Children with asthma who present to emergency departments for treatment are significantly more likely to test positive for one or more respiratory pathogens, reported Dr. Joanna Merckx of the Montreal Children’s Hospital at the McGill University Health Centre, and her associates.

Nearly two-thirds of patients tested positive for one or more respiratory viruses in a study conducted by Dr. Merckx and her associates. “Given the documented safety of influenza immunization in children with asthma and its expected protective effect,” such cases should be among those prioritized to receive influenza immunization.

nata_zhekova/Thinkstock

A separate study cited by Dr. Merckx and her associates observed the same outcome for rhinovirus patients but more patients diagnosed with nonrhinovirus pathogens, especially human metapneumovirus (hMPV) and PIV, had moderate, rather than severe, symptoms and were much more likely to experience higher treatment failure, particularly those infected with RSV, influenza, and PIV.

“It appears reasonable to pursue strategies to improve immunization coverage for influenza and invest in efforts for the development of vaccines for RSV and rhinovirus,” they said.

In cases in which respiratory pathogens were present (especially nonrhinovirus pathogens), greater treatment failure occurred, despite use of inhaler and corticosteroids. The researchers noted that severity of condition at time of treatment and patient response to treatment should be considered as two separate, distinct dimensions of viral infection impact in children with acute asthma. “The high prevalence of rhinovirus C in children presenting with asthma exacerbation, its presumed association with asthma-related hospitalization, and its peak in the fall,” also should be considered as a leading cause for more potential severe disease.

Dr. Merckx and her associates did point to several possibly significant implications with their findings. Intensifying treatment using inhaled anticholinergics or magnesium sulfate could block the vagally mediated reflex bronchoconstriction typically seen in cases of asthma exacerbation worsened by viral infection. Although these therapies currently only are used only in severe reactions, it may be useful to examine their efficacy in any cases triggered by RSV, influenza, and PIV because these have been associated with a poor treatment response.

While it still is necessary to clarify its mechanism of action, azithromycin’s demonstrated benefit in preschoolers with severe reactions suggests it could be a possible alternative pathogen–nonspecific therapy to address antineutrophilic inflammation, they said.

Any treatment intensification would first require clear identification of responsible pathogens using on-site diagnostic measures in the ED. Until such testing is possible, preventive measures need to be prioritized, they advised.

Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.

SOURCE: Merckx J et al. Pediatrics. 2018 Jun;142(1):e20174105.

Children with asthma who present to emergency departments for treatment are significantly more likely to test positive for one or more respiratory pathogens, reported Dr. Joanna Merckx of the Montreal Children’s Hospital at the McGill University Health Centre, and her associates.

Nearly two-thirds of patients tested positive for one or more respiratory viruses in a study conducted by Dr. Merckx and her associates. “Given the documented safety of influenza immunization in children with asthma and its expected protective effect,” such cases should be among those prioritized to receive influenza immunization.

nata_zhekova/Thinkstock

A separate study cited by Dr. Merckx and her associates observed the same outcome for rhinovirus patients but more patients diagnosed with nonrhinovirus pathogens, especially human metapneumovirus (hMPV) and PIV, had moderate, rather than severe, symptoms and were much more likely to experience higher treatment failure, particularly those infected with RSV, influenza, and PIV.

“It appears reasonable to pursue strategies to improve immunization coverage for influenza and invest in efforts for the development of vaccines for RSV and rhinovirus,” they said.

In cases in which respiratory pathogens were present (especially nonrhinovirus pathogens), greater treatment failure occurred, despite use of inhaler and corticosteroids. The researchers noted that severity of condition at time of treatment and patient response to treatment should be considered as two separate, distinct dimensions of viral infection impact in children with acute asthma. “The high prevalence of rhinovirus C in children presenting with asthma exacerbation, its presumed association with asthma-related hospitalization, and its peak in the fall,” also should be considered as a leading cause for more potential severe disease.

Dr. Merckx and her associates did point to several possibly significant implications with their findings. Intensifying treatment using inhaled anticholinergics or magnesium sulfate could block the vagally mediated reflex bronchoconstriction typically seen in cases of asthma exacerbation worsened by viral infection. Although these therapies currently only are used only in severe reactions, it may be useful to examine their efficacy in any cases triggered by RSV, influenza, and PIV because these have been associated with a poor treatment response.

While it still is necessary to clarify its mechanism of action, azithromycin’s demonstrated benefit in preschoolers with severe reactions suggests it could be a possible alternative pathogen–nonspecific therapy to address antineutrophilic inflammation, they said.

Any treatment intensification would first require clear identification of responsible pathogens using on-site diagnostic measures in the ED. Until such testing is possible, preventive measures need to be prioritized, they advised.

Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.

SOURCE: Merckx J et al. Pediatrics. 2018 Jun;142(1):e20174105.

Children with asthma who present to emergency departments for treatment are significantly more likely to test positive for one or more respiratory pathogens, reported Dr. Joanna Merckx of the Montreal Children’s Hospital at the McGill University Health Centre, and her associates.

Nearly two-thirds of patients tested positive for one or more respiratory viruses in a study conducted by Dr. Merckx and her associates. “Given the documented safety of influenza immunization in children with asthma and its expected protective effect,” such cases should be among those prioritized to receive influenza immunization.

nata_zhekova/Thinkstock

A separate study cited by Dr. Merckx and her associates observed the same outcome for rhinovirus patients but more patients diagnosed with nonrhinovirus pathogens, especially human metapneumovirus (hMPV) and PIV, had moderate, rather than severe, symptoms and were much more likely to experience higher treatment failure, particularly those infected with RSV, influenza, and PIV.

“It appears reasonable to pursue strategies to improve immunization coverage for influenza and invest in efforts for the development of vaccines for RSV and rhinovirus,” they said.

In cases in which respiratory pathogens were present (especially nonrhinovirus pathogens), greater treatment failure occurred, despite use of inhaler and corticosteroids. The researchers noted that severity of condition at time of treatment and patient response to treatment should be considered as two separate, distinct dimensions of viral infection impact in children with acute asthma. “The high prevalence of rhinovirus C in children presenting with asthma exacerbation, its presumed association with asthma-related hospitalization, and its peak in the fall,” also should be considered as a leading cause for more potential severe disease.

Dr. Merckx and her associates did point to several possibly significant implications with their findings. Intensifying treatment using inhaled anticholinergics or magnesium sulfate could block the vagally mediated reflex bronchoconstriction typically seen in cases of asthma exacerbation worsened by viral infection. Although these therapies currently only are used only in severe reactions, it may be useful to examine their efficacy in any cases triggered by RSV, influenza, and PIV because these have been associated with a poor treatment response.

While it still is necessary to clarify its mechanism of action, azithromycin’s demonstrated benefit in preschoolers with severe reactions suggests it could be a possible alternative pathogen–nonspecific therapy to address antineutrophilic inflammation, they said.

Any treatment intensification would first require clear identification of responsible pathogens using on-site diagnostic measures in the ED. Until such testing is possible, preventive measures need to be prioritized, they advised.

Dr. Merckx had no relevant disclosures; two of her associates reported receiving grants, salary rewards, and/or unrestricted donations from various pharmaceutical companies or foundations.

SOURCE: Merckx J et al. Pediatrics. 2018 Jun;142(1):e20174105.

There is growing literature around clonal hematopoiesis (CH) but many questions persist about its clinical significance. On June 14, Hematology News hosted a Twitter question-and-answer session with Aaron Viny, MD, who is on the staff of the leukemia service at Memorial Sloan Kettering Cancer Center in New York and is a member of the Hematology News editorial advisory board, to answer questions about CH and interpret the latest research. The following is an edited version of the Q&A session.

Question: Can you get us started by explaining the difference between clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance?

Question: So are there differences in CH depending on the gene mutated?

Dr. Viny: Hard to say. The most common mutations found in CH are DNMT3A, TET2, PPM1D, and ASXL1, as shown in the Cell Stem Cell paper by Catherine C. Coombs, MD, and Ross Levine, MD (2017 Sep 7;21[3]:374-82.e4). So in the setting of patients with acute myeloid leukemia, there are data from several groups showing that persistence of DNMT3A, TET2, and ASXL1 have less recurrence risk, compared with the field. This, of course, does not apply to CH in the absence of a hematologic disorder.

Question: Are you aware of any screening programs for clonal hematopoiesis?

Dr. Viny: Currently at Memorial Sloan Kettering, patients who undergo MSK-IMPACT testing of their solid tumor have a germ line control from blood that is also sequenced. These samples are screened for CH mutations. In fact, there are two recent papers showing one key issue with tumor sequencing and CH: A blood sample is necessary to resolve the compartment of the CH mutation (that is, not in the solid tumor). The papers are JAMA Oncol. 2018 Jun 5. doi: 10.1001/jamaoncol.2018.2297 and Clin Cancer Res. 2018 Jun 4. doi: 10.1158/1078-0432.CCR-18-1201.

Question: Will patients with CH in screened samples be notified of the results?

Dr. Viny: Yes. The patients are being referred to the Memorial Sloan Kettering clonal hematopoiesis clinic run by Dr. Levine and Kelly Bolton, MD.

Question: Once you screen and detect CH, how should these patients be followed?

Dr. Viny: First, what are the risks these patients face? Extensive work by Siddhartha Jaiswal, MD, PhD, shows that there is an increased risk of cardiovascular disease and an increased risk for leukemia. So with regards to the latter, following with serial complete blood counts seems sufficient, with a bone marrow biopsy at the detection of any cytopenias. With regard to cardiovascular risk, I consider CH akin to an unmodifiable cardiac risk factor. Patients should be counseled to exercise, and depending on any other cardiac risk factors, interventions such as blood pressure control, lipid control, and daily aspirin use should be addressed accordingly.

Question: Is this BRCA1 all over again?

Dr. Viny: Perhaps. With BRCA1, we now have a few decades of follow-up to better understand the risks and even intervene with preventive interventions. Clonal hematopoiesis needs the follow-up and research to support clinical action.

Question: Could you please refer your readers to your favorite review on clonal hematopoiesis?

Dr. Viny: An outstanding review of the mechanisms and molecular consequences of clonal hematopoiesis is in Cell Stem Cell (2018 Feb 1;22[2]:157-70).

Question: Are there any effects of previous radiation on the development of CH?

Dr. Viny: Let’s start by saying that CH in the absence of prior cancer is probably a different entity. Radiation, tobacco use, and increased age all increase the risk for detection of a CH somatic mutation.

Question: What are the clinical implications of CH?

Dr. Viny: While I think it is still too soon to say if these are the only clinical implications, both increased risk of hematologic malignancy and increased risk of cardiovascular disease are the best studied and described to date. Here’s an excellent article on the cardiovascular risk: N Engl J Med. 2017 Jul 13;377(2):111-21. Of interest, it seems that the increased risk, while being relatively low, does not plateau over time.

Question: What do you think about TET2 mutations being among the most frequent mutations in CH, but IDH being relatively rare?

Dr. Viny: Great question. Both are affecting demethylation and epigenetic instability. While I don’t think the answer is known, perhaps the IDH mutations have a more dominant effect on hematopoietic output. The majority of the CH data uses blood; maybe the marrow tells a different story.

Question: Can we cure clonal hematopoiesis with vitamin C?

Dr. Viny: You clearly know the recent work by Iannis Aifantis, PhD, showing the effects of vitamin C on TET enzyme activity, published here: Cell. 2017 Sep 7;170(6):1079-95. For CH patients with TET2 mutations, a high-dose vitamin C regimen sounds very exciting. There is also complementary work by Sean Morrison, PhD, published in Nature (2017 Sep 28;549[7673]:476-81).

Question: Is there a limit to the sequencing depth and variant allele fraction needed to identify clonal hematopoiesis? At what point is CH not CH?

Dr. Viny: So this is as much a technical question as it is a biological question. As of now we can reliably detect variant allele fraction in CH to 0.1%, at best. What is detectable and what is clinically relevant are questions that still need to be answered.

Question: There seems to be a lot of good research going on in CH. What are the big knowledge gaps that future studies should be targeting?

Dr. Viny: First, what are the functional and molecular consequences of the varying alleles in CH? Second, are there other clinical risks to CH beyond leukemia and cardiovascular disease? And third, does inflammation cause CH or does CH cause inflammation?

Dr. Viny is with the Memorial Sloan Kettering Cancer Center, New York, where he is a clinical instructor; is on the staff of the leukemia service; and is a clinical researcher in the Ross Levine Lab. Connect with him on Twitter at @TheDoctorIsVin.

There is growing literature around clonal hematopoiesis (CH) but many questions persist about its clinical significance. On June 14, Hematology News hosted a Twitter question-and-answer session with Aaron Viny, MD, who is on the staff of the leukemia service at Memorial Sloan Kettering Cancer Center in New York and is a member of the Hematology News editorial advisory board, to answer questions about CH and interpret the latest research. The following is an edited version of the Q&A session.

Question: Can you get us started by explaining the difference between clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance?

Question: So are there differences in CH depending on the gene mutated?

Dr. Viny: Hard to say. The most common mutations found in CH are DNMT3A, TET2, PPM1D, and ASXL1, as shown in the Cell Stem Cell paper by Catherine C. Coombs, MD, and Ross Levine, MD (2017 Sep 7;21[3]:374-82.e4). So in the setting of patients with acute myeloid leukemia, there are data from several groups showing that persistence of DNMT3A, TET2, and ASXL1 have less recurrence risk, compared with the field. This, of course, does not apply to CH in the absence of a hematologic disorder.

Question: Are you aware of any screening programs for clonal hematopoiesis?

Dr. Viny: Currently at Memorial Sloan Kettering, patients who undergo MSK-IMPACT testing of their solid tumor have a germ line control from blood that is also sequenced. These samples are screened for CH mutations. In fact, there are two recent papers showing one key issue with tumor sequencing and CH: A blood sample is necessary to resolve the compartment of the CH mutation (that is, not in the solid tumor). The papers are JAMA Oncol. 2018 Jun 5. doi: 10.1001/jamaoncol.2018.2297 and Clin Cancer Res. 2018 Jun 4. doi: 10.1158/1078-0432.CCR-18-1201.

Question: Will patients with CH in screened samples be notified of the results?

Dr. Viny: Yes. The patients are being referred to the Memorial Sloan Kettering clonal hematopoiesis clinic run by Dr. Levine and Kelly Bolton, MD.

Question: Once you screen and detect CH, how should these patients be followed?

Dr. Viny: First, what are the risks these patients face? Extensive work by Siddhartha Jaiswal, MD, PhD, shows that there is an increased risk of cardiovascular disease and an increased risk for leukemia. So with regards to the latter, following with serial complete blood counts seems sufficient, with a bone marrow biopsy at the detection of any cytopenias. With regard to cardiovascular risk, I consider CH akin to an unmodifiable cardiac risk factor. Patients should be counseled to exercise, and depending on any other cardiac risk factors, interventions such as blood pressure control, lipid control, and daily aspirin use should be addressed accordingly.

Question: Is this BRCA1 all over again?

Dr. Viny: Perhaps. With BRCA1, we now have a few decades of follow-up to better understand the risks and even intervene with preventive interventions. Clonal hematopoiesis needs the follow-up and research to support clinical action.

Question: Could you please refer your readers to your favorite review on clonal hematopoiesis?

Dr. Viny: An outstanding review of the mechanisms and molecular consequences of clonal hematopoiesis is in Cell Stem Cell (2018 Feb 1;22[2]:157-70).

Question: Are there any effects of previous radiation on the development of CH?

Dr. Viny: Let’s start by saying that CH in the absence of prior cancer is probably a different entity. Radiation, tobacco use, and increased age all increase the risk for detection of a CH somatic mutation.

Question: What are the clinical implications of CH?

Dr. Viny: While I think it is still too soon to say if these are the only clinical implications, both increased risk of hematologic malignancy and increased risk of cardiovascular disease are the best studied and described to date. Here’s an excellent article on the cardiovascular risk: N Engl J Med. 2017 Jul 13;377(2):111-21. Of interest, it seems that the increased risk, while being relatively low, does not plateau over time.

Question: What do you think about TET2 mutations being among the most frequent mutations in CH, but IDH being relatively rare?

Dr. Viny: Great question. Both are affecting demethylation and epigenetic instability. While I don’t think the answer is known, perhaps the IDH mutations have a more dominant effect on hematopoietic output. The majority of the CH data uses blood; maybe the marrow tells a different story.

Question: Can we cure clonal hematopoiesis with vitamin C?

Dr. Viny: You clearly know the recent work by Iannis Aifantis, PhD, showing the effects of vitamin C on TET enzyme activity, published here: Cell. 2017 Sep 7;170(6):1079-95. For CH patients with TET2 mutations, a high-dose vitamin C regimen sounds very exciting. There is also complementary work by Sean Morrison, PhD, published in Nature (2017 Sep 28;549[7673]:476-81).

Question: Is there a limit to the sequencing depth and variant allele fraction needed to identify clonal hematopoiesis? At what point is CH not CH?

Dr. Viny: So this is as much a technical question as it is a biological question. As of now we can reliably detect variant allele fraction in CH to 0.1%, at best. What is detectable and what is clinically relevant are questions that still need to be answered.

Question: There seems to be a lot of good research going on in CH. What are the big knowledge gaps that future studies should be targeting?

Dr. Viny: First, what are the functional and molecular consequences of the varying alleles in CH? Second, are there other clinical risks to CH beyond leukemia and cardiovascular disease? And third, does inflammation cause CH or does CH cause inflammation?

Dr. Viny is with the Memorial Sloan Kettering Cancer Center, New York, where he is a clinical instructor; is on the staff of the leukemia service; and is a clinical researcher in the Ross Levine Lab. Connect with him on Twitter at @TheDoctorIsVin.

There is growing literature around clonal hematopoiesis (CH) but many questions persist about its clinical significance. On June 14, Hematology News hosted a Twitter question-and-answer session with Aaron Viny, MD, who is on the staff of the leukemia service at Memorial Sloan Kettering Cancer Center in New York and is a member of the Hematology News editorial advisory board, to answer questions about CH and interpret the latest research. The following is an edited version of the Q&A session.

Question: Can you get us started by explaining the difference between clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance?

Question: So are there differences in CH depending on the gene mutated?

Dr. Viny: Hard to say. The most common mutations found in CH are DNMT3A, TET2, PPM1D, and ASXL1, as shown in the Cell Stem Cell paper by Catherine C. Coombs, MD, and Ross Levine, MD (2017 Sep 7;21[3]:374-82.e4). So in the setting of patients with acute myeloid leukemia, there are data from several groups showing that persistence of DNMT3A, TET2, and ASXL1 have less recurrence risk, compared with the field. This, of course, does not apply to CH in the absence of a hematologic disorder.

Question: Are you aware of any screening programs for clonal hematopoiesis?

Dr. Viny: Currently at Memorial Sloan Kettering, patients who undergo MSK-IMPACT testing of their solid tumor have a germ line control from blood that is also sequenced. These samples are screened for CH mutations. In fact, there are two recent papers showing one key issue with tumor sequencing and CH: A blood sample is necessary to resolve the compartment of the CH mutation (that is, not in the solid tumor). The papers are JAMA Oncol. 2018 Jun 5. doi: 10.1001/jamaoncol.2018.2297 and Clin Cancer Res. 2018 Jun 4. doi: 10.1158/1078-0432.CCR-18-1201.

Question: Will patients with CH in screened samples be notified of the results?

Dr. Viny: Yes. The patients are being referred to the Memorial Sloan Kettering clonal hematopoiesis clinic run by Dr. Levine and Kelly Bolton, MD.

Question: Once you screen and detect CH, how should these patients be followed?

Dr. Viny: First, what are the risks these patients face? Extensive work by Siddhartha Jaiswal, MD, PhD, shows that there is an increased risk of cardiovascular disease and an increased risk for leukemia. So with regards to the latter, following with serial complete blood counts seems sufficient, with a bone marrow biopsy at the detection of any cytopenias. With regard to cardiovascular risk, I consider CH akin to an unmodifiable cardiac risk factor. Patients should be counseled to exercise, and depending on any other cardiac risk factors, interventions such as blood pressure control, lipid control, and daily aspirin use should be addressed accordingly.

Question: Is this BRCA1 all over again?

Dr. Viny: Perhaps. With BRCA1, we now have a few decades of follow-up to better understand the risks and even intervene with preventive interventions. Clonal hematopoiesis needs the follow-up and research to support clinical action.

Question: Could you please refer your readers to your favorite review on clonal hematopoiesis?

Dr. Viny: An outstanding review of the mechanisms and molecular consequences of clonal hematopoiesis is in Cell Stem Cell (2018 Feb 1;22[2]:157-70).

Question: Are there any effects of previous radiation on the development of CH?

Dr. Viny: Let’s start by saying that CH in the absence of prior cancer is probably a different entity. Radiation, tobacco use, and increased age all increase the risk for detection of a CH somatic mutation.

Question: What are the clinical implications of CH?

Dr. Viny: While I think it is still too soon to say if these are the only clinical implications, both increased risk of hematologic malignancy and increased risk of cardiovascular disease are the best studied and described to date. Here’s an excellent article on the cardiovascular risk: N Engl J Med. 2017 Jul 13;377(2):111-21. Of interest, it seems that the increased risk, while being relatively low, does not plateau over time.

Question: What do you think about TET2 mutations being among the most frequent mutations in CH, but IDH being relatively rare?

Dr. Viny: Great question. Both are affecting demethylation and epigenetic instability. While I don’t think the answer is known, perhaps the IDH mutations have a more dominant effect on hematopoietic output. The majority of the CH data uses blood; maybe the marrow tells a different story.

Question: Can we cure clonal hematopoiesis with vitamin C?

Dr. Viny: You clearly know the recent work by Iannis Aifantis, PhD, showing the effects of vitamin C on TET enzyme activity, published here: Cell. 2017 Sep 7;170(6):1079-95. For CH patients with TET2 mutations, a high-dose vitamin C regimen sounds very exciting. There is also complementary work by Sean Morrison, PhD, published in Nature (2017 Sep 28;549[7673]:476-81).

Question: Is there a limit to the sequencing depth and variant allele fraction needed to identify clonal hematopoiesis? At what point is CH not CH?

Dr. Viny: So this is as much a technical question as it is a biological question. As of now we can reliably detect variant allele fraction in CH to 0.1%, at best. What is detectable and what is clinically relevant are questions that still need to be answered.

Question: There seems to be a lot of good research going on in CH. What are the big knowledge gaps that future studies should be targeting?

Dr. Viny: First, what are the functional and molecular consequences of the varying alleles in CH? Second, are there other clinical risks to CH beyond leukemia and cardiovascular disease? And third, does inflammation cause CH or does CH cause inflammation?

Dr. Viny is with the Memorial Sloan Kettering Cancer Center, New York, where he is a clinical instructor; is on the staff of the leukemia service; and is a clinical researcher in the Ross Levine Lab. Connect with him on Twitter at @TheDoctorIsVin.

NSAID use around the time of conception is associated with a high risk of miscarriage, and a statistically significant dose-response relationship in which the risk increased at a greater duration of exposure was established in a case-control study published in the American Journal of Obstetrics and Gynecology.

The cohorts in the study were NSAID users, acetaminophen-only users, and controls exposed to neither NSAIDs or acetaminophen. The reasoning for including the acetaminophen cohort is that the drug has a similar indication but does not inhibit prostaglandin biosynthesis, as NSAIDs do. Prostaglandin is important for implantation in early pregnancy. The basic facts of what NSAIDs do and how implantation works have led to theories about miscarriage risk, but previous studies have not been conclusive, said De-Kun Li, MD, PhD, of Kaiser Permanente, and his coauthors.

Denise Fulton/MDedge News

[email protected]

SOURCE: Li DK et al. Am J Obstet Gynecol. 2018 Jun. doi: 10.1016/j.ajog.2018.06.002.

NSAID use around the time of conception is associated with a high risk of miscarriage, and a statistically significant dose-response relationship in which the risk increased at a greater duration of exposure was established in a case-control study published in the American Journal of Obstetrics and Gynecology.

The cohorts in the study were NSAID users, acetaminophen-only users, and controls exposed to neither NSAIDs or acetaminophen. The reasoning for including the acetaminophen cohort is that the drug has a similar indication but does not inhibit prostaglandin biosynthesis, as NSAIDs do. Prostaglandin is important for implantation in early pregnancy. The basic facts of what NSAIDs do and how implantation works have led to theories about miscarriage risk, but previous studies have not been conclusive, said De-Kun Li, MD, PhD, of Kaiser Permanente, and his coauthors.

Denise Fulton/MDedge News

[email protected]

SOURCE: Li DK et al. Am J Obstet Gynecol. 2018 Jun. doi: 10.1016/j.ajog.2018.06.002.

NSAID use around the time of conception is associated with a high risk of miscarriage, and a statistically significant dose-response relationship in which the risk increased at a greater duration of exposure was established in a case-control study published in the American Journal of Obstetrics and Gynecology.

The cohorts in the study were NSAID users, acetaminophen-only users, and controls exposed to neither NSAIDs or acetaminophen. The reasoning for including the acetaminophen cohort is that the drug has a similar indication but does not inhibit prostaglandin biosynthesis, as NSAIDs do. Prostaglandin is important for implantation in early pregnancy. The basic facts of what NSAIDs do and how implantation works have led to theories about miscarriage risk, but previous studies have not been conclusive, said De-Kun Li, MD, PhD, of Kaiser Permanente, and his coauthors.

Denise Fulton/MDedge News

[email protected]

SOURCE: Li DK et al. Am J Obstet Gynecol. 2018 Jun. doi: 10.1016/j.ajog.2018.06.002.

CHICAGO – Analysis of U.S. national cancer registry data shows that, contrary to expectation, the use of Mohs micrographic surgery for treatment of melanoma in situ did not increase following adoption of the Affordable Care Act, Sean Condon, MD, reported at the annual meeting of the American College of Mohs Surgery.

Ditto for the use of Mohs in patients with the rare cutaneous malignancies for which published evidence clearly demonstrates Mohs outperforms wide local excision, which is employed seven times more frequently than Mohs in such situations.

Bruce Jancin/MDedge News

“These rare cutaneous malignancies were historically treated with wide local excision. However, numerous studies have lately shown that lower recurrence rates were found with Mohs compared with wide local excision,” Dr. Condon noted.

Nonetheless, the proportion of the rare cutaneous malignancies treated using Mohs was unaffected by implementation of the ACA. Nor was it influenced one way or the other by publication of the joint Mohs appropriate use criteria in 2012: The Mohs-treated proportion of such cases was 15.25% in 2010-2011 and 14.6% in 2013-2014.

Similarly, even though the appropriate use criteria identified melanoma in situ as Mohs appropriate, the proportion of those malignancies treated via Mohs was the same before and after the 2012 release of the criteria.

“It’s commonly thought that Mohs is overused. However, our study and our data clearly identify that Mohs is being underutilized for melanoma in situ and for rare cutaneous malignancies. This represents a knowledge gap for other specialties regarding best-practice therapy,” Dr. Condon said.

He and his coinvestigators searched for socioeconomic predictors of Mohs utilization by matching the nationally representative SEER data with U.S. census data. They examined the impact of three metrics: insurance status, income, and poverty. They found that low-income patients and those in the highest quartile of poverty were significantly less likely to have Mohs surgery for their melanoma in situ and rare cutaneous malignancies throughout the study years. Lack of health insurance had no impact on Mohs utilization for melanoma in situ but was independently associated with decreased likelihood of Mohs for the rare cutaneous malignancies. White patients were 2-fold to 2.4-fold more likely to have Mohs surgery for their rare cutaneous malignancies than were black patients.

“One can conclude that Mohs micrographic surgery may be skewed toward more affluent patients, and lower socioeconomic status areas have less Mohs access. So our data from this study support a role for targeted education and improved patient access to Mohs,” Dr. Condon said.

He noted that because the SEER registries don’t track squamous or basal cell carcinomas, it’s unknown whether Mohs is also underutilized for the higher-risk forms of these most common of all skin cancers.

Dr. Condon reported having no financial conflicts regarding his study, conducted free of commercial support.

[email protected]

CHICAGO – Analysis of U.S. national cancer registry data shows that, contrary to expectation, the use of Mohs micrographic surgery for treatment of melanoma in situ did not increase following adoption of the Affordable Care Act, Sean Condon, MD, reported at the annual meeting of the American College of Mohs Surgery.

Ditto for the use of Mohs in patients with the rare cutaneous malignancies for which published evidence clearly demonstrates Mohs outperforms wide local excision, which is employed seven times more frequently than Mohs in such situations.

Bruce Jancin/MDedge News

“These rare cutaneous malignancies were historically treated with wide local excision. However, numerous studies have lately shown that lower recurrence rates were found with Mohs compared with wide local excision,” Dr. Condon noted.

Nonetheless, the proportion of the rare cutaneous malignancies treated using Mohs was unaffected by implementation of the ACA. Nor was it influenced one way or the other by publication of the joint Mohs appropriate use criteria in 2012: The Mohs-treated proportion of such cases was 15.25% in 2010-2011 and 14.6% in 2013-2014.

Similarly, even though the appropriate use criteria identified melanoma in situ as Mohs appropriate, the proportion of those malignancies treated via Mohs was the same before and after the 2012 release of the criteria.

“It’s commonly thought that Mohs is overused. However, our study and our data clearly identify that Mohs is being underutilized for melanoma in situ and for rare cutaneous malignancies. This represents a knowledge gap for other specialties regarding best-practice therapy,” Dr. Condon said.

He and his coinvestigators searched for socioeconomic predictors of Mohs utilization by matching the nationally representative SEER data with U.S. census data. They examined the impact of three metrics: insurance status, income, and poverty. They found that low-income patients and those in the highest quartile of poverty were significantly less likely to have Mohs surgery for their melanoma in situ and rare cutaneous malignancies throughout the study years. Lack of health insurance had no impact on Mohs utilization for melanoma in situ but was independently associated with decreased likelihood of Mohs for the rare cutaneous malignancies. White patients were 2-fold to 2.4-fold more likely to have Mohs surgery for their rare cutaneous malignancies than were black patients.

“One can conclude that Mohs micrographic surgery may be skewed toward more affluent patients, and lower socioeconomic status areas have less Mohs access. So our data from this study support a role for targeted education and improved patient access to Mohs,” Dr. Condon said.

He noted that because the SEER registries don’t track squamous or basal cell carcinomas, it’s unknown whether Mohs is also underutilized for the higher-risk forms of these most common of all skin cancers.

Dr. Condon reported having no financial conflicts regarding his study, conducted free of commercial support.

[email protected]

CHICAGO – Analysis of U.S. national cancer registry data shows that, contrary to expectation, the use of Mohs micrographic surgery for treatment of melanoma in situ did not increase following adoption of the Affordable Care Act, Sean Condon, MD, reported at the annual meeting of the American College of Mohs Surgery.

Ditto for the use of Mohs in patients with the rare cutaneous malignancies for which published evidence clearly demonstrates Mohs outperforms wide local excision, which is employed seven times more frequently than Mohs in such situations.

Bruce Jancin/MDedge News

“These rare cutaneous malignancies were historically treated with wide local excision. However, numerous studies have lately shown that lower recurrence rates were found with Mohs compared with wide local excision,” Dr. Condon noted.

Nonetheless, the proportion of the rare cutaneous malignancies treated using Mohs was unaffected by implementation of the ACA. Nor was it influenced one way or the other by publication of the joint Mohs appropriate use criteria in 2012: The Mohs-treated proportion of such cases was 15.25% in 2010-2011 and 14.6% in 2013-2014.

Similarly, even though the appropriate use criteria identified melanoma in situ as Mohs appropriate, the proportion of those malignancies treated via Mohs was the same before and after the 2012 release of the criteria.

“It’s commonly thought that Mohs is overused. However, our study and our data clearly identify that Mohs is being underutilized for melanoma in situ and for rare cutaneous malignancies. This represents a knowledge gap for other specialties regarding best-practice therapy,” Dr. Condon said.

He and his coinvestigators searched for socioeconomic predictors of Mohs utilization by matching the nationally representative SEER data with U.S. census data. They examined the impact of three metrics: insurance status, income, and poverty. They found that low-income patients and those in the highest quartile of poverty were significantly less likely to have Mohs surgery for their melanoma in situ and rare cutaneous malignancies throughout the study years. Lack of health insurance had no impact on Mohs utilization for melanoma in situ but was independently associated with decreased likelihood of Mohs for the rare cutaneous malignancies. White patients were 2-fold to 2.4-fold more likely to have Mohs surgery for their rare cutaneous malignancies than were black patients.

“One can conclude that Mohs micrographic surgery may be skewed toward more affluent patients, and lower socioeconomic status areas have less Mohs access. So our data from this study support a role for targeted education and improved patient access to Mohs,” Dr. Condon said.

He noted that because the SEER registries don’t track squamous or basal cell carcinomas, it’s unknown whether Mohs is also underutilized for the higher-risk forms of these most common of all skin cancers.

Dr. Condon reported having no financial conflicts regarding his study, conducted free of commercial support.

[email protected]

Hospitalists are key players in improving hospital performance, but they may be overlooking a leading cause of morbidity and mortality, especially among older adults.

Research suggests that at the time of hospital admission, some 20%-50% of all patients are at risk for malnutrition or are malnourished, but only 7% of those patients are diagnosed during their stay, according to research cited in an abstract presented at HM17.¹

“Because individuals who are malnourished lack sufficient nutrients to promote healing and rehabilitation, and are at increased risk of medical complications, it can have a serious impact on patient safety indicators, such as rates of pressure ulcers, wound healing, and risk of falls,” said lead author Eleanor Fitall of Avalere Health. “Early identification and subsequent treatment of these patients is the best way to prevent this risk.”

To address the issue, Avalere Health and the Academy of Nutrition and Dietetics established the Malnutrition Quality Improvement Initiative (MQii), a multi-stakeholder effort to identify tools to support hospital-based care teams in improving malnutrition care quality. They developed a malnutrition Toolkit, which was piloted in 2016 and was shown to effectively improve malnutrition care.

“Since the poster presentation in May, we have successfully implemented the Toolkit at 50 hospitals via a multi-hospital Learning Collaborative,” Ms. Fitall said. They are now recruiting hospitals and health systems to participate in an expanded Learning Collaborative. Interested sites should contact the MQii team at [email protected].

“By supporting efforts to improve malnutrition care in the inpatient setting, hospitalists can help reduce the incidence of these problems as well as decrease rates of readmissions and reduce patient lengths of stay,” Ms. Fitall said. “Hospitalists are critical to addressing malnutrition care gaps in the hospital. Dietitians that have undertaken malnutrition quality improvement projects using the MQii Toolkit have found that they are most successful when hospitalists are actively engaged in the team, particularly when looking to improve the rate of malnutrition diagnosis. Hospitalists are ideally positioned to champion these efforts.”

Support for MQii was provided by Abbott, she said.
 

Reference

1. Fitall E, Bruno M, Jones K, Lynch J, Silver H, Godamunne K, Valladares A, Mitchell K. Malnutrition Care: “Low Hanging Fruit” for Hospitalist Clinical Performance Improvement [abstract]. J Hosp Med. 2017;12(suppl 2).

Hospitalists are key players in improving hospital performance, but they may be overlooking a leading cause of morbidity and mortality, especially among older adults.

Research suggests that at the time of hospital admission, some 20%-50% of all patients are at risk for malnutrition or are malnourished, but only 7% of those patients are diagnosed during their stay, according to research cited in an abstract presented at HM17.¹

“Because individuals who are malnourished lack sufficient nutrients to promote healing and rehabilitation, and are at increased risk of medical complications, it can have a serious impact on patient safety indicators, such as rates of pressure ulcers, wound healing, and risk of falls,” said lead author Eleanor Fitall of Avalere Health. “Early identification and subsequent treatment of these patients is the best way to prevent this risk.”

To address the issue, Avalere Health and the Academy of Nutrition and Dietetics established the Malnutrition Quality Improvement Initiative (MQii), a multi-stakeholder effort to identify tools to support hospital-based care teams in improving malnutrition care quality. They developed a malnutrition Toolkit, which was piloted in 2016 and was shown to effectively improve malnutrition care.

“Since the poster presentation in May, we have successfully implemented the Toolkit at 50 hospitals via a multi-hospital Learning Collaborative,” Ms. Fitall said. They are now recruiting hospitals and health systems to participate in an expanded Learning Collaborative. Interested sites should contact the MQii team at [email protected].

“By supporting efforts to improve malnutrition care in the inpatient setting, hospitalists can help reduce the incidence of these problems as well as decrease rates of readmissions and reduce patient lengths of stay,” Ms. Fitall said. “Hospitalists are critical to addressing malnutrition care gaps in the hospital. Dietitians that have undertaken malnutrition quality improvement projects using the MQii Toolkit have found that they are most successful when hospitalists are actively engaged in the team, particularly when looking to improve the rate of malnutrition diagnosis. Hospitalists are ideally positioned to champion these efforts.”

Support for MQii was provided by Abbott, she said.
 

Reference

1. Fitall E, Bruno M, Jones K, Lynch J, Silver H, Godamunne K, Valladares A, Mitchell K. Malnutrition Care: “Low Hanging Fruit” for Hospitalist Clinical Performance Improvement [abstract]. J Hosp Med. 2017;12(suppl 2).

Hospitalists are key players in improving hospital performance, but they may be overlooking a leading cause of morbidity and mortality, especially among older adults.

Research suggests that at the time of hospital admission, some 20%-50% of all patients are at risk for malnutrition or are malnourished, but only 7% of those patients are diagnosed during their stay, according to research cited in an abstract presented at HM17.¹

“Because individuals who are malnourished lack sufficient nutrients to promote healing and rehabilitation, and are at increased risk of medical complications, it can have a serious impact on patient safety indicators, such as rates of pressure ulcers, wound healing, and risk of falls,” said lead author Eleanor Fitall of Avalere Health. “Early identification and subsequent treatment of these patients is the best way to prevent this risk.”

To address the issue, Avalere Health and the Academy of Nutrition and Dietetics established the Malnutrition Quality Improvement Initiative (MQii), a multi-stakeholder effort to identify tools to support hospital-based care teams in improving malnutrition care quality. They developed a malnutrition Toolkit, which was piloted in 2016 and was shown to effectively improve malnutrition care.

“Since the poster presentation in May, we have successfully implemented the Toolkit at 50 hospitals via a multi-hospital Learning Collaborative,” Ms. Fitall said. They are now recruiting hospitals and health systems to participate in an expanded Learning Collaborative. Interested sites should contact the MQii team at [email protected].

“By supporting efforts to improve malnutrition care in the inpatient setting, hospitalists can help reduce the incidence of these problems as well as decrease rates of readmissions and reduce patient lengths of stay,” Ms. Fitall said. “Hospitalists are critical to addressing malnutrition care gaps in the hospital. Dietitians that have undertaken malnutrition quality improvement projects using the MQii Toolkit have found that they are most successful when hospitalists are actively engaged in the team, particularly when looking to improve the rate of malnutrition diagnosis. Hospitalists are ideally positioned to champion these efforts.”

Support for MQii was provided by Abbott, she said.
 

Reference

1. Fitall E, Bruno M, Jones K, Lynch J, Silver H, Godamunne K, Valladares A, Mitchell K. Malnutrition Care: “Low Hanging Fruit” for Hospitalist Clinical Performance Improvement [abstract]. J Hosp Med. 2017;12(suppl 2).

A new study finds that two nearly ubiquitous herpes viruses, HHV-6a and HHV-7, are abundant in the brains of people with Alzheimer’s disease. Also today, midlife retinopathy predicts ischemic stroke, fingernails may hold a clue for relapsing scabies, and canakinumab cuts gout attacks by nearly half.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

A new study finds that two nearly ubiquitous herpes viruses, HHV-6a and HHV-7, are abundant in the brains of people with Alzheimer’s disease. Also today, midlife retinopathy predicts ischemic stroke, fingernails may hold a clue for relapsing scabies, and canakinumab cuts gout attacks by nearly half.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

A new study finds that two nearly ubiquitous herpes viruses, HHV-6a and HHV-7, are abundant in the brains of people with Alzheimer’s disease. Also today, midlife retinopathy predicts ischemic stroke, fingernails may hold a clue for relapsing scabies, and canakinumab cuts gout attacks by nearly half.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Photo from EHA

STOCKHOLM—Results of a phase 3 study suggest the long-acting C5 complement inhibitor ravulizumab produces similar results as eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Treatment with ravulizumab every 8 weeks proved noninferior to treatment with eculizumab every 2 weeks for the co-primary endpoints of transfusion avoidance and hemolysis as measured by lactate dehydrogenase (LDH) normalization.

Ravulizumab also proved noninferior with regard to secondary efficacy endpoints and had a safety profile similar to that of eculizumab.

These results suggest ravulizumab could be a more convenient alternative for PNH patients, according to Jong Wook Lee, MD, of Seoul St. Mary’s Hospital in Seoul, South Korea.

Dr Lee presented these results as a late-breaking abstract (LB2603) at the 23rd Congress of the European Hematology Association (EHA).

The study was sponsored by Alexion Pharmaceuticals.

The trial enrolled adults with PNH naive to complement inhibitor therapy. They were randomized to receive ravulizumab (n=125) or eculizumab (n=121) for 183 days.

More than half of patients were male—52% in the ravulizumab arm and 57% in the eculizumab arm.  Most patients were Asian (57.6% in the ravulizumab arm and 47.1% in the eculizumab arm) or white (34.4% and 42.1%, respectively).

Patients’ mean age at first infusion was 44.8 in the ravulizumab arm and 46.2 in the eculizumab arm. The mean number of years from PNH diagnosis to consent was 6.7 and 6.4, respectively.

The mean LDH at baseline was 1634 U/L in the ravulizumab arm and 1578 U/L in the eculizumab arm. The mean FACIT-Fatigue score was 36.7 and 36.9, respectively.

All 125 ravulizumab patients completed 26 weeks of treatment, as did 119 of the eculizumab patients. One hundred twenty-four ravulizumab patients entered the extension phase, as did 119 eculizumab patients.

Efficacy

The study’s primary efficacy endpoints were transfusion avoidance and LDH normalization from day 29 to 183. Dr Lee said ravulizumab proved noninferior to eculizumab for both endpoints, and point estimates favored ravulizumab.

The proportion of patients who remained transfusion-free was 73.6% in the ravulizumab arm and 66.1% in the eculizumab arm (difference, 6.8; 95% CI, -4.66, 18.14).

The proportion of patients who achieved LDH normalization was 53.6% and 49.4%, respectively (difference, 1.19; 95% CI, 0.8, 1.77).

Secondary efficacy endpoints included the percentage change in LDH from baseline, change in FACIT-Fatigue score from baseline, and the proportions of patients with breakthrough hemolysis and stabilized hemoglobin.

Again, ravulizumab was noninferior to eculizumab for all endpoints, with point estimates favoring ravulizumab.

The LDH percentage change was -76.84% in the ravulizumab arm and -76.02% in the eculizumab arm (difference, 0.83; 95% CI, -3.56, 5.21).

The change (improvement) in FACIT-Fatigue score was 7.07 and 6.40, respectively (difference, 0.67; 95% CI, -1.21, 2.55).

The percentage of patients with hemoglobin stabilization was 68.0% in the ravulizumab arm and 64.5% in the eculizumab arm (difference, 2.9; 95% CI, -8.80, 14.64).

The percentage of patients with breakthrough hemolysis was 4.0% and 10.7%, respectively (difference, 6.7; 95% CI, -0.18, 14.21).

Dr Lee noted that the proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab arm than the ravulizumab arm—13 patients with 15 events and 5 patients with 5 events, respectively.

He said this was likely due to the immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5 μg/mL) achieved by ravulizumab. Complete inhibition was observed after the first ravulizumab infusion and was sustained throughout the 26-week treatment period.

Safety

Dr Lee said ravulizumab had a similar safety profile to eculizumab, and both drugs were well tolerated.

Most patients experienced a treatment-emergent adverse event (TEAE)—88% in the ravulizumab arm and 86.8% in the eculizumab arm.

The most common TEAEs (in the ravulizumab and eculizumab arms, respectively) were headache (36.0% and 33.1%), nasopharyngitis (8.8% and 14.9%), upper respiratory tract infection (10.4% and 5.8%), and pyrexia (4.8% and 10.7%).

Serious AEs occurred in 8.8% of patients in the ravulizumab arm and 7.4% of those in the eculizumab arm.

Major adverse vascular events occurred in 2 patients in the ravulizumab arm and 1 in the eculizumab arm. There were no meningococcal infections in either arm.

One patient in the eculizumab arm was discontinued from the study and died of lung cancer (which was unrelated to treatment).

Photo from EHA

STOCKHOLM—Results of a phase 3 study suggest the long-acting C5 complement inhibitor ravulizumab produces similar results as eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Treatment with ravulizumab every 8 weeks proved noninferior to treatment with eculizumab every 2 weeks for the co-primary endpoints of transfusion avoidance and hemolysis as measured by lactate dehydrogenase (LDH) normalization.

Ravulizumab also proved noninferior with regard to secondary efficacy endpoints and had a safety profile similar to that of eculizumab.

These results suggest ravulizumab could be a more convenient alternative for PNH patients, according to Jong Wook Lee, MD, of Seoul St. Mary’s Hospital in Seoul, South Korea.

Dr Lee presented these results as a late-breaking abstract (LB2603) at the 23rd Congress of the European Hematology Association (EHA).

The study was sponsored by Alexion Pharmaceuticals.

The trial enrolled adults with PNH naive to complement inhibitor therapy. They were randomized to receive ravulizumab (n=125) or eculizumab (n=121) for 183 days.

More than half of patients were male—52% in the ravulizumab arm and 57% in the eculizumab arm.  Most patients were Asian (57.6% in the ravulizumab arm and 47.1% in the eculizumab arm) or white (34.4% and 42.1%, respectively).

Patients’ mean age at first infusion was 44.8 in the ravulizumab arm and 46.2 in the eculizumab arm. The mean number of years from PNH diagnosis to consent was 6.7 and 6.4, respectively.

The mean LDH at baseline was 1634 U/L in the ravulizumab arm and 1578 U/L in the eculizumab arm. The mean FACIT-Fatigue score was 36.7 and 36.9, respectively.

All 125 ravulizumab patients completed 26 weeks of treatment, as did 119 of the eculizumab patients. One hundred twenty-four ravulizumab patients entered the extension phase, as did 119 eculizumab patients.

Efficacy

The study’s primary efficacy endpoints were transfusion avoidance and LDH normalization from day 29 to 183. Dr Lee said ravulizumab proved noninferior to eculizumab for both endpoints, and point estimates favored ravulizumab.

The proportion of patients who remained transfusion-free was 73.6% in the ravulizumab arm and 66.1% in the eculizumab arm (difference, 6.8; 95% CI, -4.66, 18.14).

The proportion of patients who achieved LDH normalization was 53.6% and 49.4%, respectively (difference, 1.19; 95% CI, 0.8, 1.77).

Secondary efficacy endpoints included the percentage change in LDH from baseline, change in FACIT-Fatigue score from baseline, and the proportions of patients with breakthrough hemolysis and stabilized hemoglobin.

Again, ravulizumab was noninferior to eculizumab for all endpoints, with point estimates favoring ravulizumab.

The LDH percentage change was -76.84% in the ravulizumab arm and -76.02% in the eculizumab arm (difference, 0.83; 95% CI, -3.56, 5.21).

The change (improvement) in FACIT-Fatigue score was 7.07 and 6.40, respectively (difference, 0.67; 95% CI, -1.21, 2.55).

The percentage of patients with hemoglobin stabilization was 68.0% in the ravulizumab arm and 64.5% in the eculizumab arm (difference, 2.9; 95% CI, -8.80, 14.64).

The percentage of patients with breakthrough hemolysis was 4.0% and 10.7%, respectively (difference, 6.7; 95% CI, -0.18, 14.21).

Dr Lee noted that the proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab arm than the ravulizumab arm—13 patients with 15 events and 5 patients with 5 events, respectively.

He said this was likely due to the immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5 μg/mL) achieved by ravulizumab. Complete inhibition was observed after the first ravulizumab infusion and was sustained throughout the 26-week treatment period.

Safety

Dr Lee said ravulizumab had a similar safety profile to eculizumab, and both drugs were well tolerated.

Most patients experienced a treatment-emergent adverse event (TEAE)—88% in the ravulizumab arm and 86.8% in the eculizumab arm.

The most common TEAEs (in the ravulizumab and eculizumab arms, respectively) were headache (36.0% and 33.1%), nasopharyngitis (8.8% and 14.9%), upper respiratory tract infection (10.4% and 5.8%), and pyrexia (4.8% and 10.7%).

Serious AEs occurred in 8.8% of patients in the ravulizumab arm and 7.4% of those in the eculizumab arm.

Major adverse vascular events occurred in 2 patients in the ravulizumab arm and 1 in the eculizumab arm. There were no meningococcal infections in either arm.

One patient in the eculizumab arm was discontinued from the study and died of lung cancer (which was unrelated to treatment).

Photo from EHA

STOCKHOLM—Results of a phase 3 study suggest the long-acting C5 complement inhibitor ravulizumab produces similar results as eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Treatment with ravulizumab every 8 weeks proved noninferior to treatment with eculizumab every 2 weeks for the co-primary endpoints of transfusion avoidance and hemolysis as measured by lactate dehydrogenase (LDH) normalization.

Ravulizumab also proved noninferior with regard to secondary efficacy endpoints and had a safety profile similar to that of eculizumab.

These results suggest ravulizumab could be a more convenient alternative for PNH patients, according to Jong Wook Lee, MD, of Seoul St. Mary’s Hospital in Seoul, South Korea.

Dr Lee presented these results as a late-breaking abstract (LB2603) at the 23rd Congress of the European Hematology Association (EHA).

The study was sponsored by Alexion Pharmaceuticals.

The trial enrolled adults with PNH naive to complement inhibitor therapy. They were randomized to receive ravulizumab (n=125) or eculizumab (n=121) for 183 days.

More than half of patients were male—52% in the ravulizumab arm and 57% in the eculizumab arm.  Most patients were Asian (57.6% in the ravulizumab arm and 47.1% in the eculizumab arm) or white (34.4% and 42.1%, respectively).

Patients’ mean age at first infusion was 44.8 in the ravulizumab arm and 46.2 in the eculizumab arm. The mean number of years from PNH diagnosis to consent was 6.7 and 6.4, respectively.

The mean LDH at baseline was 1634 U/L in the ravulizumab arm and 1578 U/L in the eculizumab arm. The mean FACIT-Fatigue score was 36.7 and 36.9, respectively.

All 125 ravulizumab patients completed 26 weeks of treatment, as did 119 of the eculizumab patients. One hundred twenty-four ravulizumab patients entered the extension phase, as did 119 eculizumab patients.

Efficacy

The study’s primary efficacy endpoints were transfusion avoidance and LDH normalization from day 29 to 183. Dr Lee said ravulizumab proved noninferior to eculizumab for both endpoints, and point estimates favored ravulizumab.

The proportion of patients who remained transfusion-free was 73.6% in the ravulizumab arm and 66.1% in the eculizumab arm (difference, 6.8; 95% CI, -4.66, 18.14).

The proportion of patients who achieved LDH normalization was 53.6% and 49.4%, respectively (difference, 1.19; 95% CI, 0.8, 1.77).

Secondary efficacy endpoints included the percentage change in LDH from baseline, change in FACIT-Fatigue score from baseline, and the proportions of patients with breakthrough hemolysis and stabilized hemoglobin.

Again, ravulizumab was noninferior to eculizumab for all endpoints, with point estimates favoring ravulizumab.

The LDH percentage change was -76.84% in the ravulizumab arm and -76.02% in the eculizumab arm (difference, 0.83; 95% CI, -3.56, 5.21).

The change (improvement) in FACIT-Fatigue score was 7.07 and 6.40, respectively (difference, 0.67; 95% CI, -1.21, 2.55).

The percentage of patients with hemoglobin stabilization was 68.0% in the ravulizumab arm and 64.5% in the eculizumab arm (difference, 2.9; 95% CI, -8.80, 14.64).

The percentage of patients with breakthrough hemolysis was 4.0% and 10.7%, respectively (difference, 6.7; 95% CI, -0.18, 14.21).

Dr Lee noted that the proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab arm than the ravulizumab arm—13 patients with 15 events and 5 patients with 5 events, respectively.

He said this was likely due to the immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5 μg/mL) achieved by ravulizumab. Complete inhibition was observed after the first ravulizumab infusion and was sustained throughout the 26-week treatment period.

Safety

Dr Lee said ravulizumab had a similar safety profile to eculizumab, and both drugs were well tolerated.

Most patients experienced a treatment-emergent adverse event (TEAE)—88% in the ravulizumab arm and 86.8% in the eculizumab arm.

The most common TEAEs (in the ravulizumab and eculizumab arms, respectively) were headache (36.0% and 33.1%), nasopharyngitis (8.8% and 14.9%), upper respiratory tract infection (10.4% and 5.8%), and pyrexia (4.8% and 10.7%).

Serious AEs occurred in 8.8% of patients in the ravulizumab arm and 7.4% of those in the eculizumab arm.

Major adverse vascular events occurred in 2 patients in the ravulizumab arm and 1 in the eculizumab arm. There were no meningococcal infections in either arm.

One patient in the eculizumab arm was discontinued from the study and died of lung cancer (which was unrelated to treatment).

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Photo by Daniel Gay

The US Food and Drug Administration (FDA) has approved 2 Grifols blood screening assays—Procleix Ultrio Elite and Procleix WNV.

Procleix WNV is a qualitative in vitro nucleic acid assay for the detection of West Nile virus RNA in plasma and serum of human blood donors.

Procleix Ultrio Elite is a blood screening assay that delivers simultaneous results for human immunodeficiency virus type 1, hepatitis C virus, and hepatitis B virus. It also detects human immunodeficiency virus type 2.

Procleix Ultrio Elite can be used to test pools of plasma composed of up to 96 individual donations from donors of source plasma.

Grifols will begin commercializing the Procleix Ultrio Elite and Procleix WNV assays in the US later this year.

“These FDA approvals demonstrate our ongoing commitment to expand Grifols comprehensive nucleic acid testing (NAT) solutions portfolio to help labs administer NAT,” said Carsten Schroeder, president of Grifols’s Diagnostic Division.

Procleix Ultrio Elite and Procleix WNV will run on the fully automated NAT blood screening platform Procleix Panther system. The device is an integrated NAT system that fully automates all necessary steps to perform Procleix assays, from sample processing through amplification, detection, and data reduction.

“The addition of the Procleix Panther system with these assays will allow blood centers to efficiently screen for infectious diseases on one simple, automated platform while adapting to changes in donation volume and regulatory requirements,” Schroeder said.

Photo by Daniel Gay

The US Food and Drug Administration (FDA) has approved 2 Grifols blood screening assays—Procleix Ultrio Elite and Procleix WNV.

Procleix WNV is a qualitative in vitro nucleic acid assay for the detection of West Nile virus RNA in plasma and serum of human blood donors.

Procleix Ultrio Elite is a blood screening assay that delivers simultaneous results for human immunodeficiency virus type 1, hepatitis C virus, and hepatitis B virus. It also detects human immunodeficiency virus type 2.

Procleix Ultrio Elite can be used to test pools of plasma composed of up to 96 individual donations from donors of source plasma.

Grifols will begin commercializing the Procleix Ultrio Elite and Procleix WNV assays in the US later this year.

“These FDA approvals demonstrate our ongoing commitment to expand Grifols comprehensive nucleic acid testing (NAT) solutions portfolio to help labs administer NAT,” said Carsten Schroeder, president of Grifols’s Diagnostic Division.

Procleix Ultrio Elite and Procleix WNV will run on the fully automated NAT blood screening platform Procleix Panther system. The device is an integrated NAT system that fully automates all necessary steps to perform Procleix assays, from sample processing through amplification, detection, and data reduction.

“The addition of the Procleix Panther system with these assays will allow blood centers to efficiently screen for infectious diseases on one simple, automated platform while adapting to changes in donation volume and regulatory requirements,” Schroeder said.

Photo by Daniel Gay

The US Food and Drug Administration (FDA) has approved 2 Grifols blood screening assays—Procleix Ultrio Elite and Procleix WNV.

Procleix WNV is a qualitative in vitro nucleic acid assay for the detection of West Nile virus RNA in plasma and serum of human blood donors.

Procleix Ultrio Elite is a blood screening assay that delivers simultaneous results for human immunodeficiency virus type 1, hepatitis C virus, and hepatitis B virus. It also detects human immunodeficiency virus type 2.

Procleix Ultrio Elite can be used to test pools of plasma composed of up to 96 individual donations from donors of source plasma.

Grifols will begin commercializing the Procleix Ultrio Elite and Procleix WNV assays in the US later this year.

“These FDA approvals demonstrate our ongoing commitment to expand Grifols comprehensive nucleic acid testing (NAT) solutions portfolio to help labs administer NAT,” said Carsten Schroeder, president of Grifols’s Diagnostic Division.

Procleix Ultrio Elite and Procleix WNV will run on the fully automated NAT blood screening platform Procleix Panther system. The device is an integrated NAT system that fully automates all necessary steps to perform Procleix assays, from sample processing through amplification, detection, and data reduction.

“The addition of the Procleix Panther system with these assays will allow blood centers to efficiently screen for infectious diseases on one simple, automated platform while adapting to changes in donation volume and regulatory requirements,” Schroeder said.