Hematology Times

Jacqueline Mays, DDS, PhD

Photo courtesy of NIH

SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).

A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.

The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.

However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.

Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).

Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.

According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.

Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.

“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.

“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”

Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.

In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.

The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.

Patient population

The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.

The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.

The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.

Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.

Treatment

The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.

The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.

Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.

Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.

Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.

Safety

Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.

However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.

On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.

Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).

Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.

Efficacy

The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.

Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.

Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.

Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.

Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.

Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).

Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).

Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).

The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).

“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”

Jacqueline Mays, DDS, PhD

Photo courtesy of NIH

SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).

A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.

The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.

However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.

Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).

Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.

According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.

Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.

“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.

“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”

Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.

In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.

The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.

Patient population

The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.

The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.

The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.

Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.

Treatment

The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.

The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.

Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.

Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.

Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.

Safety

Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.

However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.

On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.

Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).

Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.

Efficacy

The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.

Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.

Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.

Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.

Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.

Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).

Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).

Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).

The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).

“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”

Jacqueline Mays, DDS, PhD

Photo courtesy of NIH

SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).

A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.

The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.

However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.

Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).

Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.

According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.

Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.

“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.

“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”

Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.

In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.

The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.

Patient population

The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.

The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.

The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.

Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.

Treatment

The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.

The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.

Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.

Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.

Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.

Safety

Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.

However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.

On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.

Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).

Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.

Efficacy

The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.

Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.

Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.

Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.

Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.

Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).

Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).

Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).

The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).

“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”

Skeletal remains of an

individual from Velia, Italy

Photo courtesy of Luca

Bandioli, Pigorini Museum

An analysis of 2000-year-old human remains from several regions across the Italian peninsula has confirmed the presence of Plasmodium falciparum malaria during the Roman Empire, according to researchers.

The team found mitochondrial genomic evidence of P falciparum malaria, coaxed from the teeth of bodies buried in 3 Italian cemeteries, dating back to the Imperial period.

The researchers said these finding provide a key reference point for when and where the malaria parasite existed in humans, as well as more information about the evolution of human disease.

The team reported these findings in Current Biology.

“There is extensive written evidence describing fevers that sound like malaria in ancient Greece and Rome, but the specific malaria species responsible is unknown,” said study author Stephanie Marciniak, PhD, of Pennsylvania State University in University Park.

“Our data confirm that the species was likely Plasmodium falciparum and that it affected people in different ecological and cultural environments. These results open up new questions to explore, particularly how widespread this parasite was and what burden it placed upon communities in Imperial Roman Italy.”

Dr Marciniak and her colleagues sampled teeth taken from 58 adults interred at 3 Imperial period Italian cemeteries: Isola Sacra, Velia, and Vagnari.

Located on the coast, Velia and Isola Sacra were known as important port cities and trading centers. Vagnari is located further inland and believed to be the burial site of laborers who would have worked on a Roman rural estate.

The researchers mined tiny DNA fragments from dental pulp. They were able to extract, purify, and enrich specifically for the Plasmodium species known to infect humans.

The team noted that usable DNA is challenging to extract because the parasites primarily dwell within the bloodstream and organs, which decompose and break down over time—in this instance, over the course of 2 millennia.

However, the researchers recovered more than half of the P falciparum mitochondrial genome from 2 individuals from Velia and Vagnari.

Skeletal remains of an

individual from Velia, Italy

Photo courtesy of Luca

Bandioli, Pigorini Museum

An analysis of 2000-year-old human remains from several regions across the Italian peninsula has confirmed the presence of Plasmodium falciparum malaria during the Roman Empire, according to researchers.

The team found mitochondrial genomic evidence of P falciparum malaria, coaxed from the teeth of bodies buried in 3 Italian cemeteries, dating back to the Imperial period.

The researchers said these finding provide a key reference point for when and where the malaria parasite existed in humans, as well as more information about the evolution of human disease.

The team reported these findings in Current Biology.

“There is extensive written evidence describing fevers that sound like malaria in ancient Greece and Rome, but the specific malaria species responsible is unknown,” said study author Stephanie Marciniak, PhD, of Pennsylvania State University in University Park.

“Our data confirm that the species was likely Plasmodium falciparum and that it affected people in different ecological and cultural environments. These results open up new questions to explore, particularly how widespread this parasite was and what burden it placed upon communities in Imperial Roman Italy.”

Dr Marciniak and her colleagues sampled teeth taken from 58 adults interred at 3 Imperial period Italian cemeteries: Isola Sacra, Velia, and Vagnari.

Located on the coast, Velia and Isola Sacra were known as important port cities and trading centers. Vagnari is located further inland and believed to be the burial site of laborers who would have worked on a Roman rural estate.

The researchers mined tiny DNA fragments from dental pulp. They were able to extract, purify, and enrich specifically for the Plasmodium species known to infect humans.

The team noted that usable DNA is challenging to extract because the parasites primarily dwell within the bloodstream and organs, which decompose and break down over time—in this instance, over the course of 2 millennia.

However, the researchers recovered more than half of the P falciparum mitochondrial genome from 2 individuals from Velia and Vagnari.

Skeletal remains of an

individual from Velia, Italy

Photo courtesy of Luca

Bandioli, Pigorini Museum

An analysis of 2000-year-old human remains from several regions across the Italian peninsula has confirmed the presence of Plasmodium falciparum malaria during the Roman Empire, according to researchers.

The team found mitochondrial genomic evidence of P falciparum malaria, coaxed from the teeth of bodies buried in 3 Italian cemeteries, dating back to the Imperial period.

The researchers said these finding provide a key reference point for when and where the malaria parasite existed in humans, as well as more information about the evolution of human disease.

The team reported these findings in Current Biology.

“There is extensive written evidence describing fevers that sound like malaria in ancient Greece and Rome, but the specific malaria species responsible is unknown,” said study author Stephanie Marciniak, PhD, of Pennsylvania State University in University Park.

“Our data confirm that the species was likely Plasmodium falciparum and that it affected people in different ecological and cultural environments. These results open up new questions to explore, particularly how widespread this parasite was and what burden it placed upon communities in Imperial Roman Italy.”

Dr Marciniak and her colleagues sampled teeth taken from 58 adults interred at 3 Imperial period Italian cemeteries: Isola Sacra, Velia, and Vagnari.

Located on the coast, Velia and Isola Sacra were known as important port cities and trading centers. Vagnari is located further inland and believed to be the burial site of laborers who would have worked on a Roman rural estate.

The researchers mined tiny DNA fragments from dental pulp. They were able to extract, purify, and enrich specifically for the Plasmodium species known to infect humans.

The team noted that usable DNA is challenging to extract because the parasites primarily dwell within the bloodstream and organs, which decompose and break down over time—in this instance, over the course of 2 millennia.

However, the researchers recovered more than half of the P falciparum mitochondrial genome from 2 individuals from Velia and Vagnari.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Researchers have estimated the global incidence of 32 cancer types and deaths related to these malignancies in 2015.

The group’s data, published in JAMA Oncology, suggest there were 17.5 million cancer cases and 8.7 million cancer deaths last year.

There were 78,000 cases of Hodgkin lymphoma and 24,000 deaths from the disease, as well as 666,000 cases of non-Hodgkin lymphoma (NHL) and 231,000 NHL deaths.

There were 154,000 cases of multiple myeloma and 101,000 deaths from the disease.

And there were 606,000 cases of leukemia, with 353,000 leukemia deaths. This included 161,000 cases of acute lymphoid leukemia (110,000 deaths), 191,000 cases of chronic lymphoid leukemia (61,000 deaths), 190,000 cases of acute myeloid leukemia (147,000 deaths), and 64,000 cases of chronic myeloid leukemia (35,000 deaths).

The data also show that, between 2005 and 2015, cancer cases increased by 33%, mostly due to population aging and growth, plus changes in age-specific cancer rates.

Globally, the odds of developing cancer during a lifetime were 1 in 3 for men and 1 in 4 for women in 2015.

Prostate cancer was the most common cancer in men (1.6 million cases), although tracheal, bronchus, and lung cancer was the leading cause of cancer deaths for men.

Breast cancer was the most common cancer for women (2.4 million cases) and the leading cause of cancer deaths in women.

The most common childhood cancers were leukemia, “other neoplasms,” NHL, and brain and nervous system cancers.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Researchers have estimated the global incidence of 32 cancer types and deaths related to these malignancies in 2015.

The group’s data, published in JAMA Oncology, suggest there were 17.5 million cancer cases and 8.7 million cancer deaths last year.

There were 78,000 cases of Hodgkin lymphoma and 24,000 deaths from the disease, as well as 666,000 cases of non-Hodgkin lymphoma (NHL) and 231,000 NHL deaths.

There were 154,000 cases of multiple myeloma and 101,000 deaths from the disease.

And there were 606,000 cases of leukemia, with 353,000 leukemia deaths. This included 161,000 cases of acute lymphoid leukemia (110,000 deaths), 191,000 cases of chronic lymphoid leukemia (61,000 deaths), 190,000 cases of acute myeloid leukemia (147,000 deaths), and 64,000 cases of chronic myeloid leukemia (35,000 deaths).

The data also show that, between 2005 and 2015, cancer cases increased by 33%, mostly due to population aging and growth, plus changes in age-specific cancer rates.

Globally, the odds of developing cancer during a lifetime were 1 in 3 for men and 1 in 4 for women in 2015.

Prostate cancer was the most common cancer in men (1.6 million cases), although tracheal, bronchus, and lung cancer was the leading cause of cancer deaths for men.

Breast cancer was the most common cancer for women (2.4 million cases) and the leading cause of cancer deaths in women.

The most common childhood cancers were leukemia, “other neoplasms,” NHL, and brain and nervous system cancers.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Researchers have estimated the global incidence of 32 cancer types and deaths related to these malignancies in 2015.

The group’s data, published in JAMA Oncology, suggest there were 17.5 million cancer cases and 8.7 million cancer deaths last year.

There were 78,000 cases of Hodgkin lymphoma and 24,000 deaths from the disease, as well as 666,000 cases of non-Hodgkin lymphoma (NHL) and 231,000 NHL deaths.

There were 154,000 cases of multiple myeloma and 101,000 deaths from the disease.

And there were 606,000 cases of leukemia, with 353,000 leukemia deaths. This included 161,000 cases of acute lymphoid leukemia (110,000 deaths), 191,000 cases of chronic lymphoid leukemia (61,000 deaths), 190,000 cases of acute myeloid leukemia (147,000 deaths), and 64,000 cases of chronic myeloid leukemia (35,000 deaths).

The data also show that, between 2005 and 2015, cancer cases increased by 33%, mostly due to population aging and growth, plus changes in age-specific cancer rates.

Globally, the odds of developing cancer during a lifetime were 1 in 3 for men and 1 in 4 for women in 2015.

Prostate cancer was the most common cancer in men (1.6 million cases), although tracheal, bronchus, and lung cancer was the leading cause of cancer deaths for men.

Breast cancer was the most common cancer for women (2.4 million cases) and the leading cause of cancer deaths in women.

The most common childhood cancers were leukemia, “other neoplasms,” NHL, and brain and nervous system cancers.

 

 

Attendees at the 2016

ASH Annual Meeting

 

SAN DIEGO—When patients with chronic lymphocytic leukemia (CLL) cannot tolerate one Bruton’s tyrosine kinase (BTK) inhibitor, they may do well on another, according to a presentation at the 2016 ASH Annual Meeting.

Researchers conducting a phase 1/2 study found that acalabrutinib was “well-tolerated” and demonstrated “promising activity” in patients intolerant to ibrutinib.

Seventy-nine percent of patients responded to acalabrutinib.

And although 36% of patients had a recurrence of an adverse event (AE) they experienced while on ibrutinib, none of the patients discontinued acalabrutinib due to AE recurrence.

Farrukh T. Awan, MD, of The Ohio State University in Columbus, Ohio, presented these results at the meeting as abstract 638.*

Dr Awan noted that integrating ibrutinib into standard CLL therapy has improved patient outcomes, but a lack of tolerability observed in some patients suggests that more selective BTK inhibition may be desirable.

“We know that around 10% to 20% of patients who are treated with ibrutinib would have to stop therapy because of an adverse event,” Dr Awan said. “Acalabrutinib is a highly selective, potent BTK inhibitor that has shown promising efficacy, and that [research] was published last year.”

In this ongoing, phase 1/2 study, Dr Awan and his colleagues are testing acalabrutinib in patients with CLL/small lymphocytic leukemia. The study has enrolled multiple cohorts of patients—relapsed/refractory, treatment-naïve, Richter’s transformation/prolymphocytic leukemia, and ibrutinib intolerant.

At this year’s ASH meeting, Dr Awan presented data on the 33 CLL patients who were ibrutinib intolerant. The patients’ median age was 64 (range, 50-82), 61% were male, 97% had an ECOG performance status of 0-1, 52% had Rai stage III-IV, and 31% had bulky disease.

The median number of prior therapies was 4 (range, 2-13), and 91% of patients had ibrutinib as their last therapy. The median duration of prior ibrutinib treatment was 11.5 months (range, 1-62), and the median time from ending ibrutinib to starting acalabrutinib was 47 days (range, 3-331 days).

Treatment and safety

Patients received acalabrutinib at 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The patients’ median time on therapy was 12.2 months (range, 0.2-23.6 months).

Nine patients discontinued treatment—3 due to disease progression, 3 due to AEs, 2 due to an increase in BTK C481S mutation frequency in the peripheral blood and central nervous system involvement, and 1 due to physician decision (because the patient had concurrent hemophilia).

The 3 AEs that led to treatment discontinuation were fatal hemorrhagic stroke, fatal fungal infection, and metastatic endometrial cancer. All 3 events were considered unrelated to acalabrutinib.

Serious AEs occurred in 11 patients (33%). A serious AE that occurred in more than 1 patient was pneumonia (n=2).

The most common AEs were diarrhea (52%, grade 1-2), headache (39%, grade 1-2), cough (24%, grade 1-2), increased weight (24%, grade 1-2), nausea (21%, grade 1-2), contusion (18%, grade 1-2), ecchymosis (18%, grade 1-2), fatigue (18%, grade 1-2), hypertension (18% overall, 6% ≥ grade 3), pyrexia (18% overall, 3% ≥ grade 3), vomiting (18%, grade 1-2), myalgia (15% overall, 3% ≥ grade 3), rash (15%, grade 1-2), stomatitis (15%, grade 1-2), upper respiratory tract infection (15%, grade 1-2), and urinary tract infection (15%, grade 1-2).

AE recurrence

Twelve patients (36%) had a recurrence of ibrutinib-related AEs—a total of 16 events. Fourteen of these events either decreased in severity or were unchanged with acalabrutinib treatment.

The events without a change in severity were atrial fibrillation (n=1), fatigue (n=1), muscle spasms (n=1), myalgia (n=1), peripheral edema (n=1), panniculitis (n=1), and rash (n=1).

The events that decreased in severity were diarrhea (n=2), arthralgia (n=1), ecchymosis (n=1), fatigue (n=1), panniculitis (n=1), and rash (n=1).

The events that increased in severity were contusion (n=1, grade 1 to 2) and fatigue (n=1, grade 1 to 2).

None of the patients discontinued acalabrutinib due to AE recurrence.

Efficacy

Twenty-nine patients were evaluable for efficacy.

The overall response rate was 79% (n=23). One patient had a complete response (3%), 15 had a partial response (52%), and 7 had a partial response with lymphocytosis (24%). Six patients had stable disease (21%).

The median time to response was 1.9 months. Eighty-one percent of responding patients have a response duration of 12 months or longer.

The median progression-free survival has not been reached.

The research is sponsored by Acerta Pharma.

*Information presented at the meeting differs from the abstract.

 

 

Attendees at the 2016

ASH Annual Meeting

 

SAN DIEGO—When patients with chronic lymphocytic leukemia (CLL) cannot tolerate one Bruton’s tyrosine kinase (BTK) inhibitor, they may do well on another, according to a presentation at the 2016 ASH Annual Meeting.

Researchers conducting a phase 1/2 study found that acalabrutinib was “well-tolerated” and demonstrated “promising activity” in patients intolerant to ibrutinib.

Seventy-nine percent of patients responded to acalabrutinib.

And although 36% of patients had a recurrence of an adverse event (AE) they experienced while on ibrutinib, none of the patients discontinued acalabrutinib due to AE recurrence.

Farrukh T. Awan, MD, of The Ohio State University in Columbus, Ohio, presented these results at the meeting as abstract 638.*

Dr Awan noted that integrating ibrutinib into standard CLL therapy has improved patient outcomes, but a lack of tolerability observed in some patients suggests that more selective BTK inhibition may be desirable.

“We know that around 10% to 20% of patients who are treated with ibrutinib would have to stop therapy because of an adverse event,” Dr Awan said. “Acalabrutinib is a highly selective, potent BTK inhibitor that has shown promising efficacy, and that [research] was published last year.”

In this ongoing, phase 1/2 study, Dr Awan and his colleagues are testing acalabrutinib in patients with CLL/small lymphocytic leukemia. The study has enrolled multiple cohorts of patients—relapsed/refractory, treatment-naïve, Richter’s transformation/prolymphocytic leukemia, and ibrutinib intolerant.

At this year’s ASH meeting, Dr Awan presented data on the 33 CLL patients who were ibrutinib intolerant. The patients’ median age was 64 (range, 50-82), 61% were male, 97% had an ECOG performance status of 0-1, 52% had Rai stage III-IV, and 31% had bulky disease.

The median number of prior therapies was 4 (range, 2-13), and 91% of patients had ibrutinib as their last therapy. The median duration of prior ibrutinib treatment was 11.5 months (range, 1-62), and the median time from ending ibrutinib to starting acalabrutinib was 47 days (range, 3-331 days).

Treatment and safety

Patients received acalabrutinib at 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The patients’ median time on therapy was 12.2 months (range, 0.2-23.6 months).

Nine patients discontinued treatment—3 due to disease progression, 3 due to AEs, 2 due to an increase in BTK C481S mutation frequency in the peripheral blood and central nervous system involvement, and 1 due to physician decision (because the patient had concurrent hemophilia).

The 3 AEs that led to treatment discontinuation were fatal hemorrhagic stroke, fatal fungal infection, and metastatic endometrial cancer. All 3 events were considered unrelated to acalabrutinib.

Serious AEs occurred in 11 patients (33%). A serious AE that occurred in more than 1 patient was pneumonia (n=2).

The most common AEs were diarrhea (52%, grade 1-2), headache (39%, grade 1-2), cough (24%, grade 1-2), increased weight (24%, grade 1-2), nausea (21%, grade 1-2), contusion (18%, grade 1-2), ecchymosis (18%, grade 1-2), fatigue (18%, grade 1-2), hypertension (18% overall, 6% ≥ grade 3), pyrexia (18% overall, 3% ≥ grade 3), vomiting (18%, grade 1-2), myalgia (15% overall, 3% ≥ grade 3), rash (15%, grade 1-2), stomatitis (15%, grade 1-2), upper respiratory tract infection (15%, grade 1-2), and urinary tract infection (15%, grade 1-2).

AE recurrence

Twelve patients (36%) had a recurrence of ibrutinib-related AEs—a total of 16 events. Fourteen of these events either decreased in severity or were unchanged with acalabrutinib treatment.

The events without a change in severity were atrial fibrillation (n=1), fatigue (n=1), muscle spasms (n=1), myalgia (n=1), peripheral edema (n=1), panniculitis (n=1), and rash (n=1).

The events that decreased in severity were diarrhea (n=2), arthralgia (n=1), ecchymosis (n=1), fatigue (n=1), panniculitis (n=1), and rash (n=1).

The events that increased in severity were contusion (n=1, grade 1 to 2) and fatigue (n=1, grade 1 to 2).

None of the patients discontinued acalabrutinib due to AE recurrence.

Efficacy

Twenty-nine patients were evaluable for efficacy.

The overall response rate was 79% (n=23). One patient had a complete response (3%), 15 had a partial response (52%), and 7 had a partial response with lymphocytosis (24%). Six patients had stable disease (21%).

The median time to response was 1.9 months. Eighty-one percent of responding patients have a response duration of 12 months or longer.

The median progression-free survival has not been reached.

The research is sponsored by Acerta Pharma.

*Information presented at the meeting differs from the abstract.

 

 

Attendees at the 2016

ASH Annual Meeting

 

SAN DIEGO—When patients with chronic lymphocytic leukemia (CLL) cannot tolerate one Bruton’s tyrosine kinase (BTK) inhibitor, they may do well on another, according to a presentation at the 2016 ASH Annual Meeting.

Researchers conducting a phase 1/2 study found that acalabrutinib was “well-tolerated” and demonstrated “promising activity” in patients intolerant to ibrutinib.

Seventy-nine percent of patients responded to acalabrutinib.

And although 36% of patients had a recurrence of an adverse event (AE) they experienced while on ibrutinib, none of the patients discontinued acalabrutinib due to AE recurrence.

Farrukh T. Awan, MD, of The Ohio State University in Columbus, Ohio, presented these results at the meeting as abstract 638.*

Dr Awan noted that integrating ibrutinib into standard CLL therapy has improved patient outcomes, but a lack of tolerability observed in some patients suggests that more selective BTK inhibition may be desirable.

“We know that around 10% to 20% of patients who are treated with ibrutinib would have to stop therapy because of an adverse event,” Dr Awan said. “Acalabrutinib is a highly selective, potent BTK inhibitor that has shown promising efficacy, and that [research] was published last year.”

In this ongoing, phase 1/2 study, Dr Awan and his colleagues are testing acalabrutinib in patients with CLL/small lymphocytic leukemia. The study has enrolled multiple cohorts of patients—relapsed/refractory, treatment-naïve, Richter’s transformation/prolymphocytic leukemia, and ibrutinib intolerant.

At this year’s ASH meeting, Dr Awan presented data on the 33 CLL patients who were ibrutinib intolerant. The patients’ median age was 64 (range, 50-82), 61% were male, 97% had an ECOG performance status of 0-1, 52% had Rai stage III-IV, and 31% had bulky disease.

The median number of prior therapies was 4 (range, 2-13), and 91% of patients had ibrutinib as their last therapy. The median duration of prior ibrutinib treatment was 11.5 months (range, 1-62), and the median time from ending ibrutinib to starting acalabrutinib was 47 days (range, 3-331 days).

Treatment and safety

Patients received acalabrutinib at 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The patients’ median time on therapy was 12.2 months (range, 0.2-23.6 months).

Nine patients discontinued treatment—3 due to disease progression, 3 due to AEs, 2 due to an increase in BTK C481S mutation frequency in the peripheral blood and central nervous system involvement, and 1 due to physician decision (because the patient had concurrent hemophilia).

The 3 AEs that led to treatment discontinuation were fatal hemorrhagic stroke, fatal fungal infection, and metastatic endometrial cancer. All 3 events were considered unrelated to acalabrutinib.

Serious AEs occurred in 11 patients (33%). A serious AE that occurred in more than 1 patient was pneumonia (n=2).

The most common AEs were diarrhea (52%, grade 1-2), headache (39%, grade 1-2), cough (24%, grade 1-2), increased weight (24%, grade 1-2), nausea (21%, grade 1-2), contusion (18%, grade 1-2), ecchymosis (18%, grade 1-2), fatigue (18%, grade 1-2), hypertension (18% overall, 6% ≥ grade 3), pyrexia (18% overall, 3% ≥ grade 3), vomiting (18%, grade 1-2), myalgia (15% overall, 3% ≥ grade 3), rash (15%, grade 1-2), stomatitis (15%, grade 1-2), upper respiratory tract infection (15%, grade 1-2), and urinary tract infection (15%, grade 1-2).

AE recurrence

Twelve patients (36%) had a recurrence of ibrutinib-related AEs—a total of 16 events. Fourteen of these events either decreased in severity or were unchanged with acalabrutinib treatment.

The events without a change in severity were atrial fibrillation (n=1), fatigue (n=1), muscle spasms (n=1), myalgia (n=1), peripheral edema (n=1), panniculitis (n=1), and rash (n=1).

The events that decreased in severity were diarrhea (n=2), arthralgia (n=1), ecchymosis (n=1), fatigue (n=1), panniculitis (n=1), and rash (n=1).

The events that increased in severity were contusion (n=1, grade 1 to 2) and fatigue (n=1, grade 1 to 2).

None of the patients discontinued acalabrutinib due to AE recurrence.

Efficacy

Twenty-nine patients were evaluable for efficacy.

The overall response rate was 79% (n=23). One patient had a complete response (3%), 15 had a partial response (52%), and 7 had a partial response with lymphocytosis (24%). Six patients had stable disease (21%).

The median time to response was 1.9 months. Eighty-one percent of responding patients have a response duration of 12 months or longer.

The median progression-free survival has not been reached.

The research is sponsored by Acerta Pharma.

*Information presented at the meeting differs from the abstract.

Lindsey George, MD

SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector

so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.

Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).

The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.

Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.

Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 10¹² vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.

Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.

They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.

In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.

So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.

The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm³ or more.

At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.

Results

The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.

They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 10¹¹ vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.

Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.

One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.

Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.

After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and

achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.

Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.

He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.

“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.

Capsid immune responses

Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.

Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.

Two patients had capsid immune responses requiring steroid treatment.

One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.

After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.

The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.

After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.

He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.

Overall transgene-derived FIX activity

At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.

They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.

No patient developed FIX alloinhibitory antibodies.

One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.

The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.

The researchers recommend a larger cohort and continued observation to confirm these results.

Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.

*Information presented at the meeting differs from the abstract.

Lindsey George, MD

SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector

so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.

Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).

The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.

Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.

Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 10¹² vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.

Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.

They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.

In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.

So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.

The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm³ or more.

At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.

Results

The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.

They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 10¹¹ vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.

Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.

One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.

Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.

After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and

achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.

Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.

He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.

“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.

Capsid immune responses

Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.

Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.

Two patients had capsid immune responses requiring steroid treatment.

One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.

After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.

The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.

After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.

He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.

Overall transgene-derived FIX activity

At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.

They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.

No patient developed FIX alloinhibitory antibodies.

One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.

The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.

The researchers recommend a larger cohort and continued observation to confirm these results.

Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.

*Information presented at the meeting differs from the abstract.

Lindsey George, MD

SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector

so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.

Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).

The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.

Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.

Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 10¹² vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.

Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.

They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.

In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.

So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.

The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm³ or more.

At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.

Results

The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.

They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 10¹¹ vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.

Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.

One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.

Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.

After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and

achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.

Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.

He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.

“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.

Capsid immune responses

Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.

Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.

Two patients had capsid immune responses requiring steroid treatment.

One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.

After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.

The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.

After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.

He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.

Overall transgene-derived FIX activity

At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.

They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.

No patient developed FIX alloinhibitory antibodies.

One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.

The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.

The researchers recommend a larger cohort and continued observation to confirm these results.

Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.

*Information presented at the meeting differs from the abstract.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.

Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).

Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.

“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”

Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).

The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.

Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.

Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.

“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”

She noted that many of her PV patients are young, working professionals.

Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).

These results are consistent with those from a previous US LANDMARK survey of MPN patients.

The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.

“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.

In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).

“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”

A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”

*Information presented at the meeting differs from the abstract.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.

Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).

Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.

“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”

Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).

The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.

Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.

Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.

“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”

She noted that many of her PV patients are young, working professionals.

Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).

These results are consistent with those from a previous US LANDMARK survey of MPN patients.

The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.

“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.

In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).

“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”

A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”

*Information presented at the meeting differs from the abstract.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.

Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).

Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.

“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”

Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).

The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.

Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.

Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.

“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”

She noted that many of her PV patients are young, working professionals.

Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).

These results are consistent with those from a previous US LANDMARK survey of MPN patients.

The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.

“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.

In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).

“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”

A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”

*Information presented at the meeting differs from the abstract.

Francois-Xavier Mahon, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.

About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.

Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).

Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.

“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”

Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.

Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.

At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.

Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.

Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.

The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.

*Information presented at the meeting differs from the abstract.

Francois-Xavier Mahon, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.

About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.

Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).

Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.

“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”

Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.

Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.

At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.

Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.

Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.

The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.

*Information presented at the meeting differs from the abstract.

Francois-Xavier Mahon, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.

About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.

Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).

Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.

“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”

Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.

Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.

At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.

Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.

Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.

The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.

*Information presented at the meeting differs from the abstract.

Attendees at the 2016

ASH Annual Meeting

SAN DIEGO—Interim results of the phase 3 GALLIUM trial suggest an obinutuzumab-based treatment regimen provides a progression-free survival (PFS) benefit over a rituximab-based regimen for patients with previously untreated follicular lymphoma (FL).

According to investigators, patients who received obinutuzumab plus chemotherapy followed by obinutuzumab maintenance had a “clinically meaningful” improvement in PFS, when compared to patients who received rituximab plus chemotherapy followed by rituximab maintenance.

However, there was no significant difference between the treatment arms with regard to overall survival. And the incidence of non-fatal adverse events (AEs) was higher among the patients who received obinutuzumab.

Nevertheless, the data suggest that obinutuzumab-based therapy significantly improves outcomes and should be considered as a first-line treatment for FL, according to Robert Marcus, MBBS, of King’s College Hospital in London, UK.

Dr Marcus presented data from GALLIUM during the plenary session at the 2016 ASH Annual Meeting (abstract 6). GALLIUM is sponsored by Hoffmann-La Roche.

Patients and treatment

The study has enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to obinutuzumab plus chemotherapy followed by obinutuzumab alone for up to 2 years, and half were randomized to rituximab plus chemotherapy followed by rituximab alone for up to 2 years.

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine. The regimens were selected by each participating study site prior to beginning enrollment.

Baseline characteristics were similar between the treatment arms. The median age was about 60 (overall range, 23-88), roughly 40% of patients had high-risk disease, and the median time from diagnosis to randomization was about 1.5 months.

A total of 341 patients in the rituximab arm and 361 patients in the obinutuzumab arm completed maintenance therapy.

The median follow-up was 34.5 months. Maintenance is ongoing in 114 patients—54 on rituximab and 60 on obinutuzumab.

Efficacy

At the end of induction, the overall response rate was 86.9% in the rituximab arm and 88.5% in the obinutuzumab arm. The complete response rates were 23.8% and 19.5%, respectively. And the rates of stable disease were 1.3% and 0.5%, respectively.

The study’s primary endpoint is investigator-assessed PFS. The 3-year PFS rate is 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

According to an independent review committee, the 3-year PFS is 77.9% in the rituximab arm and 81.9% in the obinutuzumab arm (HR=0.71, P=0.0138).

The 3-year overall survival is 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

Safety

The overall incidence of AEs was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of AEs leading to treatment discontinuation was 14.2% and 16.3%, respectively. And the incidence of second neoplasms was 2.7% and 4.7%, respectively.

Grade 5 AEs occurred in 3.4% of patients in the rituximab arm and 4.0% of patients in the obinutuzumab arm. The investigators found that fatal AEs were more common in patients taking bendamustine, regardless of the treatment arm.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Attendees at the 2016

ASH Annual Meeting

SAN DIEGO—Interim results of the phase 3 GALLIUM trial suggest an obinutuzumab-based treatment regimen provides a progression-free survival (PFS) benefit over a rituximab-based regimen for patients with previously untreated follicular lymphoma (FL).

According to investigators, patients who received obinutuzumab plus chemotherapy followed by obinutuzumab maintenance had a “clinically meaningful” improvement in PFS, when compared to patients who received rituximab plus chemotherapy followed by rituximab maintenance.

However, there was no significant difference between the treatment arms with regard to overall survival. And the incidence of non-fatal adverse events (AEs) was higher among the patients who received obinutuzumab.

Nevertheless, the data suggest that obinutuzumab-based therapy significantly improves outcomes and should be considered as a first-line treatment for FL, according to Robert Marcus, MBBS, of King’s College Hospital in London, UK.

Dr Marcus presented data from GALLIUM during the plenary session at the 2016 ASH Annual Meeting (abstract 6). GALLIUM is sponsored by Hoffmann-La Roche.

Patients and treatment

The study has enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to obinutuzumab plus chemotherapy followed by obinutuzumab alone for up to 2 years, and half were randomized to rituximab plus chemotherapy followed by rituximab alone for up to 2 years.

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine. The regimens were selected by each participating study site prior to beginning enrollment.

Baseline characteristics were similar between the treatment arms. The median age was about 60 (overall range, 23-88), roughly 40% of patients had high-risk disease, and the median time from diagnosis to randomization was about 1.5 months.

A total of 341 patients in the rituximab arm and 361 patients in the obinutuzumab arm completed maintenance therapy.

The median follow-up was 34.5 months. Maintenance is ongoing in 114 patients—54 on rituximab and 60 on obinutuzumab.

Efficacy

At the end of induction, the overall response rate was 86.9% in the rituximab arm and 88.5% in the obinutuzumab arm. The complete response rates were 23.8% and 19.5%, respectively. And the rates of stable disease were 1.3% and 0.5%, respectively.

The study’s primary endpoint is investigator-assessed PFS. The 3-year PFS rate is 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

According to an independent review committee, the 3-year PFS is 77.9% in the rituximab arm and 81.9% in the obinutuzumab arm (HR=0.71, P=0.0138).

The 3-year overall survival is 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

Safety

The overall incidence of AEs was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of AEs leading to treatment discontinuation was 14.2% and 16.3%, respectively. And the incidence of second neoplasms was 2.7% and 4.7%, respectively.

Grade 5 AEs occurred in 3.4% of patients in the rituximab arm and 4.0% of patients in the obinutuzumab arm. The investigators found that fatal AEs were more common in patients taking bendamustine, regardless of the treatment arm.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Attendees at the 2016

ASH Annual Meeting

SAN DIEGO—Interim results of the phase 3 GALLIUM trial suggest an obinutuzumab-based treatment regimen provides a progression-free survival (PFS) benefit over a rituximab-based regimen for patients with previously untreated follicular lymphoma (FL).

According to investigators, patients who received obinutuzumab plus chemotherapy followed by obinutuzumab maintenance had a “clinically meaningful” improvement in PFS, when compared to patients who received rituximab plus chemotherapy followed by rituximab maintenance.

However, there was no significant difference between the treatment arms with regard to overall survival. And the incidence of non-fatal adverse events (AEs) was higher among the patients who received obinutuzumab.

Nevertheless, the data suggest that obinutuzumab-based therapy significantly improves outcomes and should be considered as a first-line treatment for FL, according to Robert Marcus, MBBS, of King’s College Hospital in London, UK.

Dr Marcus presented data from GALLIUM during the plenary session at the 2016 ASH Annual Meeting (abstract 6). GALLIUM is sponsored by Hoffmann-La Roche.

Patients and treatment

The study has enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.

Half of the FL patients (n=601) were randomized to obinutuzumab plus chemotherapy followed by obinutuzumab alone for up to 2 years, and half were randomized to rituximab plus chemotherapy followed by rituximab alone for up to 2 years.

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine. The regimens were selected by each participating study site prior to beginning enrollment.

Baseline characteristics were similar between the treatment arms. The median age was about 60 (overall range, 23-88), roughly 40% of patients had high-risk disease, and the median time from diagnosis to randomization was about 1.5 months.

A total of 341 patients in the rituximab arm and 361 patients in the obinutuzumab arm completed maintenance therapy.

The median follow-up was 34.5 months. Maintenance is ongoing in 114 patients—54 on rituximab and 60 on obinutuzumab.

Efficacy

At the end of induction, the overall response rate was 86.9% in the rituximab arm and 88.5% in the obinutuzumab arm. The complete response rates were 23.8% and 19.5%, respectively. And the rates of stable disease were 1.3% and 0.5%, respectively.

The study’s primary endpoint is investigator-assessed PFS. The 3-year PFS rate is 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).

According to an independent review committee, the 3-year PFS is 77.9% in the rituximab arm and 81.9% in the obinutuzumab arm (HR=0.71, P=0.0138).

The 3-year overall survival is 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).

Safety

The overall incidence of AEs was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.

The incidence of AEs leading to treatment discontinuation was 14.2% and 16.3%, respectively. And the incidence of second neoplasms was 2.7% and 4.7%, respectively.

Grade 5 AEs occurred in 3.4% of patients in the rituximab arm and 4.0% of patients in the obinutuzumab arm. The investigators found that fatal AEs were more common in patients taking bendamustine, regardless of the treatment arm.

Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).

Structure of PTEN

Researchers say they have discovered an important molecular link between Fanconi anemia (FA) and PTEN, a gene associated with uterine, prostate, and brain cancer.

They say this discovery enhances our understanding of the molecular basis of Fanconi anemia and could lead to improved treatment outcomes for both Fanconi anemia and cancer patients.

The researchers detailed their discovery in Scientific Reports.

They explained that Fanconi anemia proteins function primarily in DNA interstrand crosslink (ICL) repair, and they wanted to determine the role of the PTEN phosphatase in this process.

“The PTEN gene codes for a phosphatase—an enzyme that removes phosphate groups from proteins,” said study author Niall Howlett, PhD, of the University of Rhode Island in Kingston, Rhode Island.

“Many Fanconi anemia proteins have phosphate groups attached to them when they become activated. However, how these phosphate groups are removed is poorly understood.”

With this in mind, the researchers performed an experiment to determine if Fanconi anemia and PTEN are biochemically linked.

The team knew that cells from Fanconi anemia patients are sensitive to ICL-inducing agents, so they set out to determine if PTEN-deficient cells are sensitive to these agents as well.

“By testing if cells with mutations in the PTEN gene were also sensitive to [ICL-inducing] agents, we discovered that Fanconi anemia patient cells and PTEN-deficient cells were practically indistinguishable in terms of sensitivity to these drugs,” Dr Howlett said.

“This strongly suggested that the Fanconi anemia proteins and PTEN might work together to repair the DNA damage caused by [ICL-inducing] agents.”

Using epistasis analysis, Dr Howlett and his colleagues found that Fanconi anemia proteins and PTEN do indeed function together in ICL repair.

“Before this work, Fanconi anemia and PTEN weren’t even on the same radar,” Dr Howlett said. “This is really important to understanding how this disease arises and what its molecular underpinnings are. The more we can find out about its molecular basis, the more likely we are to come up with strategies to treat the disease.”

Dr Howlett and his colleagues believe their research is equally important to cancer patients. Since this study showed that cells missing PTEN are highly sensitive to ICL-inducing agents, the team believes it should be possible to predict whether a particular cancer patient will respond to this class of drugs by conducting a simple DNA test.

“We can now predict that if a patient has cancer associated with mutations in PTEN, then it is likely that the cancer will be sensitive to [ICL-inducing] agents,” Dr Howlett said. “This could lead to improved outcomes for patients with certain types of PTEN mutations.”

Structure of PTEN

Researchers say they have discovered an important molecular link between Fanconi anemia (FA) and PTEN, a gene associated with uterine, prostate, and brain cancer.

They say this discovery enhances our understanding of the molecular basis of Fanconi anemia and could lead to improved treatment outcomes for both Fanconi anemia and cancer patients.

The researchers detailed their discovery in Scientific Reports.

They explained that Fanconi anemia proteins function primarily in DNA interstrand crosslink (ICL) repair, and they wanted to determine the role of the PTEN phosphatase in this process.

“The PTEN gene codes for a phosphatase—an enzyme that removes phosphate groups from proteins,” said study author Niall Howlett, PhD, of the University of Rhode Island in Kingston, Rhode Island.

“Many Fanconi anemia proteins have phosphate groups attached to them when they become activated. However, how these phosphate groups are removed is poorly understood.”

With this in mind, the researchers performed an experiment to determine if Fanconi anemia and PTEN are biochemically linked.

The team knew that cells from Fanconi anemia patients are sensitive to ICL-inducing agents, so they set out to determine if PTEN-deficient cells are sensitive to these agents as well.

“By testing if cells with mutations in the PTEN gene were also sensitive to [ICL-inducing] agents, we discovered that Fanconi anemia patient cells and PTEN-deficient cells were practically indistinguishable in terms of sensitivity to these drugs,” Dr Howlett said.

“This strongly suggested that the Fanconi anemia proteins and PTEN might work together to repair the DNA damage caused by [ICL-inducing] agents.”

Using epistasis analysis, Dr Howlett and his colleagues found that Fanconi anemia proteins and PTEN do indeed function together in ICL repair.

“Before this work, Fanconi anemia and PTEN weren’t even on the same radar,” Dr Howlett said. “This is really important to understanding how this disease arises and what its molecular underpinnings are. The more we can find out about its molecular basis, the more likely we are to come up with strategies to treat the disease.”

Dr Howlett and his colleagues believe their research is equally important to cancer patients. Since this study showed that cells missing PTEN are highly sensitive to ICL-inducing agents, the team believes it should be possible to predict whether a particular cancer patient will respond to this class of drugs by conducting a simple DNA test.

“We can now predict that if a patient has cancer associated with mutations in PTEN, then it is likely that the cancer will be sensitive to [ICL-inducing] agents,” Dr Howlett said. “This could lead to improved outcomes for patients with certain types of PTEN mutations.”

Structure of PTEN

Researchers say they have discovered an important molecular link between Fanconi anemia (FA) and PTEN, a gene associated with uterine, prostate, and brain cancer.

They say this discovery enhances our understanding of the molecular basis of Fanconi anemia and could lead to improved treatment outcomes for both Fanconi anemia and cancer patients.

The researchers detailed their discovery in Scientific Reports.

They explained that Fanconi anemia proteins function primarily in DNA interstrand crosslink (ICL) repair, and they wanted to determine the role of the PTEN phosphatase in this process.

“The PTEN gene codes for a phosphatase—an enzyme that removes phosphate groups from proteins,” said study author Niall Howlett, PhD, of the University of Rhode Island in Kingston, Rhode Island.

“Many Fanconi anemia proteins have phosphate groups attached to them when they become activated. However, how these phosphate groups are removed is poorly understood.”

With this in mind, the researchers performed an experiment to determine if Fanconi anemia and PTEN are biochemically linked.

The team knew that cells from Fanconi anemia patients are sensitive to ICL-inducing agents, so they set out to determine if PTEN-deficient cells are sensitive to these agents as well.

“By testing if cells with mutations in the PTEN gene were also sensitive to [ICL-inducing] agents, we discovered that Fanconi anemia patient cells and PTEN-deficient cells were practically indistinguishable in terms of sensitivity to these drugs,” Dr Howlett said.

“This strongly suggested that the Fanconi anemia proteins and PTEN might work together to repair the DNA damage caused by [ICL-inducing] agents.”

Using epistasis analysis, Dr Howlett and his colleagues found that Fanconi anemia proteins and PTEN do indeed function together in ICL repair.

“Before this work, Fanconi anemia and PTEN weren’t even on the same radar,” Dr Howlett said. “This is really important to understanding how this disease arises and what its molecular underpinnings are. The more we can find out about its molecular basis, the more likely we are to come up with strategies to treat the disease.”

Dr Howlett and his colleagues believe their research is equally important to cancer patients. Since this study showed that cells missing PTEN are highly sensitive to ICL-inducing agents, the team believes it should be possible to predict whether a particular cancer patient will respond to this class of drugs by conducting a simple DNA test.

“We can now predict that if a patient has cancer associated with mutations in PTEN, then it is likely that the cancer will be sensitive to [ICL-inducing] agents,” Dr Howlett said. “This could lead to improved outcomes for patients with certain types of PTEN mutations.”

Harry Erba, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—A targeted therapy combined with standard chemotherapy can produce rapid, deep remissions in patients with newly diagnosed acute myeloid leukemia (AML), according to research presented at the 2016 ASH Annual Meeting.

In this phase 1b study, investigators tested vadastuximab talirine, an antibody drug conjugate targeting CD33, in combination with 7+3 chemotherapy—a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days.

The combination produced a high rate of response, which included minimal residual disease (MRD)-negative complete remissions (CRs).

The treatment also resulted in “acceptable” on-target myelosuppression and non-hematologic adverse events (AEs) similar to what would be expected with 7+3 alone, according to study investigator Harry Erba, MD, PhD, of the University of Alabama at Birmingham.

Dr Erba presented these results in abstract 211.* The research was sponsored by Seattle Genetics, Inc.

The study included 42 newly diagnosed AML patients with a median age of 45.5. Half the patients had intermediate-risk karyotypes, 36% had adverse karyotypes, and 17% had secondary AML.

Patients received escalating doses of vadastuximab talirine (10+10 mcg/kg [n=4] and 20+10 mcg/kg [n=38]) in combination with 7+3 induction (cytarabine at 100 mg/m² and daunorubicin at 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle. Responses were assessed on days 15 and 28.

A second induction regimen and post-remission therapies were prescribed according to investigator choice and did not include vadastuximab talirine.

Results

The maximum tolerated dose of vadastuximab talirine was 20+10 mcg/kg.

Hematologic treatment-related AEs included febrile neutropenia (43%, grade 1-3), thrombocytopenia (38%, grade 3-4), anemia (24%, grade 3), and neutropenia (17%, grade 3-4).

Non-hematologic treatment-related AEs included nausea (17%), fatigue (14%), diarrhea (7%), and decreased appetite (7%). All of these AEs were grade 1-2.

None of the patients experienced infusion-related reactions, veno-occlusive disease, or significant liver damage.

A total of 76% of patients responded to treatment, with 60% percent achieving a CR and 17% achieving a CR with incomplete blood count recovery (CRi).

The 76% response rate is close to what would be expected for a well-chosen population fit for a clinical trial, Dr Erba said.

There was a hint of additional benefit as well, he added.

“The first hint was that 30 out of the 32 patients [who achieved a CR/CRi] required only 1 round of chemotherapy to achieve that remission,” Dr Erba said. “This also suggested that deeper remissions may be possible.”

MRD assessments using a sensitive flow cytometric assay revealed that 25 of the 32 patients (78%) who achieved a CR/CRi were MRD-negative.

Dr Erba said a randomized, phase 2 trial of vadastuximab talirine plus 7+3 versus 7+3 alone is planned for the first quarter of 2017.

*Information presented at the meeting differs from the abstract.

Harry Erba, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—A targeted therapy combined with standard chemotherapy can produce rapid, deep remissions in patients with newly diagnosed acute myeloid leukemia (AML), according to research presented at the 2016 ASH Annual Meeting.

In this phase 1b study, investigators tested vadastuximab talirine, an antibody drug conjugate targeting CD33, in combination with 7+3 chemotherapy—a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days.

The combination produced a high rate of response, which included minimal residual disease (MRD)-negative complete remissions (CRs).

The treatment also resulted in “acceptable” on-target myelosuppression and non-hematologic adverse events (AEs) similar to what would be expected with 7+3 alone, according to study investigator Harry Erba, MD, PhD, of the University of Alabama at Birmingham.

Dr Erba presented these results in abstract 211.* The research was sponsored by Seattle Genetics, Inc.

The study included 42 newly diagnosed AML patients with a median age of 45.5. Half the patients had intermediate-risk karyotypes, 36% had adverse karyotypes, and 17% had secondary AML.

Patients received escalating doses of vadastuximab talirine (10+10 mcg/kg [n=4] and 20+10 mcg/kg [n=38]) in combination with 7+3 induction (cytarabine at 100 mg/m² and daunorubicin at 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle. Responses were assessed on days 15 and 28.

A second induction regimen and post-remission therapies were prescribed according to investigator choice and did not include vadastuximab talirine.

Results

The maximum tolerated dose of vadastuximab talirine was 20+10 mcg/kg.

Hematologic treatment-related AEs included febrile neutropenia (43%, grade 1-3), thrombocytopenia (38%, grade 3-4), anemia (24%, grade 3), and neutropenia (17%, grade 3-4).

Non-hematologic treatment-related AEs included nausea (17%), fatigue (14%), diarrhea (7%), and decreased appetite (7%). All of these AEs were grade 1-2.

None of the patients experienced infusion-related reactions, veno-occlusive disease, or significant liver damage.

A total of 76% of patients responded to treatment, with 60% percent achieving a CR and 17% achieving a CR with incomplete blood count recovery (CRi).

The 76% response rate is close to what would be expected for a well-chosen population fit for a clinical trial, Dr Erba said.

There was a hint of additional benefit as well, he added.

“The first hint was that 30 out of the 32 patients [who achieved a CR/CRi] required only 1 round of chemotherapy to achieve that remission,” Dr Erba said. “This also suggested that deeper remissions may be possible.”

MRD assessments using a sensitive flow cytometric assay revealed that 25 of the 32 patients (78%) who achieved a CR/CRi were MRD-negative.

Dr Erba said a randomized, phase 2 trial of vadastuximab talirine plus 7+3 versus 7+3 alone is planned for the first quarter of 2017.

*Information presented at the meeting differs from the abstract.

Harry Erba, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—A targeted therapy combined with standard chemotherapy can produce rapid, deep remissions in patients with newly diagnosed acute myeloid leukemia (AML), according to research presented at the 2016 ASH Annual Meeting.

In this phase 1b study, investigators tested vadastuximab talirine, an antibody drug conjugate targeting CD33, in combination with 7+3 chemotherapy—a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days.

The combination produced a high rate of response, which included minimal residual disease (MRD)-negative complete remissions (CRs).

The treatment also resulted in “acceptable” on-target myelosuppression and non-hematologic adverse events (AEs) similar to what would be expected with 7+3 alone, according to study investigator Harry Erba, MD, PhD, of the University of Alabama at Birmingham.

Dr Erba presented these results in abstract 211.* The research was sponsored by Seattle Genetics, Inc.

The study included 42 newly diagnosed AML patients with a median age of 45.5. Half the patients had intermediate-risk karyotypes, 36% had adverse karyotypes, and 17% had secondary AML.

Patients received escalating doses of vadastuximab talirine (10+10 mcg/kg [n=4] and 20+10 mcg/kg [n=38]) in combination with 7+3 induction (cytarabine at 100 mg/m² and daunorubicin at 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle. Responses were assessed on days 15 and 28.

A second induction regimen and post-remission therapies were prescribed according to investigator choice and did not include vadastuximab talirine.

Results

The maximum tolerated dose of vadastuximab talirine was 20+10 mcg/kg.

Hematologic treatment-related AEs included febrile neutropenia (43%, grade 1-3), thrombocytopenia (38%, grade 3-4), anemia (24%, grade 3), and neutropenia (17%, grade 3-4).

Non-hematologic treatment-related AEs included nausea (17%), fatigue (14%), diarrhea (7%), and decreased appetite (7%). All of these AEs were grade 1-2.

None of the patients experienced infusion-related reactions, veno-occlusive disease, or significant liver damage.

A total of 76% of patients responded to treatment, with 60% percent achieving a CR and 17% achieving a CR with incomplete blood count recovery (CRi).

The 76% response rate is close to what would be expected for a well-chosen population fit for a clinical trial, Dr Erba said.

There was a hint of additional benefit as well, he added.

“The first hint was that 30 out of the 32 patients [who achieved a CR/CRi] required only 1 round of chemotherapy to achieve that remission,” Dr Erba said. “This also suggested that deeper remissions may be possible.”

MRD assessments using a sensitive flow cytometric assay revealed that 25 of the 32 patients (78%) who achieved a CR/CRi were MRD-negative.

Dr Erba said a randomized, phase 2 trial of vadastuximab talirine plus 7+3 versus 7+3 alone is planned for the first quarter of 2017.

*Information presented at the meeting differs from the abstract.