important question in the management of hemophilia A, reported lead author H. Marijke van den Berg, MD, PhD, of University Medical Centre in Utrecht, The Netherlands.

Inhibitor development is the biggest safety concern facing infants with severe hemophilia A because it affects 25%-35% of the patient population, but no previous studies have adequately described the associated risk profile, she noted.

“Most studies until now collected data until about 50 [exposure days] and not that far beyond,” Dr. van den Berg said at the annual congress of the European Association for Haemophilia and Allied Disorders. “So we were interested to see the serum plateau in our large cohort.”

Such a plateau would represent the time point at which risk of inhibitor development approaches zero.

Dr. van den Berg and her colleagues followed 1,038 PUPs with severe hemophilia A from first exposure to FVIII onward. Data were from drawn from the PedNet Registry. From the initial group, 943 patients (91%) were followed until 50 exposure days, and 899 (87%) were followed until 75 exposure days.

Inhibitor development was defined by a minimum of two positive inhibitor titers. In addition to determining the point in time of inhibitor development, the investigators performed a survival analysis for inhibitor incidence and reported median ages at first exposure and at exposure day 75.

The results showed that 298 out of 300 instances of inhibitor development occurred within 75 exposure days, and no inhibitors developed between exposure day 75 and 150. The final two instances occurred at exposure day 249 and 262, both with a low titer.

Median age at first exposure was 1.1 years, compared with 2.3 years at exposure day 75.

These findings suggest that risk of inhibitors is “near zero” after 75 days and that risk is approaching zero just 1 year after first exposure to FVIII, she said.

The results from this study could affect the design of future clinical trials for PUPs.

“Our recommendation will be to continue frequent [inhibitor] testing until 75 exposure days,” Dr. van den Berg said.

The time frame involved is very short, so close monitoring should be feasible for investigators, she noted.

Dr. van den Berg said that additional data, including Kaplan-Meier curves, would “hopefully” be published in a journal soon.

Dr. van den Berg reported having no relevant financial disclosures.

SOURCE: van den Berg HM et al. EAHAD 2019, Abstract OR05.

PRAGUE—For previously untreated patients (PUPs) with severe hemophilia A, the risk of developing factor VIII (FVIII) alloantibodies (inhibitors) becomes negligible after 75 exposure days, according to a recent study involving more than 1,000 infants.

Will Pass/ MDedge News

This finding answers a long-standing and important question in the management of hemophilia A, reported lead author H. Marijke van den Berg, MD, PhD, of University Medical Centre in Utrecht, The Netherlands.

Inhibitor development is the biggest safety concern facing infants with severe hemophilia A because it affects 25%-35% of the patient population, but no previous studies have adequately described the associated risk profile, she noted.

“Most studies until now collected data until about 50 [exposure days] and not that far beyond,” Dr. van den Berg said at the annual congress of the European Association for Haemophilia and Allied Disorders. “So we were interested to see the serum plateau in our large cohort.”

Such a plateau would represent the time point at which risk of inhibitor development approaches zero.

Dr. van den Berg and her colleagues followed 1,038 PUPs with severe hemophilia A from first exposure to FVIII onward. Data were from drawn from the PedNet Registry. From the initial group, 943 patients (91%) were followed until 50 exposure days, and 899 (87%) were followed until 75 exposure days.

Inhibitor development was defined by a minimum of two positive inhibitor titers. In addition to determining the point in time of inhibitor development, the investigators performed a survival analysis for inhibitor incidence and reported median ages at first exposure and at exposure day 75.

The results showed that 298 out of 300 instances of inhibitor development occurred within 75 exposure days, and no inhibitors developed between exposure day 75 and 150. The final two instances occurred at exposure day 249 and 262, both with a low titer.

Median age at first exposure was 1.1 years, compared with 2.3 years at exposure day 75.

These findings suggest that risk of inhibitors is “near zero” after 75 days and that risk is approaching zero just 1 year after first exposure to FVIII, she said.

The results from this study could affect the design of future clinical trials for PUPs.

“Our recommendation will be to continue frequent [inhibitor] testing until 75 exposure days,” Dr. van den Berg said.

The time frame involved is very short, so close monitoring should be feasible for investigators, she noted.

Dr. van den Berg said that additional data, including Kaplan-Meier curves, would “hopefully” be published in a journal soon.

Dr. van den Berg reported having no relevant financial disclosures.

SOURCE: van den Berg HM et al. EAHAD 2019, Abstract OR05.

PRAGUE – Despite improvements over the past 60 years, intracranial hemorrhage (ICH) remains a significant complication in hemophilia, occurring most frequently among patients with severe forms of the disease, according to a large-scale meta-analysis involving 56 studies and nearly 80,000 patients.

Will Pass/MDedge News

The consequences of a single incident of ICH can be irreparable and life-changing, so clinician knowledge of incidence rates and risk factors is essential, said lead author Anne-Fleur Zwagemaker, a PhD candidate from Amsterdam University Medical Center.

“Intracranial hemorrhage is one of the most severe and fearful complications in hemophilia,” Ms. Zwagemaker said in a presentation at the annual congress of the European Association for Haemophilia and Allied Disorders. “Our aim was to give more precise estimates of ICH numbers and risk factors in hemophilia.”

The review is notable for its scale and quality. After eliminating studies with fewer than 50 patients or other insufficiencies, the investigators were left with 56 studies conducted between 1960 and 2018, involving 79,818 patients with hemophilia. With a mean observation period of 12 years, the data encompassed almost 1 million person-years of data.

Across all studies, 1,508 ICH events were reported. Incidence and mortality rates were 400 and 80 per 100,000 person-years, respectively.

To optimize accuracy, the investigators further restricted studies to those with a sample size of at least 365 patients, leading to a pooled incidence rate of 3.8%. Studies with relevant data showed that about half of the cases of ICH (48%) were spontaneous. Regarding most common bleed locations, about two-thirds were either subdural (30%) or intracerebral (32%).

Pooled incidence rates of ICH have decreased steadily over time, from 7%-8% during the 1960-1979 time period, to 5%-6% from 1980-1999, and most recently to about 3%.

Mortality rates during the same time periods decreased in a similar fashion, from 300, to 100, to 75 deaths per 100,000 person-years.

Additional analysis revealed an expected relationship between disease severity and likelihood of ICH. Mild cases of hemophilia had an ICH incidence rate of 0.9%, moderate cases had a rate of 1.3%, and severe cases topped the scale at 4.5%, entailing an incidence rate ratio of 2.7 between severe and nonsevere patients.

“I think our data show that in hemophilia, ICH is still a very important and frequent complication,” Ms. Zwagemaker said. “Luckily, we also see a decline in numbers, but I think it’s still very important that we identify those at risk in hemophilia and that we acknowledge it’s still a very important problem.”

Dr. Zwagemaker reported having no relevant financial disclosures.

SOURCE: Zwagemaker AF et al. EAHAD 2019, Abstract OR08.

PRAGUE – Despite improvements over the past 60 years, intracranial hemorrhage (ICH) remains a significant complication in hemophilia, occurring most frequently among patients with severe forms of the disease, according to a large-scale meta-analysis involving 56 studies and nearly 80,000 patients.

Will Pass/MDedge News

The consequences of a single incident of ICH can be irreparable and life-changing, so clinician knowledge of incidence rates and risk factors is essential, said lead author Anne-Fleur Zwagemaker, a PhD candidate from Amsterdam University Medical Center.

“Intracranial hemorrhage is one of the most severe and fearful complications in hemophilia,” Ms. Zwagemaker said in a presentation at the annual congress of the European Association for Haemophilia and Allied Disorders. “Our aim was to give more precise estimates of ICH numbers and risk factors in hemophilia.”

The review is notable for its scale and quality. After eliminating studies with fewer than 50 patients or other insufficiencies, the investigators were left with 56 studies conducted between 1960 and 2018, involving 79,818 patients with hemophilia. With a mean observation period of 12 years, the data encompassed almost 1 million person-years of data.

Across all studies, 1,508 ICH events were reported. Incidence and mortality rates were 400 and 80 per 100,000 person-years, respectively.

To optimize accuracy, the investigators further restricted studies to those with a sample size of at least 365 patients, leading to a pooled incidence rate of 3.8%. Studies with relevant data showed that about half of the cases of ICH (48%) were spontaneous. Regarding most common bleed locations, about two-thirds were either subdural (30%) or intracerebral (32%).

Pooled incidence rates of ICH have decreased steadily over time, from 7%-8% during the 1960-1979 time period, to 5%-6% from 1980-1999, and most recently to about 3%.

Mortality rates during the same time periods decreased in a similar fashion, from 300, to 100, to 75 deaths per 100,000 person-years.

Additional analysis revealed an expected relationship between disease severity and likelihood of ICH. Mild cases of hemophilia had an ICH incidence rate of 0.9%, moderate cases had a rate of 1.3%, and severe cases topped the scale at 4.5%, entailing an incidence rate ratio of 2.7 between severe and nonsevere patients.

“I think our data show that in hemophilia, ICH is still a very important and frequent complication,” Ms. Zwagemaker said. “Luckily, we also see a decline in numbers, but I think it’s still very important that we identify those at risk in hemophilia and that we acknowledge it’s still a very important problem.”

Dr. Zwagemaker reported having no relevant financial disclosures.

SOURCE: Zwagemaker AF et al. EAHAD 2019, Abstract OR08.

PRAGUE – Despite improvements over the past 60 years, intracranial hemorrhage (ICH) remains a significant complication in hemophilia, occurring most frequently among patients with severe forms of the disease, according to a large-scale meta-analysis involving 56 studies and nearly 80,000 patients.

Will Pass/MDedge News

The consequences of a single incident of ICH can be irreparable and life-changing, so clinician knowledge of incidence rates and risk factors is essential, said lead author Anne-Fleur Zwagemaker, a PhD candidate from Amsterdam University Medical Center.

“Intracranial hemorrhage is one of the most severe and fearful complications in hemophilia,” Ms. Zwagemaker said in a presentation at the annual congress of the European Association for Haemophilia and Allied Disorders. “Our aim was to give more precise estimates of ICH numbers and risk factors in hemophilia.”

The review is notable for its scale and quality. After eliminating studies with fewer than 50 patients or other insufficiencies, the investigators were left with 56 studies conducted between 1960 and 2018, involving 79,818 patients with hemophilia. With a mean observation period of 12 years, the data encompassed almost 1 million person-years of data.

Across all studies, 1,508 ICH events were reported. Incidence and mortality rates were 400 and 80 per 100,000 person-years, respectively.

To optimize accuracy, the investigators further restricted studies to those with a sample size of at least 365 patients, leading to a pooled incidence rate of 3.8%. Studies with relevant data showed that about half of the cases of ICH (48%) were spontaneous. Regarding most common bleed locations, about two-thirds were either subdural (30%) or intracerebral (32%).

Pooled incidence rates of ICH have decreased steadily over time, from 7%-8% during the 1960-1979 time period, to 5%-6% from 1980-1999, and most recently to about 3%.

Mortality rates during the same time periods decreased in a similar fashion, from 300, to 100, to 75 deaths per 100,000 person-years.

Additional analysis revealed an expected relationship between disease severity and likelihood of ICH. Mild cases of hemophilia had an ICH incidence rate of 0.9%, moderate cases had a rate of 1.3%, and severe cases topped the scale at 4.5%, entailing an incidence rate ratio of 2.7 between severe and nonsevere patients.

“I think our data show that in hemophilia, ICH is still a very important and frequent complication,” Ms. Zwagemaker said. “Luckily, we also see a decline in numbers, but I think it’s still very important that we identify those at risk in hemophilia and that we acknowledge it’s still a very important problem.”

Dr. Zwagemaker reported having no relevant financial disclosures.

SOURCE: Zwagemaker AF et al. EAHAD 2019, Abstract OR08.