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Healthcare professionals work while sick despite risk to patients
Photo by Logan Tuttle
Results of a small survey showed that many healthcare professionals reported to work while sick, despite recognizing that this could put their patients at risk.
About 95% of survey respondents acknowledged that working while sick puts patients at risk, but 83% of respondents said they had worked while sick at least once in the past year.
About 9% of respondents reported working while sick at least 5 times.
Julia E. Szymczak, PhD, of the Children’s Hospital of Philadelphia in Pennsylvania, and her colleagues reported these results in JAMA Pediatrics alongside a related editorial.
The researchers administered an anonymous survey to attending physicians and advanced practice clinicians (APCs) at the Children’s Hospital of Philadelphia. APCs included certified registered nurse practitioners, physician assistants, clinical nurse specialists, certified registered nurse anesthetists, and certified nurse midwives.
Overall, 280 attending physicians (61%) and 256 APCs (54.5%) responded. Most respondents (504, 95.3%) said working while sick put patients at risk.
However, 446 respondents (83.1%) reported working while sick at least once in the past year, and 50 respondents (9.3%) reported working while sick at least 5 times.
Respondents reported working with symptoms that included diarrhea, fever, and the onset of significant respiratory symptoms.
The reasons physicians and APCs worked while sick included not wanting to let colleagues down (98.7%), staffing concerns (94.9%), not wanting to let patients down (92.5%), fear of being ostracized by colleagues (64%), and concerns about the continuity of care (63.8%).
An analysis of written comments about why respondents work while sick highlighted 3 areas: challenges in identifying and arranging someone to cover their work and a lack of resources to accommodate sick leave, a strong cultural norm in the hospital to report for work unless one is extremely ill, and ambiguity about what symptoms constitute being too sick to work.
Dr Szymczak and her colleagues said this study suggests complex social and logistical factors cause healthcare workers to report to work sick. But these results could inform efforts to help workers make the right choice to keep their patients and colleagues safe while caring for themselves. 
Photo by Logan Tuttle
Results of a small survey showed that many healthcare professionals reported to work while sick, despite recognizing that this could put their patients at risk.
About 95% of survey respondents acknowledged that working while sick puts patients at risk, but 83% of respondents said they had worked while sick at least once in the past year.
About 9% of respondents reported working while sick at least 5 times.
Julia E. Szymczak, PhD, of the Children’s Hospital of Philadelphia in Pennsylvania, and her colleagues reported these results in JAMA Pediatrics alongside a related editorial.
The researchers administered an anonymous survey to attending physicians and advanced practice clinicians (APCs) at the Children’s Hospital of Philadelphia. APCs included certified registered nurse practitioners, physician assistants, clinical nurse specialists, certified registered nurse anesthetists, and certified nurse midwives.
Overall, 280 attending physicians (61%) and 256 APCs (54.5%) responded. Most respondents (504, 95.3%) said working while sick put patients at risk.
However, 446 respondents (83.1%) reported working while sick at least once in the past year, and 50 respondents (9.3%) reported working while sick at least 5 times.
Respondents reported working with symptoms that included diarrhea, fever, and the onset of significant respiratory symptoms.
The reasons physicians and APCs worked while sick included not wanting to let colleagues down (98.7%), staffing concerns (94.9%), not wanting to let patients down (92.5%), fear of being ostracized by colleagues (64%), and concerns about the continuity of care (63.8%).
An analysis of written comments about why respondents work while sick highlighted 3 areas: challenges in identifying and arranging someone to cover their work and a lack of resources to accommodate sick leave, a strong cultural norm in the hospital to report for work unless one is extremely ill, and ambiguity about what symptoms constitute being too sick to work.
Dr Szymczak and her colleagues said this study suggests complex social and logistical factors cause healthcare workers to report to work sick. But these results could inform efforts to help workers make the right choice to keep their patients and colleagues safe while caring for themselves.
Photo by Logan Tuttle
Results of a small survey showed that many healthcare professionals reported to work while sick, despite recognizing that this could put their patients at risk.
About 95% of survey respondents acknowledged that working while sick puts patients at risk, but 83% of respondents said they had worked while sick at least once in the past year.
About 9% of respondents reported working while sick at least 5 times.
Julia E. Szymczak, PhD, of the Children’s Hospital of Philadelphia in Pennsylvania, and her colleagues reported these results in JAMA Pediatrics alongside a related editorial.
The researchers administered an anonymous survey to attending physicians and advanced practice clinicians (APCs) at the Children’s Hospital of Philadelphia. APCs included certified registered nurse practitioners, physician assistants, clinical nurse specialists, certified registered nurse anesthetists, and certified nurse midwives.
Overall, 280 attending physicians (61%) and 256 APCs (54.5%) responded. Most respondents (504, 95.3%) said working while sick put patients at risk.
However, 446 respondents (83.1%) reported working while sick at least once in the past year, and 50 respondents (9.3%) reported working while sick at least 5 times.
Respondents reported working with symptoms that included diarrhea, fever, and the onset of significant respiratory symptoms.
The reasons physicians and APCs worked while sick included not wanting to let colleagues down (98.7%), staffing concerns (94.9%), not wanting to let patients down (92.5%), fear of being ostracized by colleagues (64%), and concerns about the continuity of care (63.8%).
An analysis of written comments about why respondents work while sick highlighted 3 areas: challenges in identifying and arranging someone to cover their work and a lack of resources to accommodate sick leave, a strong cultural norm in the hospital to report for work unless one is extremely ill, and ambiguity about what symptoms constitute being too sick to work.
Dr Szymczak and her colleagues said this study suggests complex social and logistical factors cause healthcare workers to report to work sick. But these results could inform efforts to help workers make the right choice to keep their patients and colleagues safe while caring for themselves.
NICE supports use of apixaban for VTE
Photo courtesy of the CDC
The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.
According to NICE, data from the AMPLIFY and AMPLIFY-EXT studies suggest apixaban is clinically effective for treating and preventing VTE.
And cost analyses indicate that apixaban is a cost-effective use of National Health Service (NHS) resources.
NICE said apixaban should be available on the NHS within 3 months of the guidance release date. The guidance was made available in June.
Dosing
To treat deep vein thrombosis (DVT) or pulmonary embolism (PE), 10 mg of apixaban should be taken twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months.
To prevent recurrent VTE, patients who have completed 6 months of treatment for DVT or PE should take apixaban at 2.5 mg twice a day.
“[A]pixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”
Clinical effectiveness
To assess the clinical effectiveness of apixaban, a committee advising NICE evaluated data from the AMPLIFY and AMPLIFY-EXT studies.
Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.
In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.
Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.
The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.
However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.
The committee also pointed out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.
In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.
Cost-effectiveness
The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)
Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of NHS resources.
Photo courtesy of the CDC
The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.
According to NICE, data from the AMPLIFY and AMPLIFY-EXT studies suggest apixaban is clinically effective for treating and preventing VTE.
And cost analyses indicate that apixaban is a cost-effective use of National Health Service (NHS) resources.
NICE said apixaban should be available on the NHS within 3 months of the guidance release date. The guidance was made available in June.
Dosing
To treat deep vein thrombosis (DVT) or pulmonary embolism (PE), 10 mg of apixaban should be taken twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months.
To prevent recurrent VTE, patients who have completed 6 months of treatment for DVT or PE should take apixaban at 2.5 mg twice a day.
“[A]pixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”
Clinical effectiveness
To assess the clinical effectiveness of apixaban, a committee advising NICE evaluated data from the AMPLIFY and AMPLIFY-EXT studies.
Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.
In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.
Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.
The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.
However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.
The committee also pointed out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.
In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.
Cost-effectiveness
The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)
Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of NHS resources.
Photo courtesy of the CDC
The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the anticoagulant apixaban (Eliquis) as an option for treating and preventing venous thromboembolism (VTE) in adults.
According to NICE, data from the AMPLIFY and AMPLIFY-EXT studies suggest apixaban is clinically effective for treating and preventing VTE.
And cost analyses indicate that apixaban is a cost-effective use of National Health Service (NHS) resources.
NICE said apixaban should be available on the NHS within 3 months of the guidance release date. The guidance was made available in June.
Dosing
To treat deep vein thrombosis (DVT) or pulmonary embolism (PE), 10 mg of apixaban should be taken twice a day for the first 7 days, followed by 5 mg twice a day for at least 3 months.
To prevent recurrent VTE, patients who have completed 6 months of treatment for DVT or PE should take apixaban at 2.5 mg twice a day.
“[A]pixaban is the only oral anticoagulant for which the licensed dose is lower for secondary prevention than for initial treatment of VTE,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“This could also be of potential benefit in terms of reducing the risk of bleeding where treatment is continued and therefore increase the chance that a person would take apixaban long-term.”
Clinical effectiveness
To assess the clinical effectiveness of apixaban, a committee advising NICE evaluated data from the AMPLIFY and AMPLIFY-EXT studies.
Results of the AMPLIFY study indicated that apixaban is noninferior to standard treatment for recurrent VTE—initial parenteral enoxaparin overlapped with warfarin. Apixaban was comparable in efficacy to standard therapy and induced significantly less bleeding.
In AMPLIFY-EXT, researchers compared 12 months of treatment with apixaban at 2 doses—2.5 mg and 5 mg—to placebo in patients who had previously received anticoagulant therapy for 6 to 12 months to treat a prior VTE.
Both doses of apixaban effectively prevented VTE, VTE-related events, and death. And the incidence of bleeding events was low in all treatment arms.
The NICE committee noted that there were limited data in these trials pertaining to patients who needed less than 6 months of treatment and for patients still at high risk of recurrent VTE after 6 months of treatment.
However, the committee concluded that, despite these limitations, the AMPLIFY trials were the pivotal trials that informed the marketing authorization for apixaban. As such, they were sufficient to inform a recommendation for the whole population covered by the marketing authorization.
The committee also pointed out that there were no head-to-head trials evaluating the relative effectiveness of apixaban compared with rivaroxaban and dabigatran etexilate for treating and preventing VTE.
In addition, there were insufficient data to assess the effectiveness and safety of apixaban in patients with active cancer who had VTE, so it was not possible to make a specific recommendation for this group.
Cost-effectiveness
The cost of apixaban is £1.10 per tablet for either the 2.5 mg or 5 mg dose (excluding tax). The daily cost of apixaban is £2.20. (Costs may vary in different settings because of negotiated procurement discounts.)
Analyses suggested that the incremental cost-effectiveness ratio of apixaban was less than £20,000 per quality-adjusted life-year gained for either 6 months or life-long treatment. Therefore, NICE concluded that apixaban is a cost-effective use of NHS resources.
EAP makes drug available to MM patients
Photo by Linda Bartlett
A new expanded access program (EAP) will make daratumumab, an investigational anti-CD38 monoclonal antibody, available to patients with double-refractory multiple myeloma (MM).
The multicenter EAP is open to MM patients in the US who are 18 years of age or older.
Patients must be refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or have received 3 or more prior lines of therapy, including a PI and an IMiD.
In the US, EAPs are designed to make investigational medicines available for patients with serious or life-threatening illnesses who are ineligible for ongoing interventional trials and have exhausted currently available treatment options.
This EAP will make daratumumab available at up to 40 medical centers in the US while the drug’s Biologics License Application is under review by the US Food and Drug Administration (FDA).
Additional information about the EAP can be found on clinicaltrials.gov (NCT02477891). Janssen Research & Development, LLC, the company developing daratumumab, is collaborating with the Multiple Myeloma Research Foundation on this EAP.
About daratumumab
Daratumumab is a human IgG1k monoclonal antibody that binds with high affinity to the transmembrane ectoenzyme CD38 on the surface of MM cells.
Five phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess the drug’s potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin lymphoma.
On May 1, 2013, daratumumab received breakthrough designation from the FDA for the treatment of patients with MM who have received at least 3 prior lines of therapy, including a PI and an IMiD, or who are double refractory to a PI and an IMiD.
On June 5, 2015, Janssen announced it had initiated the rolling submission of its Biologics License Application for daratumumab to the FDA for the treatment of this set of MM patients. A rolling submission allows the company to submit portions of the regulatory application to the FDA as they are completed.
The regulatory submission for daratumumab will be primarily supported by data from the phase 2 MMY2002 (SIRIUS) study, the results of which were presented at the 2015 ASCO Annual Meeting.
The application will also be supported by data from 4 other studies, including the phase 1/2 GEN501 monotherapy study.
Photo by Linda Bartlett
A new expanded access program (EAP) will make daratumumab, an investigational anti-CD38 monoclonal antibody, available to patients with double-refractory multiple myeloma (MM).
The multicenter EAP is open to MM patients in the US who are 18 years of age or older.
Patients must be refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or have received 3 or more prior lines of therapy, including a PI and an IMiD.
In the US, EAPs are designed to make investigational medicines available for patients with serious or life-threatening illnesses who are ineligible for ongoing interventional trials and have exhausted currently available treatment options.
This EAP will make daratumumab available at up to 40 medical centers in the US while the drug’s Biologics License Application is under review by the US Food and Drug Administration (FDA).
Additional information about the EAP can be found on clinicaltrials.gov (NCT02477891). Janssen Research & Development, LLC, the company developing daratumumab, is collaborating with the Multiple Myeloma Research Foundation on this EAP.
About daratumumab
Daratumumab is a human IgG1k monoclonal antibody that binds with high affinity to the transmembrane ectoenzyme CD38 on the surface of MM cells.
Five phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess the drug’s potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin lymphoma.
On May 1, 2013, daratumumab received breakthrough designation from the FDA for the treatment of patients with MM who have received at least 3 prior lines of therapy, including a PI and an IMiD, or who are double refractory to a PI and an IMiD.
On June 5, 2015, Janssen announced it had initiated the rolling submission of its Biologics License Application for daratumumab to the FDA for the treatment of this set of MM patients. A rolling submission allows the company to submit portions of the regulatory application to the FDA as they are completed.
The regulatory submission for daratumumab will be primarily supported by data from the phase 2 MMY2002 (SIRIUS) study, the results of which were presented at the 2015 ASCO Annual Meeting.
The application will also be supported by data from 4 other studies, including the phase 1/2 GEN501 monotherapy study.
Photo by Linda Bartlett
A new expanded access program (EAP) will make daratumumab, an investigational anti-CD38 monoclonal antibody, available to patients with double-refractory multiple myeloma (MM).
The multicenter EAP is open to MM patients in the US who are 18 years of age or older.
Patients must be refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or have received 3 or more prior lines of therapy, including a PI and an IMiD.
In the US, EAPs are designed to make investigational medicines available for patients with serious or life-threatening illnesses who are ineligible for ongoing interventional trials and have exhausted currently available treatment options.
This EAP will make daratumumab available at up to 40 medical centers in the US while the drug’s Biologics License Application is under review by the US Food and Drug Administration (FDA).
Additional information about the EAP can be found on clinicaltrials.gov (NCT02477891). Janssen Research & Development, LLC, the company developing daratumumab, is collaborating with the Multiple Myeloma Research Foundation on this EAP.
About daratumumab
Daratumumab is a human IgG1k monoclonal antibody that binds with high affinity to the transmembrane ectoenzyme CD38 on the surface of MM cells.
Five phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess the drug’s potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin lymphoma.
On May 1, 2013, daratumumab received breakthrough designation from the FDA for the treatment of patients with MM who have received at least 3 prior lines of therapy, including a PI and an IMiD, or who are double refractory to a PI and an IMiD.
On June 5, 2015, Janssen announced it had initiated the rolling submission of its Biologics License Application for daratumumab to the FDA for the treatment of this set of MM patients. A rolling submission allows the company to submit portions of the regulatory application to the FDA as they are completed.
The regulatory submission for daratumumab will be primarily supported by data from the phase 2 MMY2002 (SIRIUS) study, the results of which were presented at the 2015 ASCO Annual Meeting.
The application will also be supported by data from 4 other studies, including the phase 1/2 GEN501 monotherapy study.
Novel SYK inhibitor shows ‘good early evidence’ of activity
LUGANO—The phase 1, first-in-human study of the novel SYK inhibitor TAK-659 is showing “good early evidence” of antitumor activity in patients with lymphoma, according to investigators.
The agent also appears to be fairly well tolerated, with 10 categories of adverse events occurring in 2 or more patients.
Adam M. Petrich, MD, of Northwestern University in Evanston, Illinois, presented results from this ongoing study at the 13th International Congress on Malignant Lymphoma (13-ICML) as abstract 039.*
The study is supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Dr Petrich said the B-cell receptor signaling pathway is “very fertile ground with respect to development for novel targeting, particularly of B-cell malignancies, and SYK—the spleen tyrosine kinase—is an integral component of this.”
Investigators believe SYK has implications beyond B-cell lymphoma, including EBV-related malignancies, solid tumors, and myeloid leukemias.
Preclinical findings
In vitro experiments with TAK-659 showed “profound inhibition” of both SYK and FLT3, as indicated by the low IC50 levels, Dr Petrich said.
He also pointed out that the EC50 levels compare favorably to ibrutinib and idelalisib, with generally lower numbers in a broad panel of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia.
In animal models, TAK-659 exhibited a dose-dependent tumor-inhibitory property.
“And if we look at both germinal center B and non-germinal center B subtypes of large-cell lymphoma, we see activity across both types,” Dr Petrich said.
Phase 1 study
Investigators are currently conducting the phase 1 study, which is a standard 3+3 dose-escalation schema. The data cutoff for the ICML presentation was April 13, although the dose-escalation phase was still underway, and the maximum tolerated dose was not yet reached.
Based on preclinical data, the team projected the efficacious dose for humans to be approximately 600 to 1200 mg per day. Patients were started at 60 mg, and, at the next planned step of 120 mg, 2 patients developed asymptomatic lipase elevations.
“For that reason, we revised the protocol, allowed for those to not be considered dose-limiting toxicities, and explored intermediate doses,” Dr Petrich explained.
So the protocol now includes intermediate doses of 80 and 100 mg. Dr Petrich’s presentation focused on the 4 doses—60, 80, 100, and 120 mg taken orally once daily.
He said the observed human clearance of TAK-659 was approximately 3- to 4-fold lower than predicted based on the mouse pharmacokinetic (PK) data, which led to steady-state area under the curve values 3- to 4-fold higher in humans than predicted.
Patient demographics
The investigators enrolled 21 patients, 12 with solid tumors, 6 with DLBCL, and 3 with FL. The median age was 60 years, 66% were male, and 62% had received 4 or more prior therapies.
The median number of TAK-659 treatment cycles was 2 (range, 1–10), and 5 patients are still on active treatment. Dr Petrich pointed out that 4 of the 5 longest-treated patients have DLBCL, and “the record holder with DLBCL is about to celebrate 1 year on therapy.”
Safety
“The safety profile in humans showed that [TAK-659] was actually quite tolerable,” Dr Petrich said.
There were 10 categories of treatment-related adverse events (AEs) that occurred in 2 or more patients. They were, in descending order, fatigue, anemia, diarrhea, elevated AST, hypophosphatemia, nausea, rash, elevated lipase, elevated ALT, and anorexia.
The majority of AEs were grade 1 or 2. However, there were grade 3/4 cases of anemia, diarrhea, elevated AST, and hypophosphatemia. And elevated lipase—the asymptomatic, dose-limiting toxicity for which the protocol was modified—consisted entirely of grade 3 or 4 events.
Episodes of neutropenia and thrombocytopenia occurred in 1 patient each, and both were grade 1.
“So [TAK-659] seems quite well tolerated in that regard as well,” Dr Petrich observed.
The plasma profile on days 1 and 15 of cycle 1 indicate that PK steady-state conditions are generally achieved by day 8, with moderate accumulation after repeated, once-daily dosing for 15 days.
Antitumor activity
Of the 12 evaluable patients, 5 had tumor shrinkage at the 60, 80, or 100 mg dose levels. Three of the 6 DLBCL patients experienced tumor shrinkage, and there were “2 dramatic responses in patients with follicular lymphoma, including 1 CR [complete response],” Dr Petrich said.
One of these FL patients had an aggressive phenotype and never had a previous response last longer than 20 months.
“[H]e actually achieved a CR within 2 cycles—a dramatic response for his disease—and he remains on treatment, and he’s up to cycle 5 now,” Dr Petrich said.
The team concluded that the PK data support daily dosing, despite lower clearance than originally predicted.
“[There is] good early evidence of antitumor activity and no significant safety signals,” Dr Petrich said. “And the [hematologic] toxicity profile, in particular, seems to suggest this is a well-tolerated drug.”
The investigators are conducting expansion cohorts and are considering future combination studies. They recently activated a study in acute myeloid leukemia because TAK-659 has FLT3 inhibitory properties.
*Information in the abstract differs from that presented at the meeting.
LUGANO—The phase 1, first-in-human study of the novel SYK inhibitor TAK-659 is showing “good early evidence” of antitumor activity in patients with lymphoma, according to investigators.
The agent also appears to be fairly well tolerated, with 10 categories of adverse events occurring in 2 or more patients.
Adam M. Petrich, MD, of Northwestern University in Evanston, Illinois, presented results from this ongoing study at the 13th International Congress on Malignant Lymphoma (13-ICML) as abstract 039.*
The study is supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Dr Petrich said the B-cell receptor signaling pathway is “very fertile ground with respect to development for novel targeting, particularly of B-cell malignancies, and SYK—the spleen tyrosine kinase—is an integral component of this.”
Investigators believe SYK has implications beyond B-cell lymphoma, including EBV-related malignancies, solid tumors, and myeloid leukemias.
Preclinical findings
In vitro experiments with TAK-659 showed “profound inhibition” of both SYK and FLT3, as indicated by the low IC50 levels, Dr Petrich said.
He also pointed out that the EC50 levels compare favorably to ibrutinib and idelalisib, with generally lower numbers in a broad panel of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia.
In animal models, TAK-659 exhibited a dose-dependent tumor-inhibitory property.
“And if we look at both germinal center B and non-germinal center B subtypes of large-cell lymphoma, we see activity across both types,” Dr Petrich said.
Phase 1 study
Investigators are currently conducting the phase 1 study, which is a standard 3+3 dose-escalation schema. The data cutoff for the ICML presentation was April 13, although the dose-escalation phase was still underway, and the maximum tolerated dose was not yet reached.
Based on preclinical data, the team projected the efficacious dose for humans to be approximately 600 to 1200 mg per day. Patients were started at 60 mg, and, at the next planned step of 120 mg, 2 patients developed asymptomatic lipase elevations.
“For that reason, we revised the protocol, allowed for those to not be considered dose-limiting toxicities, and explored intermediate doses,” Dr Petrich explained.
So the protocol now includes intermediate doses of 80 and 100 mg. Dr Petrich’s presentation focused on the 4 doses—60, 80, 100, and 120 mg taken orally once daily.
He said the observed human clearance of TAK-659 was approximately 3- to 4-fold lower than predicted based on the mouse pharmacokinetic (PK) data, which led to steady-state area under the curve values 3- to 4-fold higher in humans than predicted.
Patient demographics
The investigators enrolled 21 patients, 12 with solid tumors, 6 with DLBCL, and 3 with FL. The median age was 60 years, 66% were male, and 62% had received 4 or more prior therapies.
The median number of TAK-659 treatment cycles was 2 (range, 1–10), and 5 patients are still on active treatment. Dr Petrich pointed out that 4 of the 5 longest-treated patients have DLBCL, and “the record holder with DLBCL is about to celebrate 1 year on therapy.”
Safety
“The safety profile in humans showed that [TAK-659] was actually quite tolerable,” Dr Petrich said.
There were 10 categories of treatment-related adverse events (AEs) that occurred in 2 or more patients. They were, in descending order, fatigue, anemia, diarrhea, elevated AST, hypophosphatemia, nausea, rash, elevated lipase, elevated ALT, and anorexia.
The majority of AEs were grade 1 or 2. However, there were grade 3/4 cases of anemia, diarrhea, elevated AST, and hypophosphatemia. And elevated lipase—the asymptomatic, dose-limiting toxicity for which the protocol was modified—consisted entirely of grade 3 or 4 events.
Episodes of neutropenia and thrombocytopenia occurred in 1 patient each, and both were grade 1.
“So [TAK-659] seems quite well tolerated in that regard as well,” Dr Petrich observed.
The plasma profile on days 1 and 15 of cycle 1 indicate that PK steady-state conditions are generally achieved by day 8, with moderate accumulation after repeated, once-daily dosing for 15 days.
Antitumor activity
Of the 12 evaluable patients, 5 had tumor shrinkage at the 60, 80, or 100 mg dose levels. Three of the 6 DLBCL patients experienced tumor shrinkage, and there were “2 dramatic responses in patients with follicular lymphoma, including 1 CR [complete response],” Dr Petrich said.
One of these FL patients had an aggressive phenotype and never had a previous response last longer than 20 months.
“[H]e actually achieved a CR within 2 cycles—a dramatic response for his disease—and he remains on treatment, and he’s up to cycle 5 now,” Dr Petrich said.
The team concluded that the PK data support daily dosing, despite lower clearance than originally predicted.
“[There is] good early evidence of antitumor activity and no significant safety signals,” Dr Petrich said. “And the [hematologic] toxicity profile, in particular, seems to suggest this is a well-tolerated drug.”
The investigators are conducting expansion cohorts and are considering future combination studies. They recently activated a study in acute myeloid leukemia because TAK-659 has FLT3 inhibitory properties.
*Information in the abstract differs from that presented at the meeting.
LUGANO—The phase 1, first-in-human study of the novel SYK inhibitor TAK-659 is showing “good early evidence” of antitumor activity in patients with lymphoma, according to investigators.
The agent also appears to be fairly well tolerated, with 10 categories of adverse events occurring in 2 or more patients.
Adam M. Petrich, MD, of Northwestern University in Evanston, Illinois, presented results from this ongoing study at the 13th International Congress on Malignant Lymphoma (13-ICML) as abstract 039.*
The study is supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Dr Petrich said the B-cell receptor signaling pathway is “very fertile ground with respect to development for novel targeting, particularly of B-cell malignancies, and SYK—the spleen tyrosine kinase—is an integral component of this.”
Investigators believe SYK has implications beyond B-cell lymphoma, including EBV-related malignancies, solid tumors, and myeloid leukemias.
Preclinical findings
In vitro experiments with TAK-659 showed “profound inhibition” of both SYK and FLT3, as indicated by the low IC50 levels, Dr Petrich said.
He also pointed out that the EC50 levels compare favorably to ibrutinib and idelalisib, with generally lower numbers in a broad panel of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia.
In animal models, TAK-659 exhibited a dose-dependent tumor-inhibitory property.
“And if we look at both germinal center B and non-germinal center B subtypes of large-cell lymphoma, we see activity across both types,” Dr Petrich said.
Phase 1 study
Investigators are currently conducting the phase 1 study, which is a standard 3+3 dose-escalation schema. The data cutoff for the ICML presentation was April 13, although the dose-escalation phase was still underway, and the maximum tolerated dose was not yet reached.
Based on preclinical data, the team projected the efficacious dose for humans to be approximately 600 to 1200 mg per day. Patients were started at 60 mg, and, at the next planned step of 120 mg, 2 patients developed asymptomatic lipase elevations.
“For that reason, we revised the protocol, allowed for those to not be considered dose-limiting toxicities, and explored intermediate doses,” Dr Petrich explained.
So the protocol now includes intermediate doses of 80 and 100 mg. Dr Petrich’s presentation focused on the 4 doses—60, 80, 100, and 120 mg taken orally once daily.
He said the observed human clearance of TAK-659 was approximately 3- to 4-fold lower than predicted based on the mouse pharmacokinetic (PK) data, which led to steady-state area under the curve values 3- to 4-fold higher in humans than predicted.
Patient demographics
The investigators enrolled 21 patients, 12 with solid tumors, 6 with DLBCL, and 3 with FL. The median age was 60 years, 66% were male, and 62% had received 4 or more prior therapies.
The median number of TAK-659 treatment cycles was 2 (range, 1–10), and 5 patients are still on active treatment. Dr Petrich pointed out that 4 of the 5 longest-treated patients have DLBCL, and “the record holder with DLBCL is about to celebrate 1 year on therapy.”
Safety
“The safety profile in humans showed that [TAK-659] was actually quite tolerable,” Dr Petrich said.
There were 10 categories of treatment-related adverse events (AEs) that occurred in 2 or more patients. They were, in descending order, fatigue, anemia, diarrhea, elevated AST, hypophosphatemia, nausea, rash, elevated lipase, elevated ALT, and anorexia.
The majority of AEs were grade 1 or 2. However, there were grade 3/4 cases of anemia, diarrhea, elevated AST, and hypophosphatemia. And elevated lipase—the asymptomatic, dose-limiting toxicity for which the protocol was modified—consisted entirely of grade 3 or 4 events.
Episodes of neutropenia and thrombocytopenia occurred in 1 patient each, and both were grade 1.
“So [TAK-659] seems quite well tolerated in that regard as well,” Dr Petrich observed.
The plasma profile on days 1 and 15 of cycle 1 indicate that PK steady-state conditions are generally achieved by day 8, with moderate accumulation after repeated, once-daily dosing for 15 days.
Antitumor activity
Of the 12 evaluable patients, 5 had tumor shrinkage at the 60, 80, or 100 mg dose levels. Three of the 6 DLBCL patients experienced tumor shrinkage, and there were “2 dramatic responses in patients with follicular lymphoma, including 1 CR [complete response],” Dr Petrich said.
One of these FL patients had an aggressive phenotype and never had a previous response last longer than 20 months.
“[H]e actually achieved a CR within 2 cycles—a dramatic response for his disease—and he remains on treatment, and he’s up to cycle 5 now,” Dr Petrich said.
The team concluded that the PK data support daily dosing, despite lower clearance than originally predicted.
“[There is] good early evidence of antitumor activity and no significant safety signals,” Dr Petrich said. “And the [hematologic] toxicity profile, in particular, seems to suggest this is a well-tolerated drug.”
The investigators are conducting expansion cohorts and are considering future combination studies. They recently activated a study in acute myeloid leukemia because TAK-659 has FLT3 inhibitory properties.
*Information in the abstract differs from that presented at the meeting.
PI3K inhibitors may promote cancer spread
Photo courtesy of
The Wistar Institute
Although PI3K inhibitors have been designed to treat cancer, new research indicates these drugs may actually exacerbate the disease.
Researchers found evidence to suggest that treatment with PI3K inhibitors alone can promote more aggressive tumor cell behavior and increase the likelihood that cancer will spread.
PI3K inhibitors appeared to reprogram the mitochondria of tumor cells and move them to “strategic” positions for invasion.
However, the researchers believe that targeting mitochondrial function along with PI3K could prevent this effect.
Dario C. Altieri, MD, of The Wistar Institute in Philadelphia, Pennsylvania, and his colleagues described these findings in PNAS.
The researchers decided to investigate how mitochondria are reprogrammed when exposed to PI3K inhibition and how mitochondria might prevent targeted agents from being as effective as expected.
“Our prior studies have confirmed that tumor cells rely on energy produced by mitochondria more significantly than previously thought,” Dr Altieri said.
“What we have shown in this study is that, in somewhat of a paradox, treatment with a PI3K inhibitor causes a tumor cell’s mitochondria to produce energy in a localized manner, promoting a far more aggressive and invasive phenotype. The treatment appears to be doing the opposite of its intended effect.”
The study showed that treatment with a PI3K inhibitor causes the mitochondria to migrate to the peripheral cytoskeleton of the tumor cells.
While the mitochondria in untreated cells cluster around the cell’s nucleus, exposure of tumor cells to PI3K therapy causes the mitochondria to move to specialized regions of the cell’s membrane implicated in cell motility and invasion.
In this “strategic” position, tumor mitochondria are ideally positioned to provide a concentrated source of energy to support an increase in cell migration and invasion.
However, the researchers said the dependence of this response on mitochondrial function may offer a new therapeutic angle.
Dr Altieri and his team have shown that targeting mitochondrial functions for tumor therapy is feasible and dramatically enhances the anticancer activity of PI3K inhibitors when used in combination.
“These findings continue to support the idea that the mitochondria of tumor cells are crucial to tumor survival and proliferation,” Dr Altieri said. “It’s certainly counterintuitive that a drug designed to fight cancer may in actuality help it spread, but by identifying why this is happening, we can develop better strategies that allow these drugs to treat tumors the way they should.”
Photo courtesy of
The Wistar Institute
Although PI3K inhibitors have been designed to treat cancer, new research indicates these drugs may actually exacerbate the disease.
Researchers found evidence to suggest that treatment with PI3K inhibitors alone can promote more aggressive tumor cell behavior and increase the likelihood that cancer will spread.
PI3K inhibitors appeared to reprogram the mitochondria of tumor cells and move them to “strategic” positions for invasion.
However, the researchers believe that targeting mitochondrial function along with PI3K could prevent this effect.
Dario C. Altieri, MD, of The Wistar Institute in Philadelphia, Pennsylvania, and his colleagues described these findings in PNAS.
The researchers decided to investigate how mitochondria are reprogrammed when exposed to PI3K inhibition and how mitochondria might prevent targeted agents from being as effective as expected.
“Our prior studies have confirmed that tumor cells rely on energy produced by mitochondria more significantly than previously thought,” Dr Altieri said.
“What we have shown in this study is that, in somewhat of a paradox, treatment with a PI3K inhibitor causes a tumor cell’s mitochondria to produce energy in a localized manner, promoting a far more aggressive and invasive phenotype. The treatment appears to be doing the opposite of its intended effect.”
The study showed that treatment with a PI3K inhibitor causes the mitochondria to migrate to the peripheral cytoskeleton of the tumor cells.
While the mitochondria in untreated cells cluster around the cell’s nucleus, exposure of tumor cells to PI3K therapy causes the mitochondria to move to specialized regions of the cell’s membrane implicated in cell motility and invasion.
In this “strategic” position, tumor mitochondria are ideally positioned to provide a concentrated source of energy to support an increase in cell migration and invasion.
However, the researchers said the dependence of this response on mitochondrial function may offer a new therapeutic angle.
Dr Altieri and his team have shown that targeting mitochondrial functions for tumor therapy is feasible and dramatically enhances the anticancer activity of PI3K inhibitors when used in combination.
“These findings continue to support the idea that the mitochondria of tumor cells are crucial to tumor survival and proliferation,” Dr Altieri said. “It’s certainly counterintuitive that a drug designed to fight cancer may in actuality help it spread, but by identifying why this is happening, we can develop better strategies that allow these drugs to treat tumors the way they should.”
Photo courtesy of
The Wistar Institute
Although PI3K inhibitors have been designed to treat cancer, new research indicates these drugs may actually exacerbate the disease.
Researchers found evidence to suggest that treatment with PI3K inhibitors alone can promote more aggressive tumor cell behavior and increase the likelihood that cancer will spread.
PI3K inhibitors appeared to reprogram the mitochondria of tumor cells and move them to “strategic” positions for invasion.
However, the researchers believe that targeting mitochondrial function along with PI3K could prevent this effect.
Dario C. Altieri, MD, of The Wistar Institute in Philadelphia, Pennsylvania, and his colleagues described these findings in PNAS.
The researchers decided to investigate how mitochondria are reprogrammed when exposed to PI3K inhibition and how mitochondria might prevent targeted agents from being as effective as expected.
“Our prior studies have confirmed that tumor cells rely on energy produced by mitochondria more significantly than previously thought,” Dr Altieri said.
“What we have shown in this study is that, in somewhat of a paradox, treatment with a PI3K inhibitor causes a tumor cell’s mitochondria to produce energy in a localized manner, promoting a far more aggressive and invasive phenotype. The treatment appears to be doing the opposite of its intended effect.”
The study showed that treatment with a PI3K inhibitor causes the mitochondria to migrate to the peripheral cytoskeleton of the tumor cells.
While the mitochondria in untreated cells cluster around the cell’s nucleus, exposure of tumor cells to PI3K therapy causes the mitochondria to move to specialized regions of the cell’s membrane implicated in cell motility and invasion.
In this “strategic” position, tumor mitochondria are ideally positioned to provide a concentrated source of energy to support an increase in cell migration and invasion.
However, the researchers said the dependence of this response on mitochondrial function may offer a new therapeutic angle.
Dr Altieri and his team have shown that targeting mitochondrial functions for tumor therapy is feasible and dramatically enhances the anticancer activity of PI3K inhibitors when used in combination.
“These findings continue to support the idea that the mitochondria of tumor cells are crucial to tumor survival and proliferation,” Dr Altieri said. “It’s certainly counterintuitive that a drug designed to fight cancer may in actuality help it spread, but by identifying why this is happening, we can develop better strategies that allow these drugs to treat tumors the way they should.”
Inhibitors increase burden of hemophilia care
TORONTO—When children with hemophilia develop inhibitors, their caregivers shoulder a greater burden, according to a pilot study.
Researchers surveyed 40 subjects on the burden of caring for a child with hemophilia and found that inhibitor development significantly increased the burden of care.
But other factors—such as the number of bleeds a child had experienced in the last 12 months—had no significant impact.
Sylvia von Mackensen, PhD, of the University Medical Centre Hamburg-Eppendorf in Hamburg, Germany, and her colleagues presented these findings at the ISTH 2015 Congress (abstract PO256-WED).
The study was a pilot test of the HEMOCAB questionnaire, which consists of 59 questions mapped to 13 domains. Caregivers were asked to select the response that best qualified their burden and were scored on a scale of 0 to 100, with higher values corresponding with greater burden.
Forty caregivers completed the questionnaire. All of them had children with hemophilia (n=40), with or without inhibitors, who were younger than 22 years of age.
Three-quarters of the caregivers were mothers, 17.5% were fathers, and 7.5% were grandmothers. The mean age of caregivers was 39.32 ± 8.9 years (range, 27-66), and the mean age of the hemophilia patients was 10.98 ± 5.5 years (range, 1-21).
Most of the patients had hemophilia A (95%), and most had severe disease (77.5%). Six children (15%) had inhibitors. Overall, patients had experienced an average of 4.83 ±8.9 bleeds (range, 0-52) in the previous 12 months.
Most of the patients (88.5%) were receiving prophylaxis. Caregivers said they spent 8.69 ± 7.7 hours per month on infusion and 3.84 ± 6.7 hours (range, 0-30) per month traveling to hemophilia treatment facilities.
Size of burden
Caregivers said the most burdensome aspects of care were the caregivers’ perception of the child (38%), emotional stress (36%), financial burden (34%), and the impact of care on the caregiver (31%).
For nearly all of the domains assessed—emotional stress, personal sacrifice, medical management, work situation, etc.—a caregivers’ burden was significantly higher if a child had inhibitors. The only exception was school-related burden.
When the researchers analyzed the impact of other factors on care burden, they found that only inhibitor development had a significant impact.
There was no impact for orthopedic joint score, age of the caregiver, age of the child, time for infusion, time traveling to a hemophilia treatment center, the number of bleeds in the past 12 months, the number of children with hemophilia per household, home treatment, caregiver marital status, location, or caregiver education.
Frequency of burden
The HEMOCAB questionnaire also included scales assessing the frequency of burden. Dr von Mackensen and her colleagues presented data from these scales for the caregivers’ perception of their child, emotional stress, and finances.
Sixty percent of caregivers said they sometimes, often, or always feel their child’s condition is a difficult situation. Seventy-three percent of caregivers expressed feelings of sadness about informing their child of what he can and cannot do due to his illness.
Seventy-four percent of caregivers said they sometimes, often, or always feel afraid their child might get injured when they are not around to help. Forty-six percent of caregivers reported feeling afraid their child’s condition might worsen, and 36% said they feared their child might die from his condition.
Forty-six percent of caregivers said their child’s hemophilia sometimes, often, or always causes financial problems. And 33% of caregivers said that, at least sometimes, their family does not have enough money because of their child’s hemophilia.
HEMOCAB is a trademark of Novo Nordisk Health Care AG. Dr von Mackensen received a consulting fee from Novo Nordisk for developing the HEMOCAB questionnaire. Leonard A. Valentino, MD, of Rush University Medical Center in Chicago, Illinois, was involved in developing the questionnaire as well but did not participate in the pilot study.
The other researchers involved in the study have received funding/consulting fees from—or are employees of—Novo Nordisk, Baxter, Bayer, OctaPharma, CSL Behring, OPKO Health, and Selexys.
TORONTO—When children with hemophilia develop inhibitors, their caregivers shoulder a greater burden, according to a pilot study.
Researchers surveyed 40 subjects on the burden of caring for a child with hemophilia and found that inhibitor development significantly increased the burden of care.
But other factors—such as the number of bleeds a child had experienced in the last 12 months—had no significant impact.
Sylvia von Mackensen, PhD, of the University Medical Centre Hamburg-Eppendorf in Hamburg, Germany, and her colleagues presented these findings at the ISTH 2015 Congress (abstract PO256-WED).
The study was a pilot test of the HEMOCAB questionnaire, which consists of 59 questions mapped to 13 domains. Caregivers were asked to select the response that best qualified their burden and were scored on a scale of 0 to 100, with higher values corresponding with greater burden.
Forty caregivers completed the questionnaire. All of them had children with hemophilia (n=40), with or without inhibitors, who were younger than 22 years of age.
Three-quarters of the caregivers were mothers, 17.5% were fathers, and 7.5% were grandmothers. The mean age of caregivers was 39.32 ± 8.9 years (range, 27-66), and the mean age of the hemophilia patients was 10.98 ± 5.5 years (range, 1-21).
Most of the patients had hemophilia A (95%), and most had severe disease (77.5%). Six children (15%) had inhibitors. Overall, patients had experienced an average of 4.83 ±8.9 bleeds (range, 0-52) in the previous 12 months.
Most of the patients (88.5%) were receiving prophylaxis. Caregivers said they spent 8.69 ± 7.7 hours per month on infusion and 3.84 ± 6.7 hours (range, 0-30) per month traveling to hemophilia treatment facilities.
Size of burden
Caregivers said the most burdensome aspects of care were the caregivers’ perception of the child (38%), emotional stress (36%), financial burden (34%), and the impact of care on the caregiver (31%).
For nearly all of the domains assessed—emotional stress, personal sacrifice, medical management, work situation, etc.—a caregivers’ burden was significantly higher if a child had inhibitors. The only exception was school-related burden.
When the researchers analyzed the impact of other factors on care burden, they found that only inhibitor development had a significant impact.
There was no impact for orthopedic joint score, age of the caregiver, age of the child, time for infusion, time traveling to a hemophilia treatment center, the number of bleeds in the past 12 months, the number of children with hemophilia per household, home treatment, caregiver marital status, location, or caregiver education.
Frequency of burden
The HEMOCAB questionnaire also included scales assessing the frequency of burden. Dr von Mackensen and her colleagues presented data from these scales for the caregivers’ perception of their child, emotional stress, and finances.
Sixty percent of caregivers said they sometimes, often, or always feel their child’s condition is a difficult situation. Seventy-three percent of caregivers expressed feelings of sadness about informing their child of what he can and cannot do due to his illness.
Seventy-four percent of caregivers said they sometimes, often, or always feel afraid their child might get injured when they are not around to help. Forty-six percent of caregivers reported feeling afraid their child’s condition might worsen, and 36% said they feared their child might die from his condition.
Forty-six percent of caregivers said their child’s hemophilia sometimes, often, or always causes financial problems. And 33% of caregivers said that, at least sometimes, their family does not have enough money because of their child’s hemophilia.
HEMOCAB is a trademark of Novo Nordisk Health Care AG. Dr von Mackensen received a consulting fee from Novo Nordisk for developing the HEMOCAB questionnaire. Leonard A. Valentino, MD, of Rush University Medical Center in Chicago, Illinois, was involved in developing the questionnaire as well but did not participate in the pilot study.
The other researchers involved in the study have received funding/consulting fees from—or are employees of—Novo Nordisk, Baxter, Bayer, OctaPharma, CSL Behring, OPKO Health, and Selexys.
TORONTO—When children with hemophilia develop inhibitors, their caregivers shoulder a greater burden, according to a pilot study.
Researchers surveyed 40 subjects on the burden of caring for a child with hemophilia and found that inhibitor development significantly increased the burden of care.
But other factors—such as the number of bleeds a child had experienced in the last 12 months—had no significant impact.
Sylvia von Mackensen, PhD, of the University Medical Centre Hamburg-Eppendorf in Hamburg, Germany, and her colleagues presented these findings at the ISTH 2015 Congress (abstract PO256-WED).
The study was a pilot test of the HEMOCAB questionnaire, which consists of 59 questions mapped to 13 domains. Caregivers were asked to select the response that best qualified their burden and were scored on a scale of 0 to 100, with higher values corresponding with greater burden.
Forty caregivers completed the questionnaire. All of them had children with hemophilia (n=40), with or without inhibitors, who were younger than 22 years of age.
Three-quarters of the caregivers were mothers, 17.5% were fathers, and 7.5% were grandmothers. The mean age of caregivers was 39.32 ± 8.9 years (range, 27-66), and the mean age of the hemophilia patients was 10.98 ± 5.5 years (range, 1-21).
Most of the patients had hemophilia A (95%), and most had severe disease (77.5%). Six children (15%) had inhibitors. Overall, patients had experienced an average of 4.83 ±8.9 bleeds (range, 0-52) in the previous 12 months.
Most of the patients (88.5%) were receiving prophylaxis. Caregivers said they spent 8.69 ± 7.7 hours per month on infusion and 3.84 ± 6.7 hours (range, 0-30) per month traveling to hemophilia treatment facilities.
Size of burden
Caregivers said the most burdensome aspects of care were the caregivers’ perception of the child (38%), emotional stress (36%), financial burden (34%), and the impact of care on the caregiver (31%).
For nearly all of the domains assessed—emotional stress, personal sacrifice, medical management, work situation, etc.—a caregivers’ burden was significantly higher if a child had inhibitors. The only exception was school-related burden.
When the researchers analyzed the impact of other factors on care burden, they found that only inhibitor development had a significant impact.
There was no impact for orthopedic joint score, age of the caregiver, age of the child, time for infusion, time traveling to a hemophilia treatment center, the number of bleeds in the past 12 months, the number of children with hemophilia per household, home treatment, caregiver marital status, location, or caregiver education.
Frequency of burden
The HEMOCAB questionnaire also included scales assessing the frequency of burden. Dr von Mackensen and her colleagues presented data from these scales for the caregivers’ perception of their child, emotional stress, and finances.
Sixty percent of caregivers said they sometimes, often, or always feel their child’s condition is a difficult situation. Seventy-three percent of caregivers expressed feelings of sadness about informing their child of what he can and cannot do due to his illness.
Seventy-four percent of caregivers said they sometimes, often, or always feel afraid their child might get injured when they are not around to help. Forty-six percent of caregivers reported feeling afraid their child’s condition might worsen, and 36% said they feared their child might die from his condition.
Forty-six percent of caregivers said their child’s hemophilia sometimes, often, or always causes financial problems. And 33% of caregivers said that, at least sometimes, their family does not have enough money because of their child’s hemophilia.
HEMOCAB is a trademark of Novo Nordisk Health Care AG. Dr von Mackensen received a consulting fee from Novo Nordisk for developing the HEMOCAB questionnaire. Leonard A. Valentino, MD, of Rush University Medical Center in Chicago, Illinois, was involved in developing the questionnaire as well but did not participate in the pilot study.
The other researchers involved in the study have received funding/consulting fees from—or are employees of—Novo Nordisk, Baxter, Bayer, OctaPharma, CSL Behring, OPKO Health, and Selexys.
HSCT outcomes ‘encouraging’ in JAKi responders
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 JAK2V617F-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.
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 JAK2V617F-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.
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 JAK2V617F-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.
Pain problems prevalent in adults with hemophilia
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.
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.
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.
PI3Kδ/γ inhibitor generates rapid responses in 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.
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.
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.
Mutations linked to response, survival in aplastic anemia
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.
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.
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.