MADRID – Abatacept doesn’t appear to increase the risk of opportunistic infections among patients with rheumatoid arthritis, Kevin Winthrop, MD, reported at the European Congress of Rheumatology.

After reviewing all of the extant safety data on the drug – all of its clinical trial and open-label study data, and case reports of abatacept-associated adverse events – Dr. Winthrop concluded that infections, including tuberculosis, fungal overgrowth, herpes simplex and herpes zoster, occur either with similar frequency or less often than among those taking placebo.

“In fact, there is a sense that abatacept is actually safer,” than some other disease-modifying antirheumatic drugs,” said Dr. Winthrop, an infectious disease specialist at Oregon Health and Science University, Portland. However, there are few data comparing safety among the agents – something he said should be examined in more detail.

His review encompassed 16 clinical trials comprising 7,044 patients who took the drug (21,330 patient/years of abatacept exposure) and 1,485 patients who took placebo. He conducted two analyses: one for opportunistic bacterial and fungal infections, and one for herpes simplex and herpes zoster.

The first analysis found 45 opportunistic bacterial or fungal infections among those taking abatacept – an incidence rate of 0.21/ 100 person-years. There were seven such infections in the placebo group – an incidence rate of 0.56/100 person-years. This difference was statistically significant.

In the abatacept cohort, there were two cases of bronchopulmonary aspergilliosis (IR 0.01) and three fungal eye infections (IR 0.01). There was also one case of gastrointestinal candidiasis; one fungal esophagitis; one cryptococcal meningitis; two pneumonias (one pseudomonal and one caused by Pneumocystis jirovecii); and two cases of respiratory monoliasis. All of these infections had an incidence rate of less than 0.01/100 person-years.

There were 17 tuberculosis cases (IR 0.08/100 person-years). Three cases were latent. Six of the cases were pulmonary and five were extrapulmonary. Two cases were unspecified. All occurred in regions with high or moderate endemic tuberculosis levels.

A meta-regression analysis examined the risk of opportunistic infections in the patients taken from the placebo-controlled clinical trials only (2,653 abatacept, 1,485 placebo). The estimated frequency of an opportunistic infection was 0.15% among those taking the drug and 0.48% among those taking placebo.

The herpes analysis examined the placebo-controlled clinical trial population as well. There were 57 cases of herpes simplex (IR 2.5/100 person-years) among those taking abatacept and 22 among those taking placebo (IR 1.8/100 person-years). The difference was not statistically significant.

There were 44 cases of herpes zoster among those taking abatacept (IR 1.9/100 person-years) and 21 among those taking placebo (IR 1.7/100 person-years).

“Basically, I think what we’re seeing here is a whole lot of nothing,” Dr. Winthrop said.

Dr. Winthrop has been a consultant for Pfizer, AbbVie, Bristol-Myers Squibb, UCB Pharma, Roche/Genentech, Amgen, Galapagos, and Eli Lilly.

[email protected]

On Twitter @Alz_gal

MADRID – Abatacept doesn’t appear to increase the risk of opportunistic infections among patients with rheumatoid arthritis, Kevin Winthrop, MD, reported at the European Congress of Rheumatology.

After reviewing all of the extant safety data on the drug – all of its clinical trial and open-label study data, and case reports of abatacept-associated adverse events – Dr. Winthrop concluded that infections, including tuberculosis, fungal overgrowth, herpes simplex and herpes zoster, occur either with similar frequency or less often than among those taking placebo.

“In fact, there is a sense that abatacept is actually safer,” than some other disease-modifying antirheumatic drugs,” said Dr. Winthrop, an infectious disease specialist at Oregon Health and Science University, Portland. However, there are few data comparing safety among the agents – something he said should be examined in more detail.

His review encompassed 16 clinical trials comprising 7,044 patients who took the drug (21,330 patient/years of abatacept exposure) and 1,485 patients who took placebo. He conducted two analyses: one for opportunistic bacterial and fungal infections, and one for herpes simplex and herpes zoster.

The first analysis found 45 opportunistic bacterial or fungal infections among those taking abatacept – an incidence rate of 0.21/ 100 person-years. There were seven such infections in the placebo group – an incidence rate of 0.56/100 person-years. This difference was statistically significant.

In the abatacept cohort, there were two cases of bronchopulmonary aspergilliosis (IR 0.01) and three fungal eye infections (IR 0.01). There was also one case of gastrointestinal candidiasis; one fungal esophagitis; one cryptococcal meningitis; two pneumonias (one pseudomonal and one caused by Pneumocystis jirovecii); and two cases of respiratory monoliasis. All of these infections had an incidence rate of less than 0.01/100 person-years.

There were 17 tuberculosis cases (IR 0.08/100 person-years). Three cases were latent. Six of the cases were pulmonary and five were extrapulmonary. Two cases were unspecified. All occurred in regions with high or moderate endemic tuberculosis levels.

A meta-regression analysis examined the risk of opportunistic infections in the patients taken from the placebo-controlled clinical trials only (2,653 abatacept, 1,485 placebo). The estimated frequency of an opportunistic infection was 0.15% among those taking the drug and 0.48% among those taking placebo.

The herpes analysis examined the placebo-controlled clinical trial population as well. There were 57 cases of herpes simplex (IR 2.5/100 person-years) among those taking abatacept and 22 among those taking placebo (IR 1.8/100 person-years). The difference was not statistically significant.

There were 44 cases of herpes zoster among those taking abatacept (IR 1.9/100 person-years) and 21 among those taking placebo (IR 1.7/100 person-years).

“Basically, I think what we’re seeing here is a whole lot of nothing,” Dr. Winthrop said.

Dr. Winthrop has been a consultant for Pfizer, AbbVie, Bristol-Myers Squibb, UCB Pharma, Roche/Genentech, Amgen, Galapagos, and Eli Lilly.

[email protected]

On Twitter @Alz_gal

MADRID – Abatacept doesn’t appear to increase the risk of opportunistic infections among patients with rheumatoid arthritis, Kevin Winthrop, MD, reported at the European Congress of Rheumatology.

After reviewing all of the extant safety data on the drug – all of its clinical trial and open-label study data, and case reports of abatacept-associated adverse events – Dr. Winthrop concluded that infections, including tuberculosis, fungal overgrowth, herpes simplex and herpes zoster, occur either with similar frequency or less often than among those taking placebo.

“In fact, there is a sense that abatacept is actually safer,” than some other disease-modifying antirheumatic drugs,” said Dr. Winthrop, an infectious disease specialist at Oregon Health and Science University, Portland. However, there are few data comparing safety among the agents – something he said should be examined in more detail.

His review encompassed 16 clinical trials comprising 7,044 patients who took the drug (21,330 patient/years of abatacept exposure) and 1,485 patients who took placebo. He conducted two analyses: one for opportunistic bacterial and fungal infections, and one for herpes simplex and herpes zoster.

The first analysis found 45 opportunistic bacterial or fungal infections among those taking abatacept – an incidence rate of 0.21/ 100 person-years. There were seven such infections in the placebo group – an incidence rate of 0.56/100 person-years. This difference was statistically significant.

In the abatacept cohort, there were two cases of bronchopulmonary aspergilliosis (IR 0.01) and three fungal eye infections (IR 0.01). There was also one case of gastrointestinal candidiasis; one fungal esophagitis; one cryptococcal meningitis; two pneumonias (one pseudomonal and one caused by Pneumocystis jirovecii); and two cases of respiratory monoliasis. All of these infections had an incidence rate of less than 0.01/100 person-years.

There were 17 tuberculosis cases (IR 0.08/100 person-years). Three cases were latent. Six of the cases were pulmonary and five were extrapulmonary. Two cases were unspecified. All occurred in regions with high or moderate endemic tuberculosis levels.

A meta-regression analysis examined the risk of opportunistic infections in the patients taken from the placebo-controlled clinical trials only (2,653 abatacept, 1,485 placebo). The estimated frequency of an opportunistic infection was 0.15% among those taking the drug and 0.48% among those taking placebo.

The herpes analysis examined the placebo-controlled clinical trial population as well. There were 57 cases of herpes simplex (IR 2.5/100 person-years) among those taking abatacept and 22 among those taking placebo (IR 1.8/100 person-years). The difference was not statistically significant.

There were 44 cases of herpes zoster among those taking abatacept (IR 1.9/100 person-years) and 21 among those taking placebo (IR 1.7/100 person-years).

“Basically, I think what we’re seeing here is a whole lot of nothing,” Dr. Winthrop said.

Dr. Winthrop has been a consultant for Pfizer, AbbVie, Bristol-Myers Squibb, UCB Pharma, Roche/Genentech, Amgen, Galapagos, and Eli Lilly.

[email protected]

On Twitter @Alz_gal

Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival, compared with placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results published in the New England Journal of Medicine.*

About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.

In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 357* to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.

Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.

Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.

They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.

Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.

The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.

Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.

There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.

HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.

Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely to mutations other than FLT3.

“It is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” possibly through inhibition of KIT, researchers said.

They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.

*CORRECTION 7/5/2017: An earlier version of this article misstated the number of patients in the placebo group as well as where the study originally appeared.

Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival, compared with placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results published in the New England Journal of Medicine.*

About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.

In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 357* to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.

Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.

Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.

They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.

Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.

The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.

Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.

There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.

HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.

Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely to mutations other than FLT3.

“It is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” possibly through inhibition of KIT, researchers said.

They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.

*CORRECTION 7/5/2017: An earlier version of this article misstated the number of patients in the placebo group as well as where the study originally appeared.

Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival, compared with placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results published in the New England Journal of Medicine.*

About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.

In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 357* to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.

Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.

Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.

They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.

Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.

The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.

Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.

There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.

HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.

Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely to mutations other than FLT3.

“It is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” possibly through inhibition of KIT, researchers said.

They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.

*CORRECTION 7/5/2017: An earlier version of this article misstated the number of patients in the placebo group as well as where the study originally appeared.

MADRID – Talk about versatility: Ibrutinib (Imbruvica), a drug with marked activity against B-cell malignancies, also appears to be a safe and acceptable option for the treatment of patients with chronic graft vs. host disease (cGVHD) for whom frontline therapies have failed.

Among 42 patients in a phase II study with steroid-refractory cGVHD, the overall response rate with ibrutinib was 67%, with one-third of responders having a complete response, reported Iskra Pusic, MD, from Washington University School of Medicine in St. Louis.

Neil Osterweil/Frontline Medical News

Investigators are currently enrolling patients in a double-blind clinical trial comparing ibrutinib or placebo in combination with corticosteroids in patients with newly diagnosed cGVHD, she noted.

The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.

MADRID – Talk about versatility: Ibrutinib (Imbruvica), a drug with marked activity against B-cell malignancies, also appears to be a safe and acceptable option for the treatment of patients with chronic graft vs. host disease (cGVHD) for whom frontline therapies have failed.

Among 42 patients in a phase II study with steroid-refractory cGVHD, the overall response rate with ibrutinib was 67%, with one-third of responders having a complete response, reported Iskra Pusic, MD, from Washington University School of Medicine in St. Louis.

Neil Osterweil/Frontline Medical News

Investigators are currently enrolling patients in a double-blind clinical trial comparing ibrutinib or placebo in combination with corticosteroids in patients with newly diagnosed cGVHD, she noted.

The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.

MADRID – Talk about versatility: Ibrutinib (Imbruvica), a drug with marked activity against B-cell malignancies, also appears to be a safe and acceptable option for the treatment of patients with chronic graft vs. host disease (cGVHD) for whom frontline therapies have failed.

Among 42 patients in a phase II study with steroid-refractory cGVHD, the overall response rate with ibrutinib was 67%, with one-third of responders having a complete response, reported Iskra Pusic, MD, from Washington University School of Medicine in St. Louis.

Neil Osterweil/Frontline Medical News

Investigators are currently enrolling patients in a double-blind clinical trial comparing ibrutinib or placebo in combination with corticosteroids in patients with newly diagnosed cGVHD, she noted.

The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.

MADRID – Aprelimast rapidly improved symptoms for patients with active psoriatic arthritis who were naive to biologics, whether or not they were on background methotrexate.

Response to the phosphodiesterase 4-inhibitor also increased with time, Peter Nash, MD, said at the European Congress of Rheumatology. By 2 weeks, 16% had achieved an ACR20 response. By 24 weeks, that had risen to 43%, and at 52 weeks, was 67%. Many patients responded even better, with 37% achieving an ACR50 response and 21% and ACR70 response by the end of the phase III placebo-controlled trial, said Dr. Nash of the University of Queensland, Brisbane, Australia.

Michele G Sullivan/Frontline Medical News

ACTIVE randomized 229 patients with active psoriatic arthritis (PsA) to either placebo or 30 mg apremilast twice daily. The primary endpoint was ACR20 response at week 16. At that time, patients who had not improved by at least 10% were offered early escape into active therapy.

Patients were a mean of 49 years old, with mean disease duration of 4 years. This is considerably shorter than the duration seen in many PsA trials, Dr. Nash said. It was a reflection of the study requirement that patients have taken no more than one synthetic disease-modifying antirheumatic agent (sDMARD) and no biologics for their disease.

The active and placebo groups separated very early in this study, with 16% of the apremilast group achieving an ACR 20 response by 2 weeks compared to 6% taking placebo. The response curves remained significantly separated throughout the entire study. By the 16-week endpoint, 38% of the active group and 20% of the placebo group had achieved ACR20. At this point, 11 of those taking apremilast asked for early escape and went on open-label apremilast at the same dose; 35 taking placebo were switched to open-label apremilast.

By 24 weeks, the ACR20 responses were 44% in the apremilast group and 25% in the placebo group. That response rate continued to rise over the year of treatment. By week 52, 67% of patients who had been on the study drug since the beginning had an ACR20, 37% an ACR50, and 21% an ACR70 response. ACR response was just as good in patients who were taking background methotrexate as those who were not, Dr. Nash said.

Compared to placebo, apremilast was associated with significantly more improvement on the Disease Activity Score-28 (CRP). Again, the response curves separated significantly by 2 weeks (–0.59 apremilast vs. –0.31 placebo) and continued to separate at 16 weeks (–1.07 vs. –0.39), and 24 weeks (–1.26 vs. –0.76). At 52 weeks, among those who had been initially randomized to apremilast, the mean DAS-28 (CRP) score had changed –1.71 from baseline.

The drug also significantly improved enthesitis relative to placebo, with rapid onset of action that continued to improve by week 24. The adverse event profile was good, Dr. Nash said. There were no opportunistic infections and no reactivations of tuberculosis. Ten in the active group and five in the placebo group withdrew due to an adverse event. Diarrhea and headache were the most common issues. Diarrhea occurred in 11% of the placebo group and 15% of the apremilast group; headache in 4% of the placebo group and 7% of the apremilast group. These were more common in the beginning of the study and tended to resolve with time, Dr. Nash said.

Thirty patients in the study had a history of depression and of these, two had a depression flare that lead to withdrawal from the study. Weight loss of at least 10% occurred in 5% of those taking apremilast.

Celgene sponsored the study. Dr. Nash has received research support from the company.

[email protected]

On Twitter @Alz_gal

MADRID – Aprelimast rapidly improved symptoms for patients with active psoriatic arthritis who were naive to biologics, whether or not they were on background methotrexate.

Response to the phosphodiesterase 4-inhibitor also increased with time, Peter Nash, MD, said at the European Congress of Rheumatology. By 2 weeks, 16% had achieved an ACR20 response. By 24 weeks, that had risen to 43%, and at 52 weeks, was 67%. Many patients responded even better, with 37% achieving an ACR50 response and 21% and ACR70 response by the end of the phase III placebo-controlled trial, said Dr. Nash of the University of Queensland, Brisbane, Australia.

Michele G Sullivan/Frontline Medical News

ACTIVE randomized 229 patients with active psoriatic arthritis (PsA) to either placebo or 30 mg apremilast twice daily. The primary endpoint was ACR20 response at week 16. At that time, patients who had not improved by at least 10% were offered early escape into active therapy.

Patients were a mean of 49 years old, with mean disease duration of 4 years. This is considerably shorter than the duration seen in many PsA trials, Dr. Nash said. It was a reflection of the study requirement that patients have taken no more than one synthetic disease-modifying antirheumatic agent (sDMARD) and no biologics for their disease.

The active and placebo groups separated very early in this study, with 16% of the apremilast group achieving an ACR 20 response by 2 weeks compared to 6% taking placebo. The response curves remained significantly separated throughout the entire study. By the 16-week endpoint, 38% of the active group and 20% of the placebo group had achieved ACR20. At this point, 11 of those taking apremilast asked for early escape and went on open-label apremilast at the same dose; 35 taking placebo were switched to open-label apremilast.

By 24 weeks, the ACR20 responses were 44% in the apremilast group and 25% in the placebo group. That response rate continued to rise over the year of treatment. By week 52, 67% of patients who had been on the study drug since the beginning had an ACR20, 37% an ACR50, and 21% an ACR70 response. ACR response was just as good in patients who were taking background methotrexate as those who were not, Dr. Nash said.

Compared to placebo, apremilast was associated with significantly more improvement on the Disease Activity Score-28 (CRP). Again, the response curves separated significantly by 2 weeks (–0.59 apremilast vs. –0.31 placebo) and continued to separate at 16 weeks (–1.07 vs. –0.39), and 24 weeks (–1.26 vs. –0.76). At 52 weeks, among those who had been initially randomized to apremilast, the mean DAS-28 (CRP) score had changed –1.71 from baseline.

The drug also significantly improved enthesitis relative to placebo, with rapid onset of action that continued to improve by week 24. The adverse event profile was good, Dr. Nash said. There were no opportunistic infections and no reactivations of tuberculosis. Ten in the active group and five in the placebo group withdrew due to an adverse event. Diarrhea and headache were the most common issues. Diarrhea occurred in 11% of the placebo group and 15% of the apremilast group; headache in 4% of the placebo group and 7% of the apremilast group. These were more common in the beginning of the study and tended to resolve with time, Dr. Nash said.

Thirty patients in the study had a history of depression and of these, two had a depression flare that lead to withdrawal from the study. Weight loss of at least 10% occurred in 5% of those taking apremilast.

Celgene sponsored the study. Dr. Nash has received research support from the company.

[email protected]

On Twitter @Alz_gal

MADRID – Aprelimast rapidly improved symptoms for patients with active psoriatic arthritis who were naive to biologics, whether or not they were on background methotrexate.

Response to the phosphodiesterase 4-inhibitor also increased with time, Peter Nash, MD, said at the European Congress of Rheumatology. By 2 weeks, 16% had achieved an ACR20 response. By 24 weeks, that had risen to 43%, and at 52 weeks, was 67%. Many patients responded even better, with 37% achieving an ACR50 response and 21% and ACR70 response by the end of the phase III placebo-controlled trial, said Dr. Nash of the University of Queensland, Brisbane, Australia.

Michele G Sullivan/Frontline Medical News

ACTIVE randomized 229 patients with active psoriatic arthritis (PsA) to either placebo or 30 mg apremilast twice daily. The primary endpoint was ACR20 response at week 16. At that time, patients who had not improved by at least 10% were offered early escape into active therapy.

Patients were a mean of 49 years old, with mean disease duration of 4 years. This is considerably shorter than the duration seen in many PsA trials, Dr. Nash said. It was a reflection of the study requirement that patients have taken no more than one synthetic disease-modifying antirheumatic agent (sDMARD) and no biologics for their disease.

The active and placebo groups separated very early in this study, with 16% of the apremilast group achieving an ACR 20 response by 2 weeks compared to 6% taking placebo. The response curves remained significantly separated throughout the entire study. By the 16-week endpoint, 38% of the active group and 20% of the placebo group had achieved ACR20. At this point, 11 of those taking apremilast asked for early escape and went on open-label apremilast at the same dose; 35 taking placebo were switched to open-label apremilast.

By 24 weeks, the ACR20 responses were 44% in the apremilast group and 25% in the placebo group. That response rate continued to rise over the year of treatment. By week 52, 67% of patients who had been on the study drug since the beginning had an ACR20, 37% an ACR50, and 21% an ACR70 response. ACR response was just as good in patients who were taking background methotrexate as those who were not, Dr. Nash said.

Compared to placebo, apremilast was associated with significantly more improvement on the Disease Activity Score-28 (CRP). Again, the response curves separated significantly by 2 weeks (–0.59 apremilast vs. –0.31 placebo) and continued to separate at 16 weeks (–1.07 vs. –0.39), and 24 weeks (–1.26 vs. –0.76). At 52 weeks, among those who had been initially randomized to apremilast, the mean DAS-28 (CRP) score had changed –1.71 from baseline.

The drug also significantly improved enthesitis relative to placebo, with rapid onset of action that continued to improve by week 24. The adverse event profile was good, Dr. Nash said. There were no opportunistic infections and no reactivations of tuberculosis. Ten in the active group and five in the placebo group withdrew due to an adverse event. Diarrhea and headache were the most common issues. Diarrhea occurred in 11% of the placebo group and 15% of the apremilast group; headache in 4% of the placebo group and 7% of the apremilast group. These were more common in the beginning of the study and tended to resolve with time, Dr. Nash said.

Thirty patients in the study had a history of depression and of these, two had a depression flare that lead to withdrawal from the study. Weight loss of at least 10% occurred in 5% of those taking apremilast.

Celgene sponsored the study. Dr. Nash has received research support from the company.

[email protected]

On Twitter @Alz_gal

SEATTLE – Intraperitoneal ropivacaine decreases postoperative pain and improves functional recovery after laparoscopic colectomy, according to randomized, blinded trial from the Royal Adelaide (Australia) Hospital.

“We recommend routine inclusion of IPLA [intraperitoneal local anesthetic] in the multimodal analgesia component of ERAS [enhanced-recovery-after-surgery] programs for laparoscopic colectomy,” the investigators concluded.

[email protected]

SEATTLE – Intraperitoneal ropivacaine decreases postoperative pain and improves functional recovery after laparoscopic colectomy, according to randomized, blinded trial from the Royal Adelaide (Australia) Hospital.

“We recommend routine inclusion of IPLA [intraperitoneal local anesthetic] in the multimodal analgesia component of ERAS [enhanced-recovery-after-surgery] programs for laparoscopic colectomy,” the investigators concluded.

[email protected]

SEATTLE – Intraperitoneal ropivacaine decreases postoperative pain and improves functional recovery after laparoscopic colectomy, according to randomized, blinded trial from the Royal Adelaide (Australia) Hospital.

“We recommend routine inclusion of IPLA [intraperitoneal local anesthetic] in the multimodal analgesia component of ERAS [enhanced-recovery-after-surgery] programs for laparoscopic colectomy,” the investigators concluded.

[email protected]

MADRID – Patients with advanced Hodgkin lymphoma who have a metabolic response after the first two cycles of extended-dose(e)BEACOPP can be spared from undergoing more than two additional cycles of the highly intensive and toxic regimen, investigators from the German Hodgkin Study Group (GHSG) contend.

Among 1,005 patients with Hodgkin lymphoma who had negative PET scans after the second cycle of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, prednisone, procarbazine), progression-free survival (PFS) was virtually identical whether patients were randomized to undergo a total of six-to-eight cycles or only four cycles, reported Peter Borchmann, MD, from the University of Cologne, Germany.

Neil Osterweil/Frontline Medical News

“For patients with negative PET-2 after initial treatment with eBEACOPP. Therapy with only two additional cycles of eBEACOPP is very effective, obviously, very safe, very short – it just takes 12 weeks – and it’s affordable,” he said.

“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far. That’s why we recommend this treatment, PET-guided extended BEACOPP in patients with newly diagnosed, advanced-stage Hodgkin lymphoma,” he added.

Although most patients in the United States with newly diagnosed Hodgkin lymphoma receive ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), BEACOPP is sometimes used for high-risk patients. BEACOPP is associated with considerable toxicities, however, including increased risk of secondary malignancies.

To see whether select patients could be cured with fewer cycles of therapy, the GHSG investigators designed the GHSG HD18 study in which patient with metabolic responses determined by fluorodeoxyglucose-PET after two eBEACOPP cycles were randomized to either two or six-to-eight additional cycles.

A total of 2,101 patients from the ages of 18-60 years with newly diagnosed advanced-stage Hodgkin lymphoma were enrolled from centers in Germany, Switzerland, Austria, the Czech Republic, and the Netherlands.

After the second cycle of therapy, patients underwent fluorodeoxyglucose-PET scans, and those with negative results were then randomized.

The trial was designed and powered for noninferiority of the shortened regimen, with a maximum allowable difference of 6%.

The trial met its primary endpoint and then some. After a median observation time of 53 months, the 5-year PFS rate for patients who received only four cycles was 91.2%, compared with 91.8% for patients who underwent six-to-eight cycles. As shown on a Kaplan-Meier curve, the two lines were superimposable and virtually impossible to tell apart.

Interestingly, 5-year overall survival was significantly better with the shorter, less toxic regimen, at 97.6% vs. 95.4%, respectively, translating into a hazard ratio favoring the shorter regimen of 0.36 (P = .006).

In addition, the four-cycle regimen was associated with fewer severe infections (8% vs 15%), and lower degrees of organ toxicity (8% vs. 18%). In addition, the rate of secondary acute myeloid leukemia or the myelodysplastic syndrome was 0.4% among the 501 patients treated with only four cycles, compared with 1.6% for the 504 patients who received six to eight cycles.

There were no treatment-related deaths among patients who underwent four cycles, compared with six deaths among patients treated with additional cycles.

In an interview, Dr. Borchmann said that the findings are likely to change the standard of care for those centers that use the BEACOPP regimen. He acknowledged that the regimen is highly toxic and requires intensive patient surveillance and management, which may be more practical in Europe where patients generally live closer to major cancer centers than in the more spacious United States.

The study was supported by German Cancer Aid, the Swiss State Secratariate for Education, Research and Innovation, and by Roche Pharma AG. Dr, Borchmann reported having no relevant disclosures.

MADRID – Patients with advanced Hodgkin lymphoma who have a metabolic response after the first two cycles of extended-dose(e)BEACOPP can be spared from undergoing more than two additional cycles of the highly intensive and toxic regimen, investigators from the German Hodgkin Study Group (GHSG) contend.

Among 1,005 patients with Hodgkin lymphoma who had negative PET scans after the second cycle of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, prednisone, procarbazine), progression-free survival (PFS) was virtually identical whether patients were randomized to undergo a total of six-to-eight cycles or only four cycles, reported Peter Borchmann, MD, from the University of Cologne, Germany.

Neil Osterweil/Frontline Medical News

“For patients with negative PET-2 after initial treatment with eBEACOPP. Therapy with only two additional cycles of eBEACOPP is very effective, obviously, very safe, very short – it just takes 12 weeks – and it’s affordable,” he said.

“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far. That’s why we recommend this treatment, PET-guided extended BEACOPP in patients with newly diagnosed, advanced-stage Hodgkin lymphoma,” he added.

Although most patients in the United States with newly diagnosed Hodgkin lymphoma receive ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), BEACOPP is sometimes used for high-risk patients. BEACOPP is associated with considerable toxicities, however, including increased risk of secondary malignancies.

To see whether select patients could be cured with fewer cycles of therapy, the GHSG investigators designed the GHSG HD18 study in which patient with metabolic responses determined by fluorodeoxyglucose-PET after two eBEACOPP cycles were randomized to either two or six-to-eight additional cycles.

A total of 2,101 patients from the ages of 18-60 years with newly diagnosed advanced-stage Hodgkin lymphoma were enrolled from centers in Germany, Switzerland, Austria, the Czech Republic, and the Netherlands.

After the second cycle of therapy, patients underwent fluorodeoxyglucose-PET scans, and those with negative results were then randomized.

The trial was designed and powered for noninferiority of the shortened regimen, with a maximum allowable difference of 6%.

The trial met its primary endpoint and then some. After a median observation time of 53 months, the 5-year PFS rate for patients who received only four cycles was 91.2%, compared with 91.8% for patients who underwent six-to-eight cycles. As shown on a Kaplan-Meier curve, the two lines were superimposable and virtually impossible to tell apart.

Interestingly, 5-year overall survival was significantly better with the shorter, less toxic regimen, at 97.6% vs. 95.4%, respectively, translating into a hazard ratio favoring the shorter regimen of 0.36 (P = .006).

In addition, the four-cycle regimen was associated with fewer severe infections (8% vs 15%), and lower degrees of organ toxicity (8% vs. 18%). In addition, the rate of secondary acute myeloid leukemia or the myelodysplastic syndrome was 0.4% among the 501 patients treated with only four cycles, compared with 1.6% for the 504 patients who received six to eight cycles.

There were no treatment-related deaths among patients who underwent four cycles, compared with six deaths among patients treated with additional cycles.

In an interview, Dr. Borchmann said that the findings are likely to change the standard of care for those centers that use the BEACOPP regimen. He acknowledged that the regimen is highly toxic and requires intensive patient surveillance and management, which may be more practical in Europe where patients generally live closer to major cancer centers than in the more spacious United States.

The study was supported by German Cancer Aid, the Swiss State Secratariate for Education, Research and Innovation, and by Roche Pharma AG. Dr, Borchmann reported having no relevant disclosures.

MADRID – Patients with advanced Hodgkin lymphoma who have a metabolic response after the first two cycles of extended-dose(e)BEACOPP can be spared from undergoing more than two additional cycles of the highly intensive and toxic regimen, investigators from the German Hodgkin Study Group (GHSG) contend.

Among 1,005 patients with Hodgkin lymphoma who had negative PET scans after the second cycle of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, prednisone, procarbazine), progression-free survival (PFS) was virtually identical whether patients were randomized to undergo a total of six-to-eight cycles or only four cycles, reported Peter Borchmann, MD, from the University of Cologne, Germany.

Neil Osterweil/Frontline Medical News

“For patients with negative PET-2 after initial treatment with eBEACOPP. Therapy with only two additional cycles of eBEACOPP is very effective, obviously, very safe, very short – it just takes 12 weeks – and it’s affordable,” he said.

“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far. That’s why we recommend this treatment, PET-guided extended BEACOPP in patients with newly diagnosed, advanced-stage Hodgkin lymphoma,” he added.

Although most patients in the United States with newly diagnosed Hodgkin lymphoma receive ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), BEACOPP is sometimes used for high-risk patients. BEACOPP is associated with considerable toxicities, however, including increased risk of secondary malignancies.

To see whether select patients could be cured with fewer cycles of therapy, the GHSG investigators designed the GHSG HD18 study in which patient with metabolic responses determined by fluorodeoxyglucose-PET after two eBEACOPP cycles were randomized to either two or six-to-eight additional cycles.

A total of 2,101 patients from the ages of 18-60 years with newly diagnosed advanced-stage Hodgkin lymphoma were enrolled from centers in Germany, Switzerland, Austria, the Czech Republic, and the Netherlands.

After the second cycle of therapy, patients underwent fluorodeoxyglucose-PET scans, and those with negative results were then randomized.

The trial was designed and powered for noninferiority of the shortened regimen, with a maximum allowable difference of 6%.

The trial met its primary endpoint and then some. After a median observation time of 53 months, the 5-year PFS rate for patients who received only four cycles was 91.2%, compared with 91.8% for patients who underwent six-to-eight cycles. As shown on a Kaplan-Meier curve, the two lines were superimposable and virtually impossible to tell apart.

Interestingly, 5-year overall survival was significantly better with the shorter, less toxic regimen, at 97.6% vs. 95.4%, respectively, translating into a hazard ratio favoring the shorter regimen of 0.36 (P = .006).

In addition, the four-cycle regimen was associated with fewer severe infections (8% vs 15%), and lower degrees of organ toxicity (8% vs. 18%). In addition, the rate of secondary acute myeloid leukemia or the myelodysplastic syndrome was 0.4% among the 501 patients treated with only four cycles, compared with 1.6% for the 504 patients who received six to eight cycles.

There were no treatment-related deaths among patients who underwent four cycles, compared with six deaths among patients treated with additional cycles.

In an interview, Dr. Borchmann said that the findings are likely to change the standard of care for those centers that use the BEACOPP regimen. He acknowledged that the regimen is highly toxic and requires intensive patient surveillance and management, which may be more practical in Europe where patients generally live closer to major cancer centers than in the more spacious United States.

The study was supported by German Cancer Aid, the Swiss State Secratariate for Education, Research and Innovation, and by Roche Pharma AG. Dr, Borchmann reported having no relevant disclosures.

MADRID – Look before you leap into anticoagulation therapy for older cancer patients, results from a Canadian cohort study suggest.

Among patients 65 and older with cancer and a venous thromboembolic event (VTE) within 6 months of the cancer diagnosis, the 7-day mortality rate from VTE was 0.5%, compared with an 11% rate of death from a major bleeding episode, reported Alejandro Lazo-Langner MD, MSc from Western University in London, Canada.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

MADRID – Look before you leap into anticoagulation therapy for older cancer patients, results from a Canadian cohort study suggest.

Among patients 65 and older with cancer and a venous thromboembolic event (VTE) within 6 months of the cancer diagnosis, the 7-day mortality rate from VTE was 0.5%, compared with an 11% rate of death from a major bleeding episode, reported Alejandro Lazo-Langner MD, MSc from Western University in London, Canada.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

MADRID – Look before you leap into anticoagulation therapy for older cancer patients, results from a Canadian cohort study suggest.

Among patients 65 and older with cancer and a venous thromboembolic event (VTE) within 6 months of the cancer diagnosis, the 7-day mortality rate from VTE was 0.5%, compared with an 11% rate of death from a major bleeding episode, reported Alejandro Lazo-Langner MD, MSc from Western University in London, Canada.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.

The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.

Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.

Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.

Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.

In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.

FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.

The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).

Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).

Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).

Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.

Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.

At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.

Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.

Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.

“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”

Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.

Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.

The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.

Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.

Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.

Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.

In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.

FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.

The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).

Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).

Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).

Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.

Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.

At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.

Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.

Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.

“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”

Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.

Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.

The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.

Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.

Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.

Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.

In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.

FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.

The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).

Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).

Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).

Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.

Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.

At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.

Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.

Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.

“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”

Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.

Syringe

The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).

The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.

The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.

It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).

“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.

Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.

“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.

The FDA based its decision on results from 4 clinical studies:

• SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
• SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
• MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
• PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL

This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.

Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.

And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.

Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.

The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.

The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:

• In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
• In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
• In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.

Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.

A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.

For further information on the new US formulation, see the full prescribing information. 

Syringe

The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).

The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.

The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.

It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).

“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.

Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.

“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.

The FDA based its decision on results from 4 clinical studies:

• SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
• SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
• MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
• PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL

This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.

Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.

And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.

Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.

The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.

The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:

• In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
• In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
• In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.

Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.

A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.

For further information on the new US formulation, see the full prescribing information. 

Syringe

The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).

The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.

The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.

It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).

“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.

Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.

“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.

The FDA based its decision on results from 4 clinical studies:

• SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
• SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
• MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
• PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL

This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.

Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.

And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.

Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.

The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.

The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:

• In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
• In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
• In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.

Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.

A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.

For further information on the new US formulation, see the full prescribing information. 

Photo by Rhoda Baer

A small study of 20 children aged 8 to 18 years with incurable or refractory cancers indicates children are reliable reporters of their symptoms and side effects.

The investigators collected reports from the children, who were enrolled on phase 1/2 clinical trials at 4 cancer centers and undergoing their first courses of chemotherapy.

The team assessed the feasibility and acceptability of collecting symptom, function, and quality of life (QOL) reports from the study participants.

The investigators also evaluated the measurement tool and interview questions at 2 time points.

They contend the youths’ self-reports potentially could be a new trial endpoint.

According to the investigators, only rarely do patient-reported outcomes (PROs) get incorporated into pediatric phase 1 or phase 2 trials.

And because these trials contribute to drug indications and labeling, the researchers decided to assess whether it was feasible to enroll young people and retain them in a PRO endeavor.

The researchers also assessed the reliability, validity, responsiveness, and range of the pediatric measures employed. They used the Patient-Reported Outcomes Measurement Information System (PROMIS) to capture statistically significant and clinically meaningful changes or minimally important differences (MIDs) in PROs.

Pamela S. Hinds, PhD, RN, of George Washington University in Washington, DC,  reported the findings on behalf of the Children's National Health System researchers in Cancer, the journal of the American Cancer Society.

"When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children's organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience," Dr Hinds said.

"Without this crucial information, the full impact of the experimental treatment on the pediatric patient is likely underreported and clinicians are hobbled in their ability to effectively manage side effects," she added.

The team recruited children and adolescents enrolled in phase 1 safety or phase 2 efficacy trials at Children's National, Seattle Children's Hospital, Children's Hospital of Philadelphia, and Boston Children's Hospital.

Findings

Sixty percent of the participants were male and 70% were white.

Median age of the participants was 13.6 years: 7 (35%) were age 8 to 12, and 13 (65%) were 13 to 17.

Thirteen participants (65%) had solid tumors, 5 (25%) had brain tumors, and 2 (10%) had lymphoma.

A total of 29 patients were eligible to participate in the trial during 20 months of screening. Five parents and 2 patients declined to participate.

The remaining 22 patients who agreed to participate accounted for a 75.9% enrollment rate. Twenty of them (90.9%) participated at the first data time point, which was at the time of enrollment, and 77.3% participated 3 weeks later at time point 2.

The authors noted that refusals to enroll were more likely to come from parents (17.2%) than the eligible patients (8.3%).

And refusals only occurred when the self-report measures were not embedded in the clinical trial.

Of the 10 protocols represented, 7 patients were enrolled on the same protocol in which the PRO measures were embedded.

The researchers administered the 6-item short-form measures for the scales of Mobility, Pain, Fatigue, Depressive Symptoms, Anxiety, and Peer Relationships.

They asked the 4 open-ended questions—concerning QOL while receiving therapy and acceptability of the patient reporting—at time point 2.

At time point 1, 3 patients did not complete 3 PROMIS measures, for a person-missing rate of 15% and a measure-missing rate of 3.3%.

At the second time point, 2 patients did not complete 1 measure each, for a person-missing rate of 11.8% and a measure-missing rate of 2%.

All but one measure at time point 1 met the reliability criterion and all measures did so at time point 2.

The research team believes their findings support the feasibility and acceptability of completing quantitative and qualitative measures regarding symptom, function, and QOL experiences among children and adolescents with incurable cancer.

The researchers note the small study size and the number of parent refusals are limitations of the trial.

Nevertheless, they recommend embedding PROs in future pediatric oncology phase 1/2 trials. 

Photo by Rhoda Baer

A small study of 20 children aged 8 to 18 years with incurable or refractory cancers indicates children are reliable reporters of their symptoms and side effects.

The investigators collected reports from the children, who were enrolled on phase 1/2 clinical trials at 4 cancer centers and undergoing their first courses of chemotherapy.

The team assessed the feasibility and acceptability of collecting symptom, function, and quality of life (QOL) reports from the study participants.

The investigators also evaluated the measurement tool and interview questions at 2 time points.

They contend the youths’ self-reports potentially could be a new trial endpoint.

According to the investigators, only rarely do patient-reported outcomes (PROs) get incorporated into pediatric phase 1 or phase 2 trials.

And because these trials contribute to drug indications and labeling, the researchers decided to assess whether it was feasible to enroll young people and retain them in a PRO endeavor.

The researchers also assessed the reliability, validity, responsiveness, and range of the pediatric measures employed. They used the Patient-Reported Outcomes Measurement Information System (PROMIS) to capture statistically significant and clinically meaningful changes or minimally important differences (MIDs) in PROs.

Pamela S. Hinds, PhD, RN, of George Washington University in Washington, DC,  reported the findings on behalf of the Children's National Health System researchers in Cancer, the journal of the American Cancer Society.

"When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children's organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience," Dr Hinds said.

"Without this crucial information, the full impact of the experimental treatment on the pediatric patient is likely underreported and clinicians are hobbled in their ability to effectively manage side effects," she added.

The team recruited children and adolescents enrolled in phase 1 safety or phase 2 efficacy trials at Children's National, Seattle Children's Hospital, Children's Hospital of Philadelphia, and Boston Children's Hospital.

Findings

Sixty percent of the participants were male and 70% were white.

Median age of the participants was 13.6 years: 7 (35%) were age 8 to 12, and 13 (65%) were 13 to 17.

Thirteen participants (65%) had solid tumors, 5 (25%) had brain tumors, and 2 (10%) had lymphoma.

A total of 29 patients were eligible to participate in the trial during 20 months of screening. Five parents and 2 patients declined to participate.

The remaining 22 patients who agreed to participate accounted for a 75.9% enrollment rate. Twenty of them (90.9%) participated at the first data time point, which was at the time of enrollment, and 77.3% participated 3 weeks later at time point 2.

The authors noted that refusals to enroll were more likely to come from parents (17.2%) than the eligible patients (8.3%).

And refusals only occurred when the self-report measures were not embedded in the clinical trial.

Of the 10 protocols represented, 7 patients were enrolled on the same protocol in which the PRO measures were embedded.

The researchers administered the 6-item short-form measures for the scales of Mobility, Pain, Fatigue, Depressive Symptoms, Anxiety, and Peer Relationships.

They asked the 4 open-ended questions—concerning QOL while receiving therapy and acceptability of the patient reporting—at time point 2.

At time point 1, 3 patients did not complete 3 PROMIS measures, for a person-missing rate of 15% and a measure-missing rate of 3.3%.

At the second time point, 2 patients did not complete 1 measure each, for a person-missing rate of 11.8% and a measure-missing rate of 2%.

All but one measure at time point 1 met the reliability criterion and all measures did so at time point 2.

The research team believes their findings support the feasibility and acceptability of completing quantitative and qualitative measures regarding symptom, function, and QOL experiences among children and adolescents with incurable cancer.

The researchers note the small study size and the number of parent refusals are limitations of the trial.

Nevertheless, they recommend embedding PROs in future pediatric oncology phase 1/2 trials. 

Photo by Rhoda Baer

A small study of 20 children aged 8 to 18 years with incurable or refractory cancers indicates children are reliable reporters of their symptoms and side effects.

The investigators collected reports from the children, who were enrolled on phase 1/2 clinical trials at 4 cancer centers and undergoing their first courses of chemotherapy.

The team assessed the feasibility and acceptability of collecting symptom, function, and quality of life (QOL) reports from the study participants.

The investigators also evaluated the measurement tool and interview questions at 2 time points.

They contend the youths’ self-reports potentially could be a new trial endpoint.

According to the investigators, only rarely do patient-reported outcomes (PROs) get incorporated into pediatric phase 1 or phase 2 trials.

And because these trials contribute to drug indications and labeling, the researchers decided to assess whether it was feasible to enroll young people and retain them in a PRO endeavor.

The researchers also assessed the reliability, validity, responsiveness, and range of the pediatric measures employed. They used the Patient-Reported Outcomes Measurement Information System (PROMIS) to capture statistically significant and clinically meaningful changes or minimally important differences (MIDs) in PROs.

Pamela S. Hinds, PhD, RN, of George Washington University in Washington, DC,  reported the findings on behalf of the Children's National Health System researchers in Cancer, the journal of the American Cancer Society.

"When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children's organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience," Dr Hinds said.

"Without this crucial information, the full impact of the experimental treatment on the pediatric patient is likely underreported and clinicians are hobbled in their ability to effectively manage side effects," she added.

The team recruited children and adolescents enrolled in phase 1 safety or phase 2 efficacy trials at Children's National, Seattle Children's Hospital, Children's Hospital of Philadelphia, and Boston Children's Hospital.

Findings

Sixty percent of the participants were male and 70% were white.

Median age of the participants was 13.6 years: 7 (35%) were age 8 to 12, and 13 (65%) were 13 to 17.

Thirteen participants (65%) had solid tumors, 5 (25%) had brain tumors, and 2 (10%) had lymphoma.

A total of 29 patients were eligible to participate in the trial during 20 months of screening. Five parents and 2 patients declined to participate.

The remaining 22 patients who agreed to participate accounted for a 75.9% enrollment rate. Twenty of them (90.9%) participated at the first data time point, which was at the time of enrollment, and 77.3% participated 3 weeks later at time point 2.

The authors noted that refusals to enroll were more likely to come from parents (17.2%) than the eligible patients (8.3%).

And refusals only occurred when the self-report measures were not embedded in the clinical trial.

Of the 10 protocols represented, 7 patients were enrolled on the same protocol in which the PRO measures were embedded.

The researchers administered the 6-item short-form measures for the scales of Mobility, Pain, Fatigue, Depressive Symptoms, Anxiety, and Peer Relationships.

They asked the 4 open-ended questions—concerning QOL while receiving therapy and acceptability of the patient reporting—at time point 2.

At time point 1, 3 patients did not complete 3 PROMIS measures, for a person-missing rate of 15% and a measure-missing rate of 3.3%.

At the second time point, 2 patients did not complete 1 measure each, for a person-missing rate of 11.8% and a measure-missing rate of 2%.

All but one measure at time point 1 met the reliability criterion and all measures did so at time point 2.

The research team believes their findings support the feasibility and acceptability of completing quantitative and qualitative measures regarding symptom, function, and QOL experiences among children and adolescents with incurable cancer.

The researchers note the small study size and the number of parent refusals are limitations of the trial.

Nevertheless, they recommend embedding PROs in future pediatric oncology phase 1/2 trials.