(Reuters Health) - Not all U.S. stroke patients eligible for thrombolytic therapy actually receive it - and the odds of getting this therapy may depend on where they live, a large study finds.

Dr. James Burke of the University of Michigan and the VA Ann Arbor Health System and colleagues examined 844,241 hospital admissions for ischemic stroke from 2007 to 2010 among U.S. patients insured by Medicare.

They sorted patients into 3,436 different hospital service areas based on home postal code to assess regional variation in thrombolysis treatment rates.

Patients were 78 years old on average. About 57% were women, and most were white. The majority had hypertension and many also had diabetes, high cholesterol or arrhythmia.

Overall, just 3.9% of these patients received thrombolysis, the researchers report online June 2 in the journal Stroke. The treatment wasn't given at all in 20% of regions, and it was more likely to occur in places with higher population density.

In the 20 regions with the highest rates of thrombolysis, roughly 10% to 14% of patients received the treatment.

After accounting for the number of strokes in each region, the proportion of patients receiving thrombolysis ranged from 2.2% in the bottom fifth of regions to 5.9% in the top fifth.

Older patients, women and minorities were less likely to receive the treatment. Regions with the lowest proportion of college graduates also had a smaller percentage of people treated with thrombolysis.

Not every patient with stroke should receive thrombolysis. One study in Cincinnati estimated that about 6% of stroke patients would be eligible, but the new findings of higher rates in the highest-performing regions suggest that more patients could benefit if they could be transported more quickly to hospitals where thrombolysis is available, the authors say.

By boosting use of the treatment in regions where it's least likely to happen up to the level in places where the therapy is most common, researchers estimated that an additional 92,847 stroke patients might get thrombolysis, averting disability for 8,078 of them.

"Prompt recognition and reaction to warning signs and effective emergency service systems can minimize delays in pre-hospital dispatch, assessment and transport, and ultimately increase the number of stroke patients reaching the hospital and being prepared for thrombolytic therapy within the 4.5-hour time window," Dr. Maurizio Paciaroni, a stroke specialist at the University of Perugia in Italy who wasn't involved in the study, said by email.

"For a variety of reasons, only a minority of patients get to the hospital within the first couple hours of a stroke," Burke said by email. Patients might not recognize symptoms or call 911 soon enough, and even when they do seek help quickly they might not end up at a hospital that's equipped to provide thrombolysis, he added.

The best outcomes are for patients who receive thrombolysis within the first hour after the blood vessel becomes blocked, said Dr. Brian Silver, director of the Comprehensive Stroke Center at Rhode Island Hospital and researcher at Brown University.

"When patients don't receive this treatment, they are up to 50% less likely to have a better outcome," Silver, who wasn't involved with the study, said by email. "This means, for some, residual speech difficulties, paralysis, vision loss, cognitive impairment and depression."

Globally, 15 million people suffer strokes each year; five million of them die and another five million are left permanently disabled, according to the World Health Organization.

(Reuters Health) - Not all U.S. stroke patients eligible for thrombolytic therapy actually receive it - and the odds of getting this therapy may depend on where they live, a large study finds.

Dr. James Burke of the University of Michigan and the VA Ann Arbor Health System and colleagues examined 844,241 hospital admissions for ischemic stroke from 2007 to 2010 among U.S. patients insured by Medicare.

They sorted patients into 3,436 different hospital service areas based on home postal code to assess regional variation in thrombolysis treatment rates.

Patients were 78 years old on average. About 57% were women, and most were white. The majority had hypertension and many also had diabetes, high cholesterol or arrhythmia.

Overall, just 3.9% of these patients received thrombolysis, the researchers report online June 2 in the journal Stroke. The treatment wasn't given at all in 20% of regions, and it was more likely to occur in places with higher population density.

In the 20 regions with the highest rates of thrombolysis, roughly 10% to 14% of patients received the treatment.

After accounting for the number of strokes in each region, the proportion of patients receiving thrombolysis ranged from 2.2% in the bottom fifth of regions to 5.9% in the top fifth.

Older patients, women and minorities were less likely to receive the treatment. Regions with the lowest proportion of college graduates also had a smaller percentage of people treated with thrombolysis.

Not every patient with stroke should receive thrombolysis. One study in Cincinnati estimated that about 6% of stroke patients would be eligible, but the new findings of higher rates in the highest-performing regions suggest that more patients could benefit if they could be transported more quickly to hospitals where thrombolysis is available, the authors say.

By boosting use of the treatment in regions where it's least likely to happen up to the level in places where the therapy is most common, researchers estimated that an additional 92,847 stroke patients might get thrombolysis, averting disability for 8,078 of them.

"Prompt recognition and reaction to warning signs and effective emergency service systems can minimize delays in pre-hospital dispatch, assessment and transport, and ultimately increase the number of stroke patients reaching the hospital and being prepared for thrombolytic therapy within the 4.5-hour time window," Dr. Maurizio Paciaroni, a stroke specialist at the University of Perugia in Italy who wasn't involved in the study, said by email.

"For a variety of reasons, only a minority of patients get to the hospital within the first couple hours of a stroke," Burke said by email. Patients might not recognize symptoms or call 911 soon enough, and even when they do seek help quickly they might not end up at a hospital that's equipped to provide thrombolysis, he added.

The best outcomes are for patients who receive thrombolysis within the first hour after the blood vessel becomes blocked, said Dr. Brian Silver, director of the Comprehensive Stroke Center at Rhode Island Hospital and researcher at Brown University.

"When patients don't receive this treatment, they are up to 50% less likely to have a better outcome," Silver, who wasn't involved with the study, said by email. "This means, for some, residual speech difficulties, paralysis, vision loss, cognitive impairment and depression."

Globally, 15 million people suffer strokes each year; five million of them die and another five million are left permanently disabled, according to the World Health Organization.

(Reuters Health) - Not all U.S. stroke patients eligible for thrombolytic therapy actually receive it - and the odds of getting this therapy may depend on where they live, a large study finds.

Dr. James Burke of the University of Michigan and the VA Ann Arbor Health System and colleagues examined 844,241 hospital admissions for ischemic stroke from 2007 to 2010 among U.S. patients insured by Medicare.

They sorted patients into 3,436 different hospital service areas based on home postal code to assess regional variation in thrombolysis treatment rates.

Patients were 78 years old on average. About 57% were women, and most were white. The majority had hypertension and many also had diabetes, high cholesterol or arrhythmia.

Overall, just 3.9% of these patients received thrombolysis, the researchers report online June 2 in the journal Stroke. The treatment wasn't given at all in 20% of regions, and it was more likely to occur in places with higher population density.

In the 20 regions with the highest rates of thrombolysis, roughly 10% to 14% of patients received the treatment.

After accounting for the number of strokes in each region, the proportion of patients receiving thrombolysis ranged from 2.2% in the bottom fifth of regions to 5.9% in the top fifth.

Older patients, women and minorities were less likely to receive the treatment. Regions with the lowest proportion of college graduates also had a smaller percentage of people treated with thrombolysis.

Not every patient with stroke should receive thrombolysis. One study in Cincinnati estimated that about 6% of stroke patients would be eligible, but the new findings of higher rates in the highest-performing regions suggest that more patients could benefit if they could be transported more quickly to hospitals where thrombolysis is available, the authors say.

By boosting use of the treatment in regions where it's least likely to happen up to the level in places where the therapy is most common, researchers estimated that an additional 92,847 stroke patients might get thrombolysis, averting disability for 8,078 of them.

"Prompt recognition and reaction to warning signs and effective emergency service systems can minimize delays in pre-hospital dispatch, assessment and transport, and ultimately increase the number of stroke patients reaching the hospital and being prepared for thrombolytic therapy within the 4.5-hour time window," Dr. Maurizio Paciaroni, a stroke specialist at the University of Perugia in Italy who wasn't involved in the study, said by email.

"For a variety of reasons, only a minority of patients get to the hospital within the first couple hours of a stroke," Burke said by email. Patients might not recognize symptoms or call 911 soon enough, and even when they do seek help quickly they might not end up at a hospital that's equipped to provide thrombolysis, he added.

The best outcomes are for patients who receive thrombolysis within the first hour after the blood vessel becomes blocked, said Dr. Brian Silver, director of the Comprehensive Stroke Center at Rhode Island Hospital and researcher at Brown University.

"When patients don't receive this treatment, they are up to 50% less likely to have a better outcome," Silver, who wasn't involved with the study, said by email. "This means, for some, residual speech difficulties, paralysis, vision loss, cognitive impairment and depression."

Globally, 15 million people suffer strokes each year; five million of them die and another five million are left permanently disabled, according to the World Health Organization.

HSCT preparation

Photo by Chad McNeeley

VIENNA—Outcomes of hematopoietic stem cell transplant (HSCT) are encouraging in myelofibrosis (MF) patients who respond well to JAK inhibitors, according to researchers.

The group found that patients with the best response to JAK inhibition had a 2-year survival probability of 91% after HSCT, compared to 32% for patients with

leukemic transformation while on a JAK inhibitor.

In addition, receiving a JAK inhibitor until HSCT could prevent the return of MF-related symptoms.

Mohamed Shanavas, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, presented these findings at the 20th Congress of the European Hematology Association (abstract S450*).

The decision to undergo HSCT is a complex one in MF, particularly for those patients who are responding to JAK inhibitors. So Dr Shanavas and his colleagues undertook a retrospective, multicenter analysis to determine if there is an association between response to JAK inhibition and HSCT outcome.

The investigators analyzed the outcomes of 100 patients who had a first HSCT for primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Patients had to have exposure to a JAK inhibitor but no history of leukemic transformation prior to taking a JAK inhibitor.

Response criteria

The researchers stratified patients’ JAK1/2 response according to the following criteria:

• Group A: Clinical improvement: Fifty percent or greater reduction in palpable spleen length for spleen palpable by ≥ 10 cm, or complete resolution of splenomegaly for spleen < 10 cm
• Group B: Stable disease: Spleen response not meeting the criteria of clinical improvement
• Group C: A 10% to 19% increase in blasts, new onset of anemia requiring transfusions, or intolerance to treatment due to side effects
• Group D: Progressive disease: New splenomegaly > 5 cm, 100% increase in spleen 5-10 cm, or 50% increase in spleen > 10 cm
• Group E: Leukemic transformation: Bone marrow or circulating blasts ≥ 20%.

Patient and treatment characteristics

Patients were a median age of 59 (range, 32–72). Fifty-seven had primary MF, 21 had post-essential thrombocythemia MF, and 22 had post-polycythemia vera MF. Sixty-two patients had JAK2^V617F-mutated disease, 37 were wild-type, and 1 had unknown JAK status.

The majority of patients had intermediate-2 or high-risk disease according to their DIPSS scores, and 42 had a transplant comorbidity index score of 3 or greater.

Most patients (n=91) had ruxolitinib as their JAK inhibitor, 6 had momelotinib, and 3 had another inhibitor.

The median duration of JAK inhibitor therapy was 5 months (range, 1–36), and 66 patients were on treatment at the time of transplant. Thirty patients had previously discontinued JAK therapy, and the status of 4 was unknown.

In terms of their response to JAK inhibitors, 23 patients were in group A (clinical improvement), 31 in group B (stable disease), 15 in group C (increased blasts/transfusion need/intolerance), 18 in group D (progressive disease), and 13 in group E (leukemic transformation).

Fifty patients received a matched unrelated donor transplant, 36 had a matched sibling donor, and 14 had either a mismatched unrelated donor or a haploidentical transplant.

Fifty-six patients had a reduced-intensity conditioning regimen, and 44 had full intensity. Fifty percent of patients had T-cell depletion prior to transplant.

Outcomes

Patients who stopped JAK inhibitor therapy 6 or more days prior to transplant (n=20) experienced more “withdrawal symptoms”—the return of MF-related symptoms—than patients in whom the interval was less than 6 days (n=46). For the most part, withdrawal symptoms were non-severe in nature.

Two patients had fatal HSCT-related toxicity of venoocclusive disease, 4 had primary graft failure, and 4 had secondary graft failure. Forty-three percent of cytomegalovirus-seropositive patients had reactivation, 6 patients had Epstein-Barr virus reactivation, 6 had adenovirus or human polyomavirus BK infections, and 7 had invasive fungal infections.

Grade 2-4 acute graft-vs-host disease (GVHD) occurred in 37% of patients at day 100, and grade 3-4 occurred in 16%. Chronic GVHD of all grades occurred in 48% of patients, and extensive chronic GVHD occurred in 23%.

The cumulative incidence of relapse at 2 years was 17%, and non-relapse mortality was 28%. Overall survival (OS) was 61%.

“We analyzed this outcome based upon the response to JAK inhibitors,” Dr Shanavas said. “Patients who were deriving clinical improvement, group A, had a superior outcome, with a probability of survival of 91% at 2 years. Patients who had leukemic transformation, group E, had an inferior OS of 32% at 2 years.”

He noted that the outcomes appeared similar in the other 3 groups, so the researchers combined them for further analysis.

“As expected,” he said, “patients who had leukemic transformation had a significantly higher relapse rate than the other groups.”

The researchers then performed a multivariate analysis and found that response to JAK inhibitors, DIPSS score prior to JAK therapy, and donor type had a significant effect on OS.

The team concluded that prior exposure to JAK inhibitors does not have a negative effect on early HSCT outcomes. And actually, patients who undergo HSCT while responding to JAK inhibitors have encouraging outcomes.

*Information in the abstract differs from that presented at the meeting.

HSCT preparation

Photo by Chad McNeeley

VIENNA—Outcomes of hematopoietic stem cell transplant (HSCT) are encouraging in myelofibrosis (MF) patients who respond well to JAK inhibitors, according to researchers.

The group found that patients with the best response to JAK inhibition had a 2-year survival probability of 91% after HSCT, compared to 32% for patients with

leukemic transformation while on a JAK inhibitor.

In addition, receiving a JAK inhibitor until HSCT could prevent the return of MF-related symptoms.

Mohamed Shanavas, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, presented these findings at the 20th Congress of the European Hematology Association (abstract S450*).

The decision to undergo HSCT is a complex one in MF, particularly for those patients who are responding to JAK inhibitors. So Dr Shanavas and his colleagues undertook a retrospective, multicenter analysis to determine if there is an association between response to JAK inhibition and HSCT outcome.

The investigators analyzed the outcomes of 100 patients who had a first HSCT for primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Patients had to have exposure to a JAK inhibitor but no history of leukemic transformation prior to taking a JAK inhibitor.

Response criteria

The researchers stratified patients’ JAK1/2 response according to the following criteria:

• Group A: Clinical improvement: Fifty percent or greater reduction in palpable spleen length for spleen palpable by ≥ 10 cm, or complete resolution of splenomegaly for spleen < 10 cm
• Group B: Stable disease: Spleen response not meeting the criteria of clinical improvement
• Group C: A 10% to 19% increase in blasts, new onset of anemia requiring transfusions, or intolerance to treatment due to side effects
• Group D: Progressive disease: New splenomegaly > 5 cm, 100% increase in spleen 5-10 cm, or 50% increase in spleen > 10 cm
• Group E: Leukemic transformation: Bone marrow or circulating blasts ≥ 20%.

Patient and treatment characteristics

Patients were a median age of 59 (range, 32–72). Fifty-seven had primary MF, 21 had post-essential thrombocythemia MF, and 22 had post-polycythemia vera MF. Sixty-two patients had JAK2^V617F-mutated disease, 37 were wild-type, and 1 had unknown JAK status.

The majority of patients had intermediate-2 or high-risk disease according to their DIPSS scores, and 42 had a transplant comorbidity index score of 3 or greater.

Most patients (n=91) had ruxolitinib as their JAK inhibitor, 6 had momelotinib, and 3 had another inhibitor.

The median duration of JAK inhibitor therapy was 5 months (range, 1–36), and 66 patients were on treatment at the time of transplant. Thirty patients had previously discontinued JAK therapy, and the status of 4 was unknown.

In terms of their response to JAK inhibitors, 23 patients were in group A (clinical improvement), 31 in group B (stable disease), 15 in group C (increased blasts/transfusion need/intolerance), 18 in group D (progressive disease), and 13 in group E (leukemic transformation).

Fifty patients received a matched unrelated donor transplant, 36 had a matched sibling donor, and 14 had either a mismatched unrelated donor or a haploidentical transplant.

Fifty-six patients had a reduced-intensity conditioning regimen, and 44 had full intensity. Fifty percent of patients had T-cell depletion prior to transplant.

Outcomes

Patients who stopped JAK inhibitor therapy 6 or more days prior to transplant (n=20) experienced more “withdrawal symptoms”—the return of MF-related symptoms—than patients in whom the interval was less than 6 days (n=46). For the most part, withdrawal symptoms were non-severe in nature.

Two patients had fatal HSCT-related toxicity of venoocclusive disease, 4 had primary graft failure, and 4 had secondary graft failure. Forty-three percent of cytomegalovirus-seropositive patients had reactivation, 6 patients had Epstein-Barr virus reactivation, 6 had adenovirus or human polyomavirus BK infections, and 7 had invasive fungal infections.

Grade 2-4 acute graft-vs-host disease (GVHD) occurred in 37% of patients at day 100, and grade 3-4 occurred in 16%. Chronic GVHD of all grades occurred in 48% of patients, and extensive chronic GVHD occurred in 23%.

The cumulative incidence of relapse at 2 years was 17%, and non-relapse mortality was 28%. Overall survival (OS) was 61%.

“We analyzed this outcome based upon the response to JAK inhibitors,” Dr Shanavas said. “Patients who were deriving clinical improvement, group A, had a superior outcome, with a probability of survival of 91% at 2 years. Patients who had leukemic transformation, group E, had an inferior OS of 32% at 2 years.”

He noted that the outcomes appeared similar in the other 3 groups, so the researchers combined them for further analysis.

“As expected,” he said, “patients who had leukemic transformation had a significantly higher relapse rate than the other groups.”

The researchers then performed a multivariate analysis and found that response to JAK inhibitors, DIPSS score prior to JAK therapy, and donor type had a significant effect on OS.

The team concluded that prior exposure to JAK inhibitors does not have a negative effect on early HSCT outcomes. And actually, patients who undergo HSCT while responding to JAK inhibitors have encouraging outcomes.

*Information in the abstract differs from that presented at the meeting.

HSCT preparation

Photo by Chad McNeeley

VIENNA—Outcomes of hematopoietic stem cell transplant (HSCT) are encouraging in myelofibrosis (MF) patients who respond well to JAK inhibitors, according to researchers.

The group found that patients with the best response to JAK inhibition had a 2-year survival probability of 91% after HSCT, compared to 32% for patients with

leukemic transformation while on a JAK inhibitor.

In addition, receiving a JAK inhibitor until HSCT could prevent the return of MF-related symptoms.

Mohamed Shanavas, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, presented these findings at the 20th Congress of the European Hematology Association (abstract S450*).

The decision to undergo HSCT is a complex one in MF, particularly for those patients who are responding to JAK inhibitors. So Dr Shanavas and his colleagues undertook a retrospective, multicenter analysis to determine if there is an association between response to JAK inhibition and HSCT outcome.

The investigators analyzed the outcomes of 100 patients who had a first HSCT for primary MF, post-essential thrombocythemia MF, or post-polycythemia vera MF. Patients had to have exposure to a JAK inhibitor but no history of leukemic transformation prior to taking a JAK inhibitor.

Response criteria

The researchers stratified patients’ JAK1/2 response according to the following criteria:

• Group A: Clinical improvement: Fifty percent or greater reduction in palpable spleen length for spleen palpable by ≥ 10 cm, or complete resolution of splenomegaly for spleen < 10 cm
• Group B: Stable disease: Spleen response not meeting the criteria of clinical improvement
• Group C: A 10% to 19% increase in blasts, new onset of anemia requiring transfusions, or intolerance to treatment due to side effects
• Group D: Progressive disease: New splenomegaly > 5 cm, 100% increase in spleen 5-10 cm, or 50% increase in spleen > 10 cm
• Group E: Leukemic transformation: Bone marrow or circulating blasts ≥ 20%.

Patient and treatment characteristics

Patients were a median age of 59 (range, 32–72). Fifty-seven had primary MF, 21 had post-essential thrombocythemia MF, and 22 had post-polycythemia vera MF. Sixty-two patients had JAK2^V617F-mutated disease, 37 were wild-type, and 1 had unknown JAK status.

The majority of patients had intermediate-2 or high-risk disease according to their DIPSS scores, and 42 had a transplant comorbidity index score of 3 or greater.

Most patients (n=91) had ruxolitinib as their JAK inhibitor, 6 had momelotinib, and 3 had another inhibitor.

The median duration of JAK inhibitor therapy was 5 months (range, 1–36), and 66 patients were on treatment at the time of transplant. Thirty patients had previously discontinued JAK therapy, and the status of 4 was unknown.

In terms of their response to JAK inhibitors, 23 patients were in group A (clinical improvement), 31 in group B (stable disease), 15 in group C (increased blasts/transfusion need/intolerance), 18 in group D (progressive disease), and 13 in group E (leukemic transformation).

Fifty patients received a matched unrelated donor transplant, 36 had a matched sibling donor, and 14 had either a mismatched unrelated donor or a haploidentical transplant.

Fifty-six patients had a reduced-intensity conditioning regimen, and 44 had full intensity. Fifty percent of patients had T-cell depletion prior to transplant.

Outcomes

Patients who stopped JAK inhibitor therapy 6 or more days prior to transplant (n=20) experienced more “withdrawal symptoms”—the return of MF-related symptoms—than patients in whom the interval was less than 6 days (n=46). For the most part, withdrawal symptoms were non-severe in nature.

Two patients had fatal HSCT-related toxicity of venoocclusive disease, 4 had primary graft failure, and 4 had secondary graft failure. Forty-three percent of cytomegalovirus-seropositive patients had reactivation, 6 patients had Epstein-Barr virus reactivation, 6 had adenovirus or human polyomavirus BK infections, and 7 had invasive fungal infections.

Grade 2-4 acute graft-vs-host disease (GVHD) occurred in 37% of patients at day 100, and grade 3-4 occurred in 16%. Chronic GVHD of all grades occurred in 48% of patients, and extensive chronic GVHD occurred in 23%.

The cumulative incidence of relapse at 2 years was 17%, and non-relapse mortality was 28%. Overall survival (OS) was 61%.

“We analyzed this outcome based upon the response to JAK inhibitors,” Dr Shanavas said. “Patients who were deriving clinical improvement, group A, had a superior outcome, with a probability of survival of 91% at 2 years. Patients who had leukemic transformation, group E, had an inferior OS of 32% at 2 years.”

He noted that the outcomes appeared similar in the other 3 groups, so the researchers combined them for further analysis.

“As expected,” he said, “patients who had leukemic transformation had a significantly higher relapse rate than the other groups.”

The researchers then performed a multivariate analysis and found that response to JAK inhibitors, DIPSS score prior to JAK therapy, and donor type had a significant effect on OS.

The team concluded that prior exposure to JAK inhibitors does not have a negative effect on early HSCT outcomes. And actually, patients who undergo HSCT while responding to JAK inhibitors have encouraging outcomes.

*Information in the abstract differs from that presented at the meeting.

Doctor with a clipboard

TORONTO—A survey of adult hemophilia patients suggests there is room for improvement in assessing and managing disease-related pain.

Roughly 85% of patients surveyed for this study, known as P-FiQ, said they had experienced acute and/or chronic pain in the past 6 months.

Although most patients had no trouble caring for themselves, the pain often had an impact on their daily lives, especially with regard to physical activity and overall mobility.

“Pain and discomfort are significant challenges for people with hemophilia,” said study investigator Michael Recht, MD, PhD, of Oregon Health Sciences University in Portland.

“These results emphasize the importance of providing comprehensive care and support beyond traditional therapy to people living with bleeding disorders.”

Dr Recht and his colleagues presented results of the P-FiQ study in 3 posters at the ISTH 2015 Congress (abstracts PO277-MON, PO297-WED, and PO298-WED).

The study included adult males with mild to severe hemophilia who had a history of joint pain or bleeding. Subjects were asked to assess pain and functional impairment using patient-reported outcome instruments.

During routine visits over the course of a year, 164 participants completed a pain history and 5 questionnaires: the EQ-5D-5L; Brief Pain Inventory Short Form, version 2; International Physical Activity Questionnaire; SF-36v2; and Hemophilia Activities List.

The patients had a median age of 34. More patients had hemophilia A (n=122) than hemophilia B (n=42), and few (n=10) had inhibitors. Sixty-one percent of patients had self-reported arthritis, bone, or joint problems.

Current patient-reported treatment regimens (n=163) were prophylaxis (42%), on-demand treatment (39%), or mostly on-demand treatment (19%). Twenty-five of the 31 patients using on-demand treatment reported using infusions ahead of activity.

Pain prevalence and management

Most participants (85.2%) said they had experienced acute and/or chronic pain over the past 6 months. Twenty-nine percent said they had experienced acute and chronic pain, 32.7% had chronic pain only, 23.5% had acute pain only, and 14.8% reported no pain.

Acute pain was most frequently described as sharp, aching, shooting, and throbbing. Chronic pain was often described as aching, nagging, throbbing, and sharp.

The most common analgesics used for acute or chronic pain were acetaminophen (69.4% and 58%, respectively), NSAIDs (40% and 52%, respectively), and hydrocodone-acetaminophen (29.4% and 33%, respectively).

The most common nonanalgesic strategies used for acute or chronic pain were ice (72.9% and 37%, respectively), rest (48.2% and 34%, respectively), factor VIII/IX or bypassing agent (48.2% and 24%, respectively), elevation (34.1% and 28%, respectively), relaxation (30.6% and 23.0%, respectively), compression (27.1% and 21%, respectively), and heat (24.7% and 15%, respectively).

Impact of pain on daily life

When completing the EQ-5D-5L questionnaire, most patients reported problems with mobility, performing usual activities, and pain or discomfort. However, most patients said they had no problems with self-care (78%) or anxiety/depression (58.5%).

A similar proportion of patients reported slight and moderate pain and discomfort (29.9% and 31.1%, respectively). Pain and discomfort was severe for 11% of patients and extreme for 1.2%, but 26.8% of patients reported no pain or discomfort.

When it came to mobility, patients reported slight (32.3%), moderate (19.5%), and severe (8.5%) problems, and 1.2% of patients said they were unable to get around. However, 38.4% of patients reported having no such problems.

About 44% of patients reported no problems performing usual activities, but 37.2% had slight problems, 14.6% had moderate problems, and 1.8% of patients each had severe problems or were unable to perform usual activities.

For the Brief Pain Inventory, pain severity and interference with daily activities were rated on a scale of 0 to 10, with 0 being no pain/no interference and 10 being pain as bad as you can imagine/pain that completely interferes with daily life.

The overall median pain severity and pain interference were 3.0 (range, 1.3-4.8) and 2.9 (range, 0.7-5.2), respectively. The median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Ankles were the most frequently reported site of pain.

When completing the International Physical Activity Questionnaire, 49.3% of patients (73/148) reported no activity in the prior week.

The median SF-36v2 scores were lower for physical health domains than mental health domains, and the overall median health score was 3.0 (range, 2.0-3.0).

The median score on the Hemophilia Activities List was 76.1 (range, 59.2-95.1). And patients said hemophilia had a greater impact on their lower extremities than upper extremities.

Dr Recht and his colleagues said these results substantiate the high prevalence of pain in adults with hemophilia. And the study highlights opportunities to improve the assessment and management of pain in these patients.

Study investigators have received funding/consulting fees from—or are employees/shareholders of—Novo Nordisk, Baxter, Biogen, Bayer, OctaPharma, Pfizer, CSL Behring, Kendrion, Alexion, Grifols, OPKO Health, Sanofi, Merck, and ProMeticLife Sciences.

Doctor with a clipboard

TORONTO—A survey of adult hemophilia patients suggests there is room for improvement in assessing and managing disease-related pain.

Roughly 85% of patients surveyed for this study, known as P-FiQ, said they had experienced acute and/or chronic pain in the past 6 months.

Although most patients had no trouble caring for themselves, the pain often had an impact on their daily lives, especially with regard to physical activity and overall mobility.

“Pain and discomfort are significant challenges for people with hemophilia,” said study investigator Michael Recht, MD, PhD, of Oregon Health Sciences University in Portland.

“These results emphasize the importance of providing comprehensive care and support beyond traditional therapy to people living with bleeding disorders.”

Dr Recht and his colleagues presented results of the P-FiQ study in 3 posters at the ISTH 2015 Congress (abstracts PO277-MON, PO297-WED, and PO298-WED).

The study included adult males with mild to severe hemophilia who had a history of joint pain or bleeding. Subjects were asked to assess pain and functional impairment using patient-reported outcome instruments.

During routine visits over the course of a year, 164 participants completed a pain history and 5 questionnaires: the EQ-5D-5L; Brief Pain Inventory Short Form, version 2; International Physical Activity Questionnaire; SF-36v2; and Hemophilia Activities List.

The patients had a median age of 34. More patients had hemophilia A (n=122) than hemophilia B (n=42), and few (n=10) had inhibitors. Sixty-one percent of patients had self-reported arthritis, bone, or joint problems.

Current patient-reported treatment regimens (n=163) were prophylaxis (42%), on-demand treatment (39%), or mostly on-demand treatment (19%). Twenty-five of the 31 patients using on-demand treatment reported using infusions ahead of activity.

Pain prevalence and management

Most participants (85.2%) said they had experienced acute and/or chronic pain over the past 6 months. Twenty-nine percent said they had experienced acute and chronic pain, 32.7% had chronic pain only, 23.5% had acute pain only, and 14.8% reported no pain.

Acute pain was most frequently described as sharp, aching, shooting, and throbbing. Chronic pain was often described as aching, nagging, throbbing, and sharp.

The most common analgesics used for acute or chronic pain were acetaminophen (69.4% and 58%, respectively), NSAIDs (40% and 52%, respectively), and hydrocodone-acetaminophen (29.4% and 33%, respectively).

The most common nonanalgesic strategies used for acute or chronic pain were ice (72.9% and 37%, respectively), rest (48.2% and 34%, respectively), factor VIII/IX or bypassing agent (48.2% and 24%, respectively), elevation (34.1% and 28%, respectively), relaxation (30.6% and 23.0%, respectively), compression (27.1% and 21%, respectively), and heat (24.7% and 15%, respectively).

Impact of pain on daily life

When completing the EQ-5D-5L questionnaire, most patients reported problems with mobility, performing usual activities, and pain or discomfort. However, most patients said they had no problems with self-care (78%) or anxiety/depression (58.5%).

A similar proportion of patients reported slight and moderate pain and discomfort (29.9% and 31.1%, respectively). Pain and discomfort was severe for 11% of patients and extreme for 1.2%, but 26.8% of patients reported no pain or discomfort.

When it came to mobility, patients reported slight (32.3%), moderate (19.5%), and severe (8.5%) problems, and 1.2% of patients said they were unable to get around. However, 38.4% of patients reported having no such problems.

About 44% of patients reported no problems performing usual activities, but 37.2% had slight problems, 14.6% had moderate problems, and 1.8% of patients each had severe problems or were unable to perform usual activities.

For the Brief Pain Inventory, pain severity and interference with daily activities were rated on a scale of 0 to 10, with 0 being no pain/no interference and 10 being pain as bad as you can imagine/pain that completely interferes with daily life.

The overall median pain severity and pain interference were 3.0 (range, 1.3-4.8) and 2.9 (range, 0.7-5.2), respectively. The median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Ankles were the most frequently reported site of pain.

When completing the International Physical Activity Questionnaire, 49.3% of patients (73/148) reported no activity in the prior week.

The median SF-36v2 scores were lower for physical health domains than mental health domains, and the overall median health score was 3.0 (range, 2.0-3.0).

The median score on the Hemophilia Activities List was 76.1 (range, 59.2-95.1). And patients said hemophilia had a greater impact on their lower extremities than upper extremities.

Dr Recht and his colleagues said these results substantiate the high prevalence of pain in adults with hemophilia. And the study highlights opportunities to improve the assessment and management of pain in these patients.

Study investigators have received funding/consulting fees from—or are employees/shareholders of—Novo Nordisk, Baxter, Biogen, Bayer, OctaPharma, Pfizer, CSL Behring, Kendrion, Alexion, Grifols, OPKO Health, Sanofi, Merck, and ProMeticLife Sciences.

Doctor with a clipboard

TORONTO—A survey of adult hemophilia patients suggests there is room for improvement in assessing and managing disease-related pain.

Roughly 85% of patients surveyed for this study, known as P-FiQ, said they had experienced acute and/or chronic pain in the past 6 months.

Although most patients had no trouble caring for themselves, the pain often had an impact on their daily lives, especially with regard to physical activity and overall mobility.

“Pain and discomfort are significant challenges for people with hemophilia,” said study investigator Michael Recht, MD, PhD, of Oregon Health Sciences University in Portland.

“These results emphasize the importance of providing comprehensive care and support beyond traditional therapy to people living with bleeding disorders.”

Dr Recht and his colleagues presented results of the P-FiQ study in 3 posters at the ISTH 2015 Congress (abstracts PO277-MON, PO297-WED, and PO298-WED).

The study included adult males with mild to severe hemophilia who had a history of joint pain or bleeding. Subjects were asked to assess pain and functional impairment using patient-reported outcome instruments.

During routine visits over the course of a year, 164 participants completed a pain history and 5 questionnaires: the EQ-5D-5L; Brief Pain Inventory Short Form, version 2; International Physical Activity Questionnaire; SF-36v2; and Hemophilia Activities List.

The patients had a median age of 34. More patients had hemophilia A (n=122) than hemophilia B (n=42), and few (n=10) had inhibitors. Sixty-one percent of patients had self-reported arthritis, bone, or joint problems.

Current patient-reported treatment regimens (n=163) were prophylaxis (42%), on-demand treatment (39%), or mostly on-demand treatment (19%). Twenty-five of the 31 patients using on-demand treatment reported using infusions ahead of activity.

Pain prevalence and management

Most participants (85.2%) said they had experienced acute and/or chronic pain over the past 6 months. Twenty-nine percent said they had experienced acute and chronic pain, 32.7% had chronic pain only, 23.5% had acute pain only, and 14.8% reported no pain.

Acute pain was most frequently described as sharp, aching, shooting, and throbbing. Chronic pain was often described as aching, nagging, throbbing, and sharp.

The most common analgesics used for acute or chronic pain were acetaminophen (69.4% and 58%, respectively), NSAIDs (40% and 52%, respectively), and hydrocodone-acetaminophen (29.4% and 33%, respectively).

The most common nonanalgesic strategies used for acute or chronic pain were ice (72.9% and 37%, respectively), rest (48.2% and 34%, respectively), factor VIII/IX or bypassing agent (48.2% and 24%, respectively), elevation (34.1% and 28%, respectively), relaxation (30.6% and 23.0%, respectively), compression (27.1% and 21%, respectively), and heat (24.7% and 15%, respectively).

Impact of pain on daily life

When completing the EQ-5D-5L questionnaire, most patients reported problems with mobility, performing usual activities, and pain or discomfort. However, most patients said they had no problems with self-care (78%) or anxiety/depression (58.5%).

A similar proportion of patients reported slight and moderate pain and discomfort (29.9% and 31.1%, respectively). Pain and discomfort was severe for 11% of patients and extreme for 1.2%, but 26.8% of patients reported no pain or discomfort.

When it came to mobility, patients reported slight (32.3%), moderate (19.5%), and severe (8.5%) problems, and 1.2% of patients said they were unable to get around. However, 38.4% of patients reported having no such problems.

About 44% of patients reported no problems performing usual activities, but 37.2% had slight problems, 14.6% had moderate problems, and 1.8% of patients each had severe problems or were unable to perform usual activities.

For the Brief Pain Inventory, pain severity and interference with daily activities were rated on a scale of 0 to 10, with 0 being no pain/no interference and 10 being pain as bad as you can imagine/pain that completely interferes with daily life.

The overall median pain severity and pain interference were 3.0 (range, 1.3-4.8) and 2.9 (range, 0.7-5.2), respectively. The median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Ankles were the most frequently reported site of pain.

When completing the International Physical Activity Questionnaire, 49.3% of patients (73/148) reported no activity in the prior week.

The median SF-36v2 scores were lower for physical health domains than mental health domains, and the overall median health score was 3.0 (range, 2.0-3.0).

The median score on the Hemophilia Activities List was 76.1 (range, 59.2-95.1). And patients said hemophilia had a greater impact on their lower extremities than upper extremities.

Dr Recht and his colleagues said these results substantiate the high prevalence of pain in adults with hemophilia. And the study highlights opportunities to improve the assessment and management of pain in these patients.

Study investigators have received funding/consulting fees from—or are employees/shareholders of—Novo Nordisk, Baxter, Biogen, Bayer, OctaPharma, Pfizer, CSL Behring, Kendrion, Alexion, Grifols, OPKO Health, Sanofi, Merck, and ProMeticLife Sciences.

Micrograph showing CLL

VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.

And 47% of the responses occurred by the first assessment on day 1 of cycle 3.

“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.

“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”

Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.

Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.

In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.

So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.

Patient demographics

Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”

She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.

“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.

Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.

Response

Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.

The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.

One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.

“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”

The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.

The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.

Adverse events

The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.

Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).

Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).

The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.

“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”

Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.

Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.

*Information in the abstract differs from that presented at the meeting.

Micrograph showing CLL

VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.

And 47% of the responses occurred by the first assessment on day 1 of cycle 3.

“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.

“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”

Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.

Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.

In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.

So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.

Patient demographics

Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”

She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.

“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.

Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.

Response

Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.

The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.

One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.

“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”

The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.

The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.

Adverse events

The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.

Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).

Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).

The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.

“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”

Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.

Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.

*Information in the abstract differs from that presented at the meeting.

Micrograph showing CLL

VIENNA—New research indicates that duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, can generate rapid partial responses in treatment-naïve patients with chronic lymphocytic leukemia (CLL).

The 18 patients in the expansion cohort of a phase 1 study of duvelisib had a median time to response of 3.7 months, according to iwCLL response criteria.

And 47% of the responses occurred by the first assessment on day 1 of cycle 3.

“One thing that does seem to be different with this drug is that you’re getting your [partial responses] a bit faster than you see with some of the other drugs,” said Susan O’Brien, MD, of UC Irvine Health in Orange, California.

“[W]hat that means in the long run is not completely clear, but there’s no question that the responses are very rapid.”

Dr O’Brien presented these findings at the 20th Congress of the European Hematology Association (abstract S434*). The research was funded by Infinity Pharmaceuticals, Inc., the company developing duvelisib.

Older CLL patients with comorbidities and patients with high-risk genomic alterations, such as 17p deletion and TP53 mutations, often don’t fare well on the standard chemoimmunotherapy. Duvelisib is being developed as a potential alternative for these patients and others with hematologic malignancies.

In the dose-escalation portion of this phase 1 study, duvelisib at 25 mg twice daily was well-tolerated and exhibited clinical activity in relapsed/refractory CLL, even in those patients with TP53 mutations and 17p deletion.

So investigators conducted the expansion cohort with 18 patients who received duvelisib at the same dose in 28-day cycles. Duvelisib is given continuously until patients have an adverse event or lose their response.

Patient demographics

Dr O’Brien said there was nothing unusual about the demographics of the study population, except the risk factors: 83% of the patients were over 65, “which is very different from what you would see in a chemoimmunotherapy trial.”

She noted that the patients’ median age was 74, and 56% of patients had either a 17p deletion or TP53 mutation.

“And that’s very unusual because . . . the percentage of patients with that abnormality in frontline CLL is about 5% to 10%,” she added.

Patients were a median of 3 years (range, 0–9) from their initial diagnosis, 47% had Rai stage 3 or greater disease, 44% had splenomegaly, and 11% had grade 4 cytopenia.

Response

Patients stayed on treatment for a median of 14 months (range, 1–20). Eight (44%) discontinued treatment—6 (33%) due to an adverse event, 1 withdrew consent, and 1 discontinued for other reasons.

The best overall response rate was 88%, which consisted of 15 partial responses. Two patients (12%) had stable disease, and there were no complete responses or cases of progressive disease.

One patient with a TP53 mutation/17p deletion withdrew consent prior to the first efficacy assessment.

“There’s no upfront progression,” Dr O’Brien said, “and the response rate was identical for patients with high-risk disease or 17p deletion.”

The median progression-free survival was not yet reached, and the rate was 92% at 18 months. One patient progressed at cycle 13.

The median overall survival was also not reached, with a 94% survival rate at 18 months. One patient died of progressive disease approximately 5 months after the last dose.

Adverse events

The most frequent adverse events (AEs) occurring in more than 25% of patients were, in order of frequency, diarrhea, rash, cough, neutropenia, peripheral edema, fatigue, nausea, pyrexia, ALT/AST increase, anemia, and dizziness.

Grade 3 AEs included diarrhea (22%), ALT/AST increase (17%), rash (11%), neutropenia (6%), fatigue (6%), and anemia (6%). The only grade 4 AE was neutropenia (28%).

Serious AEs in more than 1 patient included diarrhea (n=3), colitis (n=2), dehydration (n=2), pneumonia (n=2), and pneumonitis (n=2).

The AEs leading to treatment discontinuation were increased ALT/AST, dehydration, and spinal stenosis (all in 1 patient), as well as arthritis, pneumonitis, colitis, diarrhea, and stomatitis.

“We tend to see the transaminitis and the pneumonitis earlier, and then the late toxicity tends to be the diarrhea and colitis,” Dr O’ Brien said. “The one toxicity where I would not be inclined to try and re-treat a patient is pneumonitis, but I do think colitis can be successfully re-treated.”

Pharmacodynamic studies show very rapid inhibition of phosphorylated AKT following treatment, which is sustained throughout the whole first cycle. And following 1 cycle of duvelisib, there is near-complete inhibition of CLL proliferation, as evidenced by the reduction in Ki67.

Given these data, the investigators recommended further development of duvelisib in treatment-naïve CLL.

*Information in the abstract differs from that presented at the meeting.

Blood samples

Photo by Graham Colm

Scientists have identified genetic mutations that appear to be associated with treatment outcomes in patients with aplastic anemia.

When compared to unmutated patients, individuals with mutations in PIGA, BCOR, and BCORL1 tended to have better responses to immunosuppressive therapy and superior survival rates.

Other mutations—such as DNMT3A, ASXL1, and RUNX1—were associated with inferior response and survival rates.

Still, the investigators noted that clonal dynamics were “highly variable” in the patient samples they analyzed and might not necessarily have predicted outcomes.

Neal S. Young, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues described this research in NEJM.

The team used next-generation DNA sequencing and array-based karyotyping to analyze 668 blood samples from 439 patients, including serial samples from 82 patients.

The investigators identified 249 somatic mutations in 156 patients (36%). The most common mutations occurred in the BCOR (9.3%), BCORL1 (9.3%), DNMT3A (8.4%), PIGA (7.5%), and ASXL1 (6.2%) genes.

Thirty-six percent of patients had multiple mutations. And some patients had multiple mutations in

the same genes, including PIGA, BCOR, DNMT3A, ASXL1, RUNX1, and ZRSR2.

The investigators identified clonal hematopoiesis in 47% of patients, most frequently as acquired mutations.

The team also found that, largely, the presence and number of mutations a patient had was positively correlated with the patient’s age. The exceptions were PIGA, BCOR, and BCORL1 mutations.

Patients with mutations in PIGA, BCOR, or BCORL1 had better responses to immunosuppressive therapy and better overall and progression-free survival than unmutated patients.

Other mutations were associated with worse outcomes. Patients with mutations in ASXL1, DNMT3A, TP53, RUNX1, JAK2, JAK3, or CSMD1 did not respond as well as unmutated patients to immunosuppressive therapy.

Mutations in ASXL1, DNMT3A, TP53, RUNX1, and CSMD1 were associated with worse overall survival, and mutations in ASXL1, DNMT3A, RUNX1, JAK2, and JAK3 were associated with worse progression-free survival.

The investigators also observed an increase in the size of clones with DNMT3A, ASXL1, RUNX1, or U2AF1 mutations. But the size of clones with PIGA, BCOR, or BCORL1 mutations remained stable or decreased with time.

Blood samples

Photo by Graham Colm

Scientists have identified genetic mutations that appear to be associated with treatment outcomes in patients with aplastic anemia.

When compared to unmutated patients, individuals with mutations in PIGA, BCOR, and BCORL1 tended to have better responses to immunosuppressive therapy and superior survival rates.

Other mutations—such as DNMT3A, ASXL1, and RUNX1—were associated with inferior response and survival rates.

Still, the investigators noted that clonal dynamics were “highly variable” in the patient samples they analyzed and might not necessarily have predicted outcomes.

Neal S. Young, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues described this research in NEJM.

The team used next-generation DNA sequencing and array-based karyotyping to analyze 668 blood samples from 439 patients, including serial samples from 82 patients.

The investigators identified 249 somatic mutations in 156 patients (36%). The most common mutations occurred in the BCOR (9.3%), BCORL1 (9.3%), DNMT3A (8.4%), PIGA (7.5%), and ASXL1 (6.2%) genes.

Thirty-six percent of patients had multiple mutations. And some patients had multiple mutations in

the same genes, including PIGA, BCOR, DNMT3A, ASXL1, RUNX1, and ZRSR2.

The investigators identified clonal hematopoiesis in 47% of patients, most frequently as acquired mutations.

The team also found that, largely, the presence and number of mutations a patient had was positively correlated with the patient’s age. The exceptions were PIGA, BCOR, and BCORL1 mutations.

Patients with mutations in PIGA, BCOR, or BCORL1 had better responses to immunosuppressive therapy and better overall and progression-free survival than unmutated patients.

Other mutations were associated with worse outcomes. Patients with mutations in ASXL1, DNMT3A, TP53, RUNX1, JAK2, JAK3, or CSMD1 did not respond as well as unmutated patients to immunosuppressive therapy.

Mutations in ASXL1, DNMT3A, TP53, RUNX1, and CSMD1 were associated with worse overall survival, and mutations in ASXL1, DNMT3A, RUNX1, JAK2, and JAK3 were associated with worse progression-free survival.

The investigators also observed an increase in the size of clones with DNMT3A, ASXL1, RUNX1, or U2AF1 mutations. But the size of clones with PIGA, BCOR, or BCORL1 mutations remained stable or decreased with time.

Blood samples

Photo by Graham Colm

Scientists have identified genetic mutations that appear to be associated with treatment outcomes in patients with aplastic anemia.

When compared to unmutated patients, individuals with mutations in PIGA, BCOR, and BCORL1 tended to have better responses to immunosuppressive therapy and superior survival rates.

Other mutations—such as DNMT3A, ASXL1, and RUNX1—were associated with inferior response and survival rates.

Still, the investigators noted that clonal dynamics were “highly variable” in the patient samples they analyzed and might not necessarily have predicted outcomes.

Neal S. Young, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and his colleagues described this research in NEJM.

The team used next-generation DNA sequencing and array-based karyotyping to analyze 668 blood samples from 439 patients, including serial samples from 82 patients.

The investigators identified 249 somatic mutations in 156 patients (36%). The most common mutations occurred in the BCOR (9.3%), BCORL1 (9.3%), DNMT3A (8.4%), PIGA (7.5%), and ASXL1 (6.2%) genes.

Thirty-six percent of patients had multiple mutations. And some patients had multiple mutations in

the same genes, including PIGA, BCOR, DNMT3A, ASXL1, RUNX1, and ZRSR2.

The investigators identified clonal hematopoiesis in 47% of patients, most frequently as acquired mutations.

The team also found that, largely, the presence and number of mutations a patient had was positively correlated with the patient’s age. The exceptions were PIGA, BCOR, and BCORL1 mutations.

Patients with mutations in PIGA, BCOR, or BCORL1 had better responses to immunosuppressive therapy and better overall and progression-free survival than unmutated patients.

Other mutations were associated with worse outcomes. Patients with mutations in ASXL1, DNMT3A, TP53, RUNX1, JAK2, JAK3, or CSMD1 did not respond as well as unmutated patients to immunosuppressive therapy.

Mutations in ASXL1, DNMT3A, TP53, RUNX1, and CSMD1 were associated with worse overall survival, and mutations in ASXL1, DNMT3A, RUNX1, JAK2, and JAK3 were associated with worse progression-free survival.

The investigators also observed an increase in the size of clones with DNMT3A, ASXL1, RUNX1, or U2AF1 mutations. But the size of clones with PIGA, BCOR, or BCORL1 mutations remained stable or decreased with time.

John Pandolfino, MD, chief of gastroenterology and hepatology at Northwestern University’s Feinberg School of Medicine in Chicago, talks about best practices for colonoscopies and treating C. diff infections.

John Pandolfino, MD, chief of gastroenterology and hepatology at Northwestern University’s Feinberg School of Medicine in Chicago, talks about best practices for colonoscopies and treating C. diff infections.

John Pandolfino, MD, chief of gastroenterology and hepatology at Northwestern University’s Feinberg School of Medicine in Chicago, talks about best practices for colonoscopies and treating C. diff infections.

Excerpt of our interviews with Choosing Wisely, Lisa Shieh, MD, PhD, of Stanford University School of Medicine, discusses an example of a Choosing Wisely program.

Excerpt of our interviews with Choosing Wisely, Lisa Shieh, MD, PhD, of Stanford University School of Medicine, discusses an example of a Choosing Wisely program.

Excerpt of our interviews with Choosing Wisely, Lisa Shieh, MD, PhD, of Stanford University School of Medicine, discusses an example of a Choosing Wisely program.

Gregory Seymann, MD, discusses a Choosing Wisely program.

Gregory Seymann, MD, discusses a Choosing Wisely program.

Gregory Seymann, MD, discusses a Choosing Wisely program.

Clonal hematopoiesis was detected in DNA samples from approximately half of 439 patients with aplastic anemia, and a third of the study population carried mutations in candidate genes that correlated with clinical outcomes, according to a report published online July 2 in the New England Journal of Medicine.

Most patients with aplastic anemia respond to immunosuppressive therapy or bone marrow transplantation, but about 15% later develop myelodysplastic syndromes, acute myeloid leukemia (AML), or both. Historically, this has been attributed to “clonal evolution,” but a more accurate term is clonal hematopoiesis. However, not all patients with clonal hematopoiesis go on to develop late myelodysplastic syndromes or AML, said Dr. Tetsuichi Yoshizato of the department of pathology and tumor biology at Kyoto (Japan) University and associates.

To clarify the role of clonal hematopoiesis in aplastic anemia, the investigators analyzed DNA in blood, bone marrow, and buccal samples from 439 patients with bone marrow failure who were treated at three specialized centers in the United States and Japan.

Targeted sequencing of a panel of genes that are recurrently mutated in myeloid cancers was performed; 249 mutations were detected in candidate genes for myelodysplastic syndromes/AML in 36% of the study population. And about one-third of patients whose DNA harbored mutations had multiple (as many as 7) mutations. The most frequently mutated genes were BCOR and BCORL1 (in 9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%), which together accounted for 77% of all mutation-positive patients, the investigators reported.

In addition, 47% of patients had expanded hematopoietic cell clones. Clones carrying certain mutations were associated with a better response to immunosuppressive treatment, while clones carrying several other mutations were associated with a poor treatment response, lower survival, and progression to myelodysplastic syndromes/AML. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes.

The pattern of mutations in individual patients, however, varied markedly over time and was often unpredictable. “It should be underscored that the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative,” Dr. Yoshizato and associates said (N. Engl. J. Med. 2015 July 2 [doi:10.1056/NEJMoa1414799]).

Although further genetic research is needed before these findings can be applied clinically to guide prognosis and treatment, they already “have implications for bone marrow failure, for early events in leukemogenesis, and for normal aging,” the investigators added.

Clonal hematopoiesis was detected in DNA samples from approximately half of 439 patients with aplastic anemia, and a third of the study population carried mutations in candidate genes that correlated with clinical outcomes, according to a report published online July 2 in the New England Journal of Medicine.

Most patients with aplastic anemia respond to immunosuppressive therapy or bone marrow transplantation, but about 15% later develop myelodysplastic syndromes, acute myeloid leukemia (AML), or both. Historically, this has been attributed to “clonal evolution,” but a more accurate term is clonal hematopoiesis. However, not all patients with clonal hematopoiesis go on to develop late myelodysplastic syndromes or AML, said Dr. Tetsuichi Yoshizato of the department of pathology and tumor biology at Kyoto (Japan) University and associates.

To clarify the role of clonal hematopoiesis in aplastic anemia, the investigators analyzed DNA in blood, bone marrow, and buccal samples from 439 patients with bone marrow failure who were treated at three specialized centers in the United States and Japan.

Targeted sequencing of a panel of genes that are recurrently mutated in myeloid cancers was performed; 249 mutations were detected in candidate genes for myelodysplastic syndromes/AML in 36% of the study population. And about one-third of patients whose DNA harbored mutations had multiple (as many as 7) mutations. The most frequently mutated genes were BCOR and BCORL1 (in 9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%), which together accounted for 77% of all mutation-positive patients, the investigators reported.

In addition, 47% of patients had expanded hematopoietic cell clones. Clones carrying certain mutations were associated with a better response to immunosuppressive treatment, while clones carrying several other mutations were associated with a poor treatment response, lower survival, and progression to myelodysplastic syndromes/AML. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes.

The pattern of mutations in individual patients, however, varied markedly over time and was often unpredictable. “It should be underscored that the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative,” Dr. Yoshizato and associates said (N. Engl. J. Med. 2015 July 2 [doi:10.1056/NEJMoa1414799]).

Although further genetic research is needed before these findings can be applied clinically to guide prognosis and treatment, they already “have implications for bone marrow failure, for early events in leukemogenesis, and for normal aging,” the investigators added.

Clonal hematopoiesis was detected in DNA samples from approximately half of 439 patients with aplastic anemia, and a third of the study population carried mutations in candidate genes that correlated with clinical outcomes, according to a report published online July 2 in the New England Journal of Medicine.

Most patients with aplastic anemia respond to immunosuppressive therapy or bone marrow transplantation, but about 15% later develop myelodysplastic syndromes, acute myeloid leukemia (AML), or both. Historically, this has been attributed to “clonal evolution,” but a more accurate term is clonal hematopoiesis. However, not all patients with clonal hematopoiesis go on to develop late myelodysplastic syndromes or AML, said Dr. Tetsuichi Yoshizato of the department of pathology and tumor biology at Kyoto (Japan) University and associates.

To clarify the role of clonal hematopoiesis in aplastic anemia, the investigators analyzed DNA in blood, bone marrow, and buccal samples from 439 patients with bone marrow failure who were treated at three specialized centers in the United States and Japan.

Targeted sequencing of a panel of genes that are recurrently mutated in myeloid cancers was performed; 249 mutations were detected in candidate genes for myelodysplastic syndromes/AML in 36% of the study population. And about one-third of patients whose DNA harbored mutations had multiple (as many as 7) mutations. The most frequently mutated genes were BCOR and BCORL1 (in 9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%), which together accounted for 77% of all mutation-positive patients, the investigators reported.

In addition, 47% of patients had expanded hematopoietic cell clones. Clones carrying certain mutations were associated with a better response to immunosuppressive treatment, while clones carrying several other mutations were associated with a poor treatment response, lower survival, and progression to myelodysplastic syndromes/AML. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes.

The pattern of mutations in individual patients, however, varied markedly over time and was often unpredictable. “It should be underscored that the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative,” Dr. Yoshizato and associates said (N. Engl. J. Med. 2015 July 2 [doi:10.1056/NEJMoa1414799]).

Although further genetic research is needed before these findings can be applied clinically to guide prognosis and treatment, they already “have implications for bone marrow failure, for early events in leukemogenesis, and for normal aging,” the investigators added.