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DOACs linked to lower fracture risk versus warfarin in AFib patients
results of a recent population-based cohort study show.
The choice of direct oral anticoagulant (DOAC) didn’t appear to have an impact, as each individual agent yielded a substantially lower risk of fracture versus the vitamin K antagonist, with risk reductions ranging from 38% to 48%, according to the study authors.
This is one of the latest reports to suggest DOACs could have an edge over warfarin for preventing fractures, providing new evidence that “may help inform the benefit risk assessment” when it comes to choosing an anticoagulant for a patient with atrial fibrillation (AFib) in the clinic, wrote the authors, led by Wallis C.Y. Lau, PhD, with the University College London.
“There exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Dr. Lau and coauthors wrote in a report on the study that appears in Annals of Internal Medicine.
The case is especially compelling since fracture risk is “often neglected” when choosing an anticoagulant, the authors wrote. Surgeries to treat fracture are difficult because of the need for perioperative management of anticoagulation as “a balance between the risk for stroke and excessive bleeding must be achieved,” they added.
Based on these data, physicians should strongly consider DOACs as an alternative to vitamin K antagonists to reduce the risk of osteoporosis over the long term in patients with AFib, according to Victor Lawrence Roberts, MD, a Florida endocrinologist.
“Osteoporosis takes years, sometimes decades to develop, and if you then overlay warfarin on top of a readily evolving metabolic bone disease, you probably accelerate that process, said Dr. Roberts, professor of internal medicine at the University of Central Florida, Orlando, and editorial advisory board member of Internal Medicine News.
There’s a considerable amount of concerning preclinical data that warfarin could increase osteoporotic fracture risk. Of note, vitamin K antagonists modulate osteocalcin, a calcium-binding bone matrix protein, Dr. Roberts said.
“Osteocalcin is important for bone metabolism and health, and inhibiting osteocalcin will inhibit the ability to have a healthy bone matrix,” he explained.
The impact of anticoagulants on fracture risk is particularly relevant to patients with AFib, according to Dr. Lau and colleagues, who referenced one 2017 report showing a higher incidence of hip fracture among AFib patients versus those without AFib.
In their more recent study, Dr. Lau and colleagues reviewed electronic health records in a Hong Kong database for 23,515 older adults with a new diagnosis of AFib who received a new prescription of warfarin or DOACs including apixaban, dabigatran, or rivaroxaban.
DOAC use was consistently associated with a lower risk of osteoporotic fractures versus warfarin, regardless of the DOAC considered. The hazard ratios were 0.62 (95% confidence interval, 0.41-0.94) for apixaban, 0.65 (95% CI, 0.49-0.86) for dabigatran, and 0.52 (95% CI, 0.37-0.73) for rivaroxaban versus warfarin, the report showed.
Head-to-head comparisons between DOACS didn’t yield any statistically significant differences, though the analyses were underpowered in this respect, according to the investigators.
“This study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” they wrote. “However, any absolute risk differences were small and would likely be of minor clinical significance.”
The reduced risk of fracture for DOACs versus warfarin was consistent in men and women with AFib, suggesting that women may particularly benefit from DOACs, given that they have a higher risk of fracture than men, the investigators added.
The results of this study suggest yet another benefit of DOACs over warfarin in patients with AFib, according to internist Noel Deep, MD, who is the chief medical officer of Aspirus Langlade Hospital in Antigo, Wisconsin.
“The lower risk of osteoporotic fractures with DOACS, in addition to other advantages such as lower risk of intracranial bleeding, once- or twice-daily consistent dosing, no dietary restrictions, and no blood tests to regulate the dose might be another reason that physicians may favor them over warfarin in older individuals requiring anticoagulation,” Dr. Deep said in an interview.
Results of this and several other recent studies may help in recommending DOACs to internal medicine patients who have a diagnosis of AFib requiring anticoagulation, according to Dr. Deep, who is also a physician at Aspirus Antigo Clinic and a member of Internal Medicine News’ editorial advisory board. These include a 2019 U.S.-based study of more than 167,000 patients with AFib (JAMA Intern Med. 2019;180[2]:245‐253) showing that use of DOACs, particularly apixaban, were linked to lower fracture risk versus warfarin use. Similarly, a Danish national registry study also published in 2019 showed that the absolute risk of osteoporotic fractures was low overall and significantly lower in patients who received DOACs (J Am Coll Cardiol. 2019;74[17]:2150-2158).
Funding for the study came from the University of Hong Kong and University College London Strategic Planning Fund. The study authors reported disclosures related to Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, IQVIA, and others.
SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 18. doi: 10.7326/M19-3671.
results of a recent population-based cohort study show.
The choice of direct oral anticoagulant (DOAC) didn’t appear to have an impact, as each individual agent yielded a substantially lower risk of fracture versus the vitamin K antagonist, with risk reductions ranging from 38% to 48%, according to the study authors.
This is one of the latest reports to suggest DOACs could have an edge over warfarin for preventing fractures, providing new evidence that “may help inform the benefit risk assessment” when it comes to choosing an anticoagulant for a patient with atrial fibrillation (AFib) in the clinic, wrote the authors, led by Wallis C.Y. Lau, PhD, with the University College London.
“There exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Dr. Lau and coauthors wrote in a report on the study that appears in Annals of Internal Medicine.
The case is especially compelling since fracture risk is “often neglected” when choosing an anticoagulant, the authors wrote. Surgeries to treat fracture are difficult because of the need for perioperative management of anticoagulation as “a balance between the risk for stroke and excessive bleeding must be achieved,” they added.
Based on these data, physicians should strongly consider DOACs as an alternative to vitamin K antagonists to reduce the risk of osteoporosis over the long term in patients with AFib, according to Victor Lawrence Roberts, MD, a Florida endocrinologist.
“Osteoporosis takes years, sometimes decades to develop, and if you then overlay warfarin on top of a readily evolving metabolic bone disease, you probably accelerate that process, said Dr. Roberts, professor of internal medicine at the University of Central Florida, Orlando, and editorial advisory board member of Internal Medicine News.
There’s a considerable amount of concerning preclinical data that warfarin could increase osteoporotic fracture risk. Of note, vitamin K antagonists modulate osteocalcin, a calcium-binding bone matrix protein, Dr. Roberts said.
“Osteocalcin is important for bone metabolism and health, and inhibiting osteocalcin will inhibit the ability to have a healthy bone matrix,” he explained.
The impact of anticoagulants on fracture risk is particularly relevant to patients with AFib, according to Dr. Lau and colleagues, who referenced one 2017 report showing a higher incidence of hip fracture among AFib patients versus those without AFib.
In their more recent study, Dr. Lau and colleagues reviewed electronic health records in a Hong Kong database for 23,515 older adults with a new diagnosis of AFib who received a new prescription of warfarin or DOACs including apixaban, dabigatran, or rivaroxaban.
DOAC use was consistently associated with a lower risk of osteoporotic fractures versus warfarin, regardless of the DOAC considered. The hazard ratios were 0.62 (95% confidence interval, 0.41-0.94) for apixaban, 0.65 (95% CI, 0.49-0.86) for dabigatran, and 0.52 (95% CI, 0.37-0.73) for rivaroxaban versus warfarin, the report showed.
Head-to-head comparisons between DOACS didn’t yield any statistically significant differences, though the analyses were underpowered in this respect, according to the investigators.
“This study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” they wrote. “However, any absolute risk differences were small and would likely be of minor clinical significance.”
The reduced risk of fracture for DOACs versus warfarin was consistent in men and women with AFib, suggesting that women may particularly benefit from DOACs, given that they have a higher risk of fracture than men, the investigators added.
The results of this study suggest yet another benefit of DOACs over warfarin in patients with AFib, according to internist Noel Deep, MD, who is the chief medical officer of Aspirus Langlade Hospital in Antigo, Wisconsin.
“The lower risk of osteoporotic fractures with DOACS, in addition to other advantages such as lower risk of intracranial bleeding, once- or twice-daily consistent dosing, no dietary restrictions, and no blood tests to regulate the dose might be another reason that physicians may favor them over warfarin in older individuals requiring anticoagulation,” Dr. Deep said in an interview.
Results of this and several other recent studies may help in recommending DOACs to internal medicine patients who have a diagnosis of AFib requiring anticoagulation, according to Dr. Deep, who is also a physician at Aspirus Antigo Clinic and a member of Internal Medicine News’ editorial advisory board. These include a 2019 U.S.-based study of more than 167,000 patients with AFib (JAMA Intern Med. 2019;180[2]:245‐253) showing that use of DOACs, particularly apixaban, were linked to lower fracture risk versus warfarin use. Similarly, a Danish national registry study also published in 2019 showed that the absolute risk of osteoporotic fractures was low overall and significantly lower in patients who received DOACs (J Am Coll Cardiol. 2019;74[17]:2150-2158).
Funding for the study came from the University of Hong Kong and University College London Strategic Planning Fund. The study authors reported disclosures related to Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, IQVIA, and others.
SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 18. doi: 10.7326/M19-3671.
results of a recent population-based cohort study show.
The choice of direct oral anticoagulant (DOAC) didn’t appear to have an impact, as each individual agent yielded a substantially lower risk of fracture versus the vitamin K antagonist, with risk reductions ranging from 38% to 48%, according to the study authors.
This is one of the latest reports to suggest DOACs could have an edge over warfarin for preventing fractures, providing new evidence that “may help inform the benefit risk assessment” when it comes to choosing an anticoagulant for a patient with atrial fibrillation (AFib) in the clinic, wrote the authors, led by Wallis C.Y. Lau, PhD, with the University College London.
“There exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Dr. Lau and coauthors wrote in a report on the study that appears in Annals of Internal Medicine.
The case is especially compelling since fracture risk is “often neglected” when choosing an anticoagulant, the authors wrote. Surgeries to treat fracture are difficult because of the need for perioperative management of anticoagulation as “a balance between the risk for stroke and excessive bleeding must be achieved,” they added.
Based on these data, physicians should strongly consider DOACs as an alternative to vitamin K antagonists to reduce the risk of osteoporosis over the long term in patients with AFib, according to Victor Lawrence Roberts, MD, a Florida endocrinologist.
“Osteoporosis takes years, sometimes decades to develop, and if you then overlay warfarin on top of a readily evolving metabolic bone disease, you probably accelerate that process, said Dr. Roberts, professor of internal medicine at the University of Central Florida, Orlando, and editorial advisory board member of Internal Medicine News.
There’s a considerable amount of concerning preclinical data that warfarin could increase osteoporotic fracture risk. Of note, vitamin K antagonists modulate osteocalcin, a calcium-binding bone matrix protein, Dr. Roberts said.
“Osteocalcin is important for bone metabolism and health, and inhibiting osteocalcin will inhibit the ability to have a healthy bone matrix,” he explained.
The impact of anticoagulants on fracture risk is particularly relevant to patients with AFib, according to Dr. Lau and colleagues, who referenced one 2017 report showing a higher incidence of hip fracture among AFib patients versus those without AFib.
In their more recent study, Dr. Lau and colleagues reviewed electronic health records in a Hong Kong database for 23,515 older adults with a new diagnosis of AFib who received a new prescription of warfarin or DOACs including apixaban, dabigatran, or rivaroxaban.
DOAC use was consistently associated with a lower risk of osteoporotic fractures versus warfarin, regardless of the DOAC considered. The hazard ratios were 0.62 (95% confidence interval, 0.41-0.94) for apixaban, 0.65 (95% CI, 0.49-0.86) for dabigatran, and 0.52 (95% CI, 0.37-0.73) for rivaroxaban versus warfarin, the report showed.
Head-to-head comparisons between DOACS didn’t yield any statistically significant differences, though the analyses were underpowered in this respect, according to the investigators.
“This study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” they wrote. “However, any absolute risk differences were small and would likely be of minor clinical significance.”
The reduced risk of fracture for DOACs versus warfarin was consistent in men and women with AFib, suggesting that women may particularly benefit from DOACs, given that they have a higher risk of fracture than men, the investigators added.
The results of this study suggest yet another benefit of DOACs over warfarin in patients with AFib, according to internist Noel Deep, MD, who is the chief medical officer of Aspirus Langlade Hospital in Antigo, Wisconsin.
“The lower risk of osteoporotic fractures with DOACS, in addition to other advantages such as lower risk of intracranial bleeding, once- or twice-daily consistent dosing, no dietary restrictions, and no blood tests to regulate the dose might be another reason that physicians may favor them over warfarin in older individuals requiring anticoagulation,” Dr. Deep said in an interview.
Results of this and several other recent studies may help in recommending DOACs to internal medicine patients who have a diagnosis of AFib requiring anticoagulation, according to Dr. Deep, who is also a physician at Aspirus Antigo Clinic and a member of Internal Medicine News’ editorial advisory board. These include a 2019 U.S.-based study of more than 167,000 patients with AFib (JAMA Intern Med. 2019;180[2]:245‐253) showing that use of DOACs, particularly apixaban, were linked to lower fracture risk versus warfarin use. Similarly, a Danish national registry study also published in 2019 showed that the absolute risk of osteoporotic fractures was low overall and significantly lower in patients who received DOACs (J Am Coll Cardiol. 2019;74[17]:2150-2158).
Funding for the study came from the University of Hong Kong and University College London Strategic Planning Fund. The study authors reported disclosures related to Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, IQVIA, and others.
SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 18. doi: 10.7326/M19-3671.
FROM ANNALS OF INTERNAL MEDICINE
Universal CAR-T therapy produces CRs in relapsed/refractory T-ALL
according to initial findings from an ongoing study.
The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.
All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.
Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.
The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.
TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.
Patients and treatment
The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).
None of the patients received prior allogeneic hematopoietic stem cell transplant.
All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 106 cells/kg), three patients received dose level 2 (1 x 107 cells/kg), and one patient received dose level 3 (1.5 x 107 cells/kg) – each as a single infusion.
Expansion, response, and safety
“GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated,” Dr. Wang said. “We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14.”
All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.
One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.
In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.
However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.
All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.
“The CRS was manageable and reversible,” Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.
Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.
‘Very impressive’ early results
Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.
One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.
Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.
“[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels,” Dr. Wang said in closing, noting that further evaluation is warranted.
Indeed, the results of this next-generation CAR T-cell trial are “very impressive,” said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.
There have been concerns that “off-the-shelf” CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.
“I think it’s also important to note, however, that there’s quite a high incidence rate of grade 3 or higher toxicities, including CRS,” Dr. Chen said. “I suspect this may have something to do with the fairly high dosing levels used in this trial.”
The “big question,” however, is durability of the response, Dr. Chen said. “And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today.”
Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.
SOURCE: Wang X et al. AACR 2020, Abstract CT052.
according to initial findings from an ongoing study.
The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.
All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.
Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.
The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.
TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.
Patients and treatment
The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).
None of the patients received prior allogeneic hematopoietic stem cell transplant.
All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 106 cells/kg), three patients received dose level 2 (1 x 107 cells/kg), and one patient received dose level 3 (1.5 x 107 cells/kg) – each as a single infusion.
Expansion, response, and safety
“GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated,” Dr. Wang said. “We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14.”
All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.
One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.
In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.
However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.
All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.
“The CRS was manageable and reversible,” Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.
Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.
‘Very impressive’ early results
Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.
One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.
Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.
“[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels,” Dr. Wang said in closing, noting that further evaluation is warranted.
Indeed, the results of this next-generation CAR T-cell trial are “very impressive,” said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.
There have been concerns that “off-the-shelf” CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.
“I think it’s also important to note, however, that there’s quite a high incidence rate of grade 3 or higher toxicities, including CRS,” Dr. Chen said. “I suspect this may have something to do with the fairly high dosing levels used in this trial.”
The “big question,” however, is durability of the response, Dr. Chen said. “And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today.”
Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.
SOURCE: Wang X et al. AACR 2020, Abstract CT052.
according to initial findings from an ongoing study.
The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.
All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.
Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.
The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.
TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.
Patients and treatment
The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).
None of the patients received prior allogeneic hematopoietic stem cell transplant.
All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 106 cells/kg), three patients received dose level 2 (1 x 107 cells/kg), and one patient received dose level 3 (1.5 x 107 cells/kg) – each as a single infusion.
Expansion, response, and safety
“GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated,” Dr. Wang said. “We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14.”
All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.
One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.
In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.
However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.
All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.
“The CRS was manageable and reversible,” Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.
Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.
‘Very impressive’ early results
Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.
One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.
Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.
“[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels,” Dr. Wang said in closing, noting that further evaluation is warranted.
Indeed, the results of this next-generation CAR T-cell trial are “very impressive,” said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.
There have been concerns that “off-the-shelf” CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.
“I think it’s also important to note, however, that there’s quite a high incidence rate of grade 3 or higher toxicities, including CRS,” Dr. Chen said. “I suspect this may have something to do with the fairly high dosing levels used in this trial.”
The “big question,” however, is durability of the response, Dr. Chen said. “And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today.”
Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.
SOURCE: Wang X et al. AACR 2020, Abstract CT052.
FROM AACR 2020
Secondary acute lymphoblastic leukemia more lethal than de novo
The application of improved chemotherapy regimens and novel chemotherapy for acute lymphoblastic leukemia (ALL) has increased the complete remission rate to 85%-90%, however, secondary ALL is common, and the prolonged long-term survival rate is only 30%-50% among ALL patients.
Favorable outcomes decrease with increasing age, and overall survival is greater for adult patients with de novo ALL, compared with patients with secondary ALL, according to the Jiansheng Zhong of the department of hematology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong, China, and colleagues in a new study published online in Clinical Lymphoma, Myeloma & Leukemia.
The researchers retrospectively analyzed the results of 8,305 ALL patients undergoing chemotherapy from the Surveillance, Epidemiology, and End Results (SEER) database during 1975 to 2015, of which 7,454 (80.1%) cases were in the de novo ALL group, and 851 (19.9%) cases were in the secondary acute lymphoblastic leukemia (sALL) group. They used propensity matching before assessing overall survival between the two groups.
Demographically, the results showed that women ALL patients had a lower risk of death than men [hazard ratio (HR) = .93, P < .01], and that the mortality in blacks was higher than that of whites (HR = 1.29, P < .001).
For both ALL groups, patients aged 45-75 years and patients 75 years and older had a higher risk of death than younger patients (HR = 1.82, P < .001 and HR = 3.85, P < .001, respectively).
Although the mean age of de novo ALL group was significantly less than that of the sALL group (51.1 vs. 60.3 years, P < .001), after the propensity matching, the 1-, 2-, 3-, 4- and 5-year overall survival of the de novo ALL group was higher than that of the sALL group at all ages (18-75 years, P < .001).
The authors speculated that one reason for the across-the-board increased mortality in sALL, compared with de novo ALL, might be the fact that sALL patients have been reported to have more MLL gene rearrangements and chromosomal aberrations than are found in de novo ALL. This has previously been suggested as the reason for poor prognosis in secondary ALL patients.
One limitation of the study mentioned by the authors was the lack of individualized chemotherapy data available for analysis. “Considering that the features of sALL and chemotherapeutic modalities or therapy protocols may affect the mortality of sALL, more work is needed to be done in the future to demonstrate the association between chemotherapy and the prognosis of ALL patients, and the influence of cytogenetic lesions and molecular characteristics on sALL,” they concluded.
The authors declared they had no conflicts of interest.
SOURCE: Zhong J et al. Clin Lymphoma Myeloma Leuk. 2020 Apr 30; doi.org/10.1016/j.clml.2020.04.013.
The application of improved chemotherapy regimens and novel chemotherapy for acute lymphoblastic leukemia (ALL) has increased the complete remission rate to 85%-90%, however, secondary ALL is common, and the prolonged long-term survival rate is only 30%-50% among ALL patients.
Favorable outcomes decrease with increasing age, and overall survival is greater for adult patients with de novo ALL, compared with patients with secondary ALL, according to the Jiansheng Zhong of the department of hematology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong, China, and colleagues in a new study published online in Clinical Lymphoma, Myeloma & Leukemia.
The researchers retrospectively analyzed the results of 8,305 ALL patients undergoing chemotherapy from the Surveillance, Epidemiology, and End Results (SEER) database during 1975 to 2015, of which 7,454 (80.1%) cases were in the de novo ALL group, and 851 (19.9%) cases were in the secondary acute lymphoblastic leukemia (sALL) group. They used propensity matching before assessing overall survival between the two groups.
Demographically, the results showed that women ALL patients had a lower risk of death than men [hazard ratio (HR) = .93, P < .01], and that the mortality in blacks was higher than that of whites (HR = 1.29, P < .001).
For both ALL groups, patients aged 45-75 years and patients 75 years and older had a higher risk of death than younger patients (HR = 1.82, P < .001 and HR = 3.85, P < .001, respectively).
Although the mean age of de novo ALL group was significantly less than that of the sALL group (51.1 vs. 60.3 years, P < .001), after the propensity matching, the 1-, 2-, 3-, 4- and 5-year overall survival of the de novo ALL group was higher than that of the sALL group at all ages (18-75 years, P < .001).
The authors speculated that one reason for the across-the-board increased mortality in sALL, compared with de novo ALL, might be the fact that sALL patients have been reported to have more MLL gene rearrangements and chromosomal aberrations than are found in de novo ALL. This has previously been suggested as the reason for poor prognosis in secondary ALL patients.
One limitation of the study mentioned by the authors was the lack of individualized chemotherapy data available for analysis. “Considering that the features of sALL and chemotherapeutic modalities or therapy protocols may affect the mortality of sALL, more work is needed to be done in the future to demonstrate the association between chemotherapy and the prognosis of ALL patients, and the influence of cytogenetic lesions and molecular characteristics on sALL,” they concluded.
The authors declared they had no conflicts of interest.
SOURCE: Zhong J et al. Clin Lymphoma Myeloma Leuk. 2020 Apr 30; doi.org/10.1016/j.clml.2020.04.013.
The application of improved chemotherapy regimens and novel chemotherapy for acute lymphoblastic leukemia (ALL) has increased the complete remission rate to 85%-90%, however, secondary ALL is common, and the prolonged long-term survival rate is only 30%-50% among ALL patients.
Favorable outcomes decrease with increasing age, and overall survival is greater for adult patients with de novo ALL, compared with patients with secondary ALL, according to the Jiansheng Zhong of the department of hematology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, Guangdong, China, and colleagues in a new study published online in Clinical Lymphoma, Myeloma & Leukemia.
The researchers retrospectively analyzed the results of 8,305 ALL patients undergoing chemotherapy from the Surveillance, Epidemiology, and End Results (SEER) database during 1975 to 2015, of which 7,454 (80.1%) cases were in the de novo ALL group, and 851 (19.9%) cases were in the secondary acute lymphoblastic leukemia (sALL) group. They used propensity matching before assessing overall survival between the two groups.
Demographically, the results showed that women ALL patients had a lower risk of death than men [hazard ratio (HR) = .93, P < .01], and that the mortality in blacks was higher than that of whites (HR = 1.29, P < .001).
For both ALL groups, patients aged 45-75 years and patients 75 years and older had a higher risk of death than younger patients (HR = 1.82, P < .001 and HR = 3.85, P < .001, respectively).
Although the mean age of de novo ALL group was significantly less than that of the sALL group (51.1 vs. 60.3 years, P < .001), after the propensity matching, the 1-, 2-, 3-, 4- and 5-year overall survival of the de novo ALL group was higher than that of the sALL group at all ages (18-75 years, P < .001).
The authors speculated that one reason for the across-the-board increased mortality in sALL, compared with de novo ALL, might be the fact that sALL patients have been reported to have more MLL gene rearrangements and chromosomal aberrations than are found in de novo ALL. This has previously been suggested as the reason for poor prognosis in secondary ALL patients.
One limitation of the study mentioned by the authors was the lack of individualized chemotherapy data available for analysis. “Considering that the features of sALL and chemotherapeutic modalities or therapy protocols may affect the mortality of sALL, more work is needed to be done in the future to demonstrate the association between chemotherapy and the prognosis of ALL patients, and the influence of cytogenetic lesions and molecular characteristics on sALL,” they concluded.
The authors declared they had no conflicts of interest.
SOURCE: Zhong J et al. Clin Lymphoma Myeloma Leuk. 2020 Apr 30; doi.org/10.1016/j.clml.2020.04.013.
FROM Clinical Lymphoma, Myeloma & Leukemia
Blood test detects colon cancer in single-center study
Blood assay studied for colorectal cancer screening.
A blood test detected 11 of 11 cases of colorectal cancer in a study involving 354 patients, and also spotted a majority of cases – 40 out of 53 – in which participants had advanced adenomas, an investigator said.
Results from a single-center study of CellMax Life’s FirstSight blood test were released as a poster as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
For a study conducted at one site, the Veterans Affairs Palo Alto (Calif.) Healthcare System, Shai Friedland, MD, and colleagues recruited 354 patients between ages 45 and 80 who were scheduled for elective colonoscopy. The researchers excluded people with a personal history of cancer or inflammatory bowel disease. They used CellMax’s FirstSight test on blood samples from the study participants.
The FirstSight test result was positive for colorectal cancer in all 11 patients in the study who were found by colonoscopy to have this condition, said Dr. Friedland, who is a professor of medicine at Stanford (Calif.) University and chief of gastroenterology at the VA Palo Alto Healthcare System. Thus, the test showed a sensitivity of 100% in this instance.
Among the 53 study participants found by colonoscopy to have advanced adenoma, 40 were positive on FirstSight; thus, so the test has a sensitivity of 75.5% for this result.
Among 79 patients who had negative colonoscopy results, meaning they were judged free of cancer or polyps, the test showed 8 as having signs of disease or growths.
“If you had a large adenoma that was removed years ago and now you have a negative colonoscopy, your score might still be high,” Dr. Friedland said in a recorded presentation for DDW. “In other words, the changes that are detectable in your blood might persist even after the polypectomy.”
He said there are plans to soon start a large-scale multicenter study of the CellMax assay.
“The blood test has the potential to fill an unmet need by giving patients a highly sensitive convenient option for colorectal cancer screening,” he said.
CellMax already is seeking to position its test as a more convenient alternative to either colonoscopy or the Cologuard screening test. Many patients put off cancer screening because of the need to take time off from work and the invasive nature of colonoscopy. Exact Sciences has used direct-to-consumer advertising to promote its Cologuard home-based test as a more convenient alternative to colonoscopy, but its product requires patients to collect their own stool samples and mail them to a lab, a process many people find off-putting.
Public health advocates, including the U.S. Preventive Services Task Force (USPSTF), have for years been pressing for wider screening of American adults for colon cancer. USPSTF is in the midst of updating its recommendations on colon cancer. In announcing its latest update of these recommendations in 2016, USPSTF said “the best screening test is the one that gets done” (JAMA. 2016;315[23]:2564-75).
USPSTF pressed for maximizing the total proportion of the eligible population, a point Dr. Friedland echoed in a CellMax press release.
“For colon cancer screening to be most effective, it is essential to detect precancerous polyps and then perform a colonoscopy to remove the polyps,” said Dr. Friedland in the CellMax press release. “Giving patients the option of getting a blood test for screening would undoubtedly increase compliance and thereby reduce mortality from colorectal cancer.”
In the DDW presentation, Dr. Friedland and colleagues also said the CellMax test showed greater sensitivity (100%) for colorectal cancer and advanced precancerous lesions (75.5%) than did Cologuard (92.3% for colorectal cancer and 42.4% for advanced precancerous lesions).
Cara Connelly, Director of Public Relations and Corporate Communications for Exact Sciences said that the company “is dedicated to getting more people screened for colorectal cancer and applaud the researchers for their efforts. We look forward to hearing more about the performance of this test in a prospective multisite study with nonsymptomatic patients.”
Naresh T. Gunaratnam, MD, a gastroenterologist and research director at Huron Gastro in Ypsilanti, Mich., said he is concerned that aggressive promotion of alternative tests may obscure the benefits of colonoscopy. Dr. Gunaratnam, a 2019 winner of the American Gastroenterological Association (AGA) Distinguished Clinician Award, has been a public critic of the marketing of colon cancer tests, which emphasize the convenience of these products. When asked by MDedge to comment on the CellMax-funded study, Dr. Gunaratnam said alternative tests do have a place for the care of patients who cannot or will not have a colonoscopy.
“But if you convince a patient who would be willing to have a colonoscopy not to, that’s a disservice,” he said.
“If you want the best test, the one that is best at finding cancers and finding polyps and the only one that can remove the polyp, that’s colonoscopy,” Dr. Gunaratnam added. “One day there may be a pill you can swallow that blows up the polyps, but we’re not there yet. We have to mechanically remove them.”
SOURCE: Friedland S et al. DDW 2020, eposter 575.
Blood assay studied for colorectal cancer screening.
Blood assay studied for colorectal cancer screening.
A blood test detected 11 of 11 cases of colorectal cancer in a study involving 354 patients, and also spotted a majority of cases – 40 out of 53 – in which participants had advanced adenomas, an investigator said.
Results from a single-center study of CellMax Life’s FirstSight blood test were released as a poster as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
For a study conducted at one site, the Veterans Affairs Palo Alto (Calif.) Healthcare System, Shai Friedland, MD, and colleagues recruited 354 patients between ages 45 and 80 who were scheduled for elective colonoscopy. The researchers excluded people with a personal history of cancer or inflammatory bowel disease. They used CellMax’s FirstSight test on blood samples from the study participants.
The FirstSight test result was positive for colorectal cancer in all 11 patients in the study who were found by colonoscopy to have this condition, said Dr. Friedland, who is a professor of medicine at Stanford (Calif.) University and chief of gastroenterology at the VA Palo Alto Healthcare System. Thus, the test showed a sensitivity of 100% in this instance.
Among the 53 study participants found by colonoscopy to have advanced adenoma, 40 were positive on FirstSight; thus, so the test has a sensitivity of 75.5% for this result.
Among 79 patients who had negative colonoscopy results, meaning they were judged free of cancer or polyps, the test showed 8 as having signs of disease or growths.
“If you had a large adenoma that was removed years ago and now you have a negative colonoscopy, your score might still be high,” Dr. Friedland said in a recorded presentation for DDW. “In other words, the changes that are detectable in your blood might persist even after the polypectomy.”
He said there are plans to soon start a large-scale multicenter study of the CellMax assay.
“The blood test has the potential to fill an unmet need by giving patients a highly sensitive convenient option for colorectal cancer screening,” he said.
CellMax already is seeking to position its test as a more convenient alternative to either colonoscopy or the Cologuard screening test. Many patients put off cancer screening because of the need to take time off from work and the invasive nature of colonoscopy. Exact Sciences has used direct-to-consumer advertising to promote its Cologuard home-based test as a more convenient alternative to colonoscopy, but its product requires patients to collect their own stool samples and mail them to a lab, a process many people find off-putting.
Public health advocates, including the U.S. Preventive Services Task Force (USPSTF), have for years been pressing for wider screening of American adults for colon cancer. USPSTF is in the midst of updating its recommendations on colon cancer. In announcing its latest update of these recommendations in 2016, USPSTF said “the best screening test is the one that gets done” (JAMA. 2016;315[23]:2564-75).
USPSTF pressed for maximizing the total proportion of the eligible population, a point Dr. Friedland echoed in a CellMax press release.
“For colon cancer screening to be most effective, it is essential to detect precancerous polyps and then perform a colonoscopy to remove the polyps,” said Dr. Friedland in the CellMax press release. “Giving patients the option of getting a blood test for screening would undoubtedly increase compliance and thereby reduce mortality from colorectal cancer.”
In the DDW presentation, Dr. Friedland and colleagues also said the CellMax test showed greater sensitivity (100%) for colorectal cancer and advanced precancerous lesions (75.5%) than did Cologuard (92.3% for colorectal cancer and 42.4% for advanced precancerous lesions).
Cara Connelly, Director of Public Relations and Corporate Communications for Exact Sciences said that the company “is dedicated to getting more people screened for colorectal cancer and applaud the researchers for their efforts. We look forward to hearing more about the performance of this test in a prospective multisite study with nonsymptomatic patients.”
Naresh T. Gunaratnam, MD, a gastroenterologist and research director at Huron Gastro in Ypsilanti, Mich., said he is concerned that aggressive promotion of alternative tests may obscure the benefits of colonoscopy. Dr. Gunaratnam, a 2019 winner of the American Gastroenterological Association (AGA) Distinguished Clinician Award, has been a public critic of the marketing of colon cancer tests, which emphasize the convenience of these products. When asked by MDedge to comment on the CellMax-funded study, Dr. Gunaratnam said alternative tests do have a place for the care of patients who cannot or will not have a colonoscopy.
“But if you convince a patient who would be willing to have a colonoscopy not to, that’s a disservice,” he said.
“If you want the best test, the one that is best at finding cancers and finding polyps and the only one that can remove the polyp, that’s colonoscopy,” Dr. Gunaratnam added. “One day there may be a pill you can swallow that blows up the polyps, but we’re not there yet. We have to mechanically remove them.”
SOURCE: Friedland S et al. DDW 2020, eposter 575.
A blood test detected 11 of 11 cases of colorectal cancer in a study involving 354 patients, and also spotted a majority of cases – 40 out of 53 – in which participants had advanced adenomas, an investigator said.
Results from a single-center study of CellMax Life’s FirstSight blood test were released as a poster as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
For a study conducted at one site, the Veterans Affairs Palo Alto (Calif.) Healthcare System, Shai Friedland, MD, and colleagues recruited 354 patients between ages 45 and 80 who were scheduled for elective colonoscopy. The researchers excluded people with a personal history of cancer or inflammatory bowel disease. They used CellMax’s FirstSight test on blood samples from the study participants.
The FirstSight test result was positive for colorectal cancer in all 11 patients in the study who were found by colonoscopy to have this condition, said Dr. Friedland, who is a professor of medicine at Stanford (Calif.) University and chief of gastroenterology at the VA Palo Alto Healthcare System. Thus, the test showed a sensitivity of 100% in this instance.
Among the 53 study participants found by colonoscopy to have advanced adenoma, 40 were positive on FirstSight; thus, so the test has a sensitivity of 75.5% for this result.
Among 79 patients who had negative colonoscopy results, meaning they were judged free of cancer or polyps, the test showed 8 as having signs of disease or growths.
“If you had a large adenoma that was removed years ago and now you have a negative colonoscopy, your score might still be high,” Dr. Friedland said in a recorded presentation for DDW. “In other words, the changes that are detectable in your blood might persist even after the polypectomy.”
He said there are plans to soon start a large-scale multicenter study of the CellMax assay.
“The blood test has the potential to fill an unmet need by giving patients a highly sensitive convenient option for colorectal cancer screening,” he said.
CellMax already is seeking to position its test as a more convenient alternative to either colonoscopy or the Cologuard screening test. Many patients put off cancer screening because of the need to take time off from work and the invasive nature of colonoscopy. Exact Sciences has used direct-to-consumer advertising to promote its Cologuard home-based test as a more convenient alternative to colonoscopy, but its product requires patients to collect their own stool samples and mail them to a lab, a process many people find off-putting.
Public health advocates, including the U.S. Preventive Services Task Force (USPSTF), have for years been pressing for wider screening of American adults for colon cancer. USPSTF is in the midst of updating its recommendations on colon cancer. In announcing its latest update of these recommendations in 2016, USPSTF said “the best screening test is the one that gets done” (JAMA. 2016;315[23]:2564-75).
USPSTF pressed for maximizing the total proportion of the eligible population, a point Dr. Friedland echoed in a CellMax press release.
“For colon cancer screening to be most effective, it is essential to detect precancerous polyps and then perform a colonoscopy to remove the polyps,” said Dr. Friedland in the CellMax press release. “Giving patients the option of getting a blood test for screening would undoubtedly increase compliance and thereby reduce mortality from colorectal cancer.”
In the DDW presentation, Dr. Friedland and colleagues also said the CellMax test showed greater sensitivity (100%) for colorectal cancer and advanced precancerous lesions (75.5%) than did Cologuard (92.3% for colorectal cancer and 42.4% for advanced precancerous lesions).
Cara Connelly, Director of Public Relations and Corporate Communications for Exact Sciences said that the company “is dedicated to getting more people screened for colorectal cancer and applaud the researchers for their efforts. We look forward to hearing more about the performance of this test in a prospective multisite study with nonsymptomatic patients.”
Naresh T. Gunaratnam, MD, a gastroenterologist and research director at Huron Gastro in Ypsilanti, Mich., said he is concerned that aggressive promotion of alternative tests may obscure the benefits of colonoscopy. Dr. Gunaratnam, a 2019 winner of the American Gastroenterological Association (AGA) Distinguished Clinician Award, has been a public critic of the marketing of colon cancer tests, which emphasize the convenience of these products. When asked by MDedge to comment on the CellMax-funded study, Dr. Gunaratnam said alternative tests do have a place for the care of patients who cannot or will not have a colonoscopy.
“But if you convince a patient who would be willing to have a colonoscopy not to, that’s a disservice,” he said.
“If you want the best test, the one that is best at finding cancers and finding polyps and the only one that can remove the polyp, that’s colonoscopy,” Dr. Gunaratnam added. “One day there may be a pill you can swallow that blows up the polyps, but we’re not there yet. We have to mechanically remove them.”
SOURCE: Friedland S et al. DDW 2020, eposter 575.
FROM DDW 2020
Protective levels of vitamin D achievable in SCD with oral supplementation
Sickle cell disease is associated with worse long-term bone health than that of the general population, and SCD patients are more likely to experience vitamin D [25(OH)D] deficiency. Oral vitamin D3 supplementation can achieve protective levels in children with sickle cell disease, and a daily dose was able to achieved optimal blood levels, according to a report published online in Bone.
The researchers performed a prospective, longitudinal, single-center study of 80 children with SCD. They collected demographic, clinical, and management data, as well as 25(OH)D levels. Bone densitometries (DXA) were also collected.
Among the 80 patients were included in the analysis, there were significant differences between the means of 25(OH)D levels based on whether the patient started prophylactic treatment as an infant or not (35.7 vs. 27.9 ng/mL, respectively [P = .014]), according to the researchers.
They also found that, in multivariate analysis, an oral 800 IU daily dose of vitamin D3 was shown to be a protective factor (P = .044) in reaching optimal 25(OH)D blood levels (≥ 30 ng/mL).
Kaplan-Meier analysis showed that those patients younger than 10 years of age reached optimal levels significantly earlier than older patients when on supplementation (P = .002), as did those patients who were not being treated with hydroxyurea (P = .039), the researchers wrote.
Significant differences were seen between the mean bone mineral density in both DXAs performed when comparing suboptimal vs. optimal blood levels of 25(OH)D (0.54 g/cm2 vs. 0.64 g/cm2, respectively, P = .001), for the initial DXA, and for the most recent DXA (0.59 g/cm2 vs. 0.77 g/cm2, respectively, P = .044). “VitD3 prophylaxis is a safe practice in SCD. It is important to start this prophylactic treatment when the child is an infant. The daily regimen with 800 IU could be more effective for reaching levels ≥ 30 ng/mL, and, especially in preadolescent and adolescent patients, we should raise awareness about the importance of good bone health,” the authors concluded.
The authors reported that they had no conflicts of interest.
SOURCE: Garrido C et al. Bone. 2020;133: doi.org/10.1016/j.bone.2020.115228.
Sickle cell disease is associated with worse long-term bone health than that of the general population, and SCD patients are more likely to experience vitamin D [25(OH)D] deficiency. Oral vitamin D3 supplementation can achieve protective levels in children with sickle cell disease, and a daily dose was able to achieved optimal blood levels, according to a report published online in Bone.
The researchers performed a prospective, longitudinal, single-center study of 80 children with SCD. They collected demographic, clinical, and management data, as well as 25(OH)D levels. Bone densitometries (DXA) were also collected.
Among the 80 patients were included in the analysis, there were significant differences between the means of 25(OH)D levels based on whether the patient started prophylactic treatment as an infant or not (35.7 vs. 27.9 ng/mL, respectively [P = .014]), according to the researchers.
They also found that, in multivariate analysis, an oral 800 IU daily dose of vitamin D3 was shown to be a protective factor (P = .044) in reaching optimal 25(OH)D blood levels (≥ 30 ng/mL).
Kaplan-Meier analysis showed that those patients younger than 10 years of age reached optimal levels significantly earlier than older patients when on supplementation (P = .002), as did those patients who were not being treated with hydroxyurea (P = .039), the researchers wrote.
Significant differences were seen between the mean bone mineral density in both DXAs performed when comparing suboptimal vs. optimal blood levels of 25(OH)D (0.54 g/cm2 vs. 0.64 g/cm2, respectively, P = .001), for the initial DXA, and for the most recent DXA (0.59 g/cm2 vs. 0.77 g/cm2, respectively, P = .044). “VitD3 prophylaxis is a safe practice in SCD. It is important to start this prophylactic treatment when the child is an infant. The daily regimen with 800 IU could be more effective for reaching levels ≥ 30 ng/mL, and, especially in preadolescent and adolescent patients, we should raise awareness about the importance of good bone health,” the authors concluded.
The authors reported that they had no conflicts of interest.
SOURCE: Garrido C et al. Bone. 2020;133: doi.org/10.1016/j.bone.2020.115228.
Sickle cell disease is associated with worse long-term bone health than that of the general population, and SCD patients are more likely to experience vitamin D [25(OH)D] deficiency. Oral vitamin D3 supplementation can achieve protective levels in children with sickle cell disease, and a daily dose was able to achieved optimal blood levels, according to a report published online in Bone.
The researchers performed a prospective, longitudinal, single-center study of 80 children with SCD. They collected demographic, clinical, and management data, as well as 25(OH)D levels. Bone densitometries (DXA) were also collected.
Among the 80 patients were included in the analysis, there were significant differences between the means of 25(OH)D levels based on whether the patient started prophylactic treatment as an infant or not (35.7 vs. 27.9 ng/mL, respectively [P = .014]), according to the researchers.
They also found that, in multivariate analysis, an oral 800 IU daily dose of vitamin D3 was shown to be a protective factor (P = .044) in reaching optimal 25(OH)D blood levels (≥ 30 ng/mL).
Kaplan-Meier analysis showed that those patients younger than 10 years of age reached optimal levels significantly earlier than older patients when on supplementation (P = .002), as did those patients who were not being treated with hydroxyurea (P = .039), the researchers wrote.
Significant differences were seen between the mean bone mineral density in both DXAs performed when comparing suboptimal vs. optimal blood levels of 25(OH)D (0.54 g/cm2 vs. 0.64 g/cm2, respectively, P = .001), for the initial DXA, and for the most recent DXA (0.59 g/cm2 vs. 0.77 g/cm2, respectively, P = .044). “VitD3 prophylaxis is a safe practice in SCD. It is important to start this prophylactic treatment when the child is an infant. The daily regimen with 800 IU could be more effective for reaching levels ≥ 30 ng/mL, and, especially in preadolescent and adolescent patients, we should raise awareness about the importance of good bone health,” the authors concluded.
The authors reported that they had no conflicts of interest.
SOURCE: Garrido C et al. Bone. 2020;133: doi.org/10.1016/j.bone.2020.115228.
FROM BONE
COVID-19–associated coagulopathy
Coronavirus disease 2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), currently causing a pandemic affecting many countries around the world, beginning in December 2019 and spreading rapidly on a global scale since. Globally, its burden has been increasing rapidly, with more than 1.2 million people testing positive for the illness and 123,000 people losing their lives, as per April 15th’s WHO COVID-19 Situation Report.1 These numbers are increasing with each passing day. Clinically, SARS-CoV-2 has a highly variable course, ranging from mild disease manifested as a self-limited illness (seen in younger and healthier patients) to severe pneumonia/ARDS and multiorgan failure with intravascular coagulopathy.2
In this article, we intend to investigate and establish a comprehensive review of COVID-19–associated coagulopathy mechanisms, laboratory findings, and current management guidelines put forth by various societies globally.
Mechanism of coagulopathy
COVID-19–associated coagulopathy has been shown to predispose to both arterial and venous thrombosis through excessive inflammation and hypoxia, leading to activation of the coagulation cascade and consumption of coagulation factors, resulting in microvascular thrombosis.3 Though the exact pathophysiology for the activation of this cascade is not known, the proposed mechanism has been: endothelial damage triggering platelet activation within the lung, leading to aggregation, thrombosis, and consumption of platelets in the lung.2,5,6
Fox et al. noted similar coagulopathy findings of four deceased COVID-19 patients. Autopsy results concluded that the dominant process was diffuse alveolar damage, notable CD4+ aggregates around thrombosed small vessels, significant associated hemorrhage, and thrombotic microangiopathy restricted to the lungs. The proposed mechanism was the activation of megakaryocytes, possibly native to the lung, with platelet aggregation, formation of platelet-rich clots, and fibrin deposition playing a major role.4
It has been noted that diabetic patients are at an increased risk of vascular events and hypercoagulability with COVID-19.7 COVID-19 can also cause livedo reticularis and acrocyanosis because of the microthrombosis in the cutaneous vasculature secondary to underlying coagulopathy, as reported in a case report of two U.S. patients with COVID-19.8
Clinical and laboratory abnormalities
A recent study reported from Netherlands by Klok et al. analyzed 184 ICU patients with COVID-19 pneumonia and concluded that the cumulative incidence of acute pulmonary embolism (PE), deep vein thrombosis (DVT), ischemic stroke, MI, or systemic arterial embolism was 31% (95% confidence interval, 20%-41%). PE was the most frequent thrombotic complication and was noted in 81% of patients. Coagulopathy, defined as spontaneous prolongation of prothrombin time (PT) > 3s or activated partial thromboplastin time (aPTT) > 5s, was reported as an independent predictor of thrombotic complications.3
Hematologic abnormalities that were noted in COVID-19 coagulopathy include: decreased platelet counts, decreased fibrinogen levels, elevated PT/INR, elevated partial thromboplastin time (PTT), and elevated d-dimer.9,10 In a retrospective analysis9 by Tang et al., 71.4% of nonsurvivors and 0.6% of survivors had met the criteria of disseminated intravascular coagulation (DIC) during their hospital stay. Nonsurvivors of COVID-19 had statistically significant elevation of d-dimer levels, FDP levels, PT, and aPTT, when compared to survivors (P < .05). The overall mortality in this study was reported as 11.5%.9 In addition, elevated d-dimer, fibrin and fibrinogen degradation product (FDP) levels and longer PT and aPTT were associated with poor prognosis.
Thus, d-dimer, PT, and platelet count should be measured in all patients who present with COVID-19 infection. We can also suggest that in patients with markedly elevated d-dimer (three- to fourfold increase), admission to hospital should be considered even in the absence of severe clinical symptoms.11
COVID-19 coagulopathy management
In a retrospective study9 of 449 patients with severe COVID-19 from Wuhan, China, by Tang et al., 99 patients mainly received low-weight molecular heparin (LMWH) for 7 days or longer. No difference in 28-day mortality was noted between heparin users and nonusers (30.3% vs. 29.7%; P = .910). A lower 28-day mortality rate was noted in heparin patients with sepsis-induced coagulopathy score of ≥4.0 (40.0% vs. 64.2%; P = .029) or a d-dimer level greater than sixfold of upper limit of normal, compared with nonusers of heparin.12
Another small study of seven COVID-19 patients with acroischemia in China demonstrated that administering LMWH was successful at decreasing the d-dimer and fibrinogen degradation product levels but noted no significant improvement in clinical symptoms.13
Recently, the International Society of Thrombosis and Hemostasis and American Society of Hematology published recommendations and guidelines regarding the recognition and management of coagulopathy in COVID-19.11 Prophylactic anticoagulation therapy with LMWH was recommended in all hospitalized patients with COVID-19, provided there was an absence of any contraindications (active bleeding, platelet count less than 25 x 109/L and fibrinogen less than 0.5 g/dL). Anticoagulation with LMWH was associated with better prognosis in severe COVID-19 patients and in COVID-19 patients with markedly elevated d-dimer, as it also has anti-inflammatory effects.12 This anti-inflammatory property of heparin has been documented in previous studies but the underlying mechanism is unknown and more research is required.14,15
Despite coagulopathy being noticed with cases of COVID-19, bleeding has been a rare finding in COVID-19 infections. If bleeding is noted, recommendations were made to keep platelet levels greater than 50 x109/L, fibrinogen less than 2.0 g/L, and INR [international normalized ratio] greater than 1.5.11 Mechanical thromboprophylaxis should be used when pharmacologic thromboprophylaxis is contraindicated.16
COVID-19 patients with new diagnoses of venous thromboembolism (VTE) or atrial fibrillation should be prescribed therapeutic anticoagulation. Patients who are already on anticoagulation for VTE or atrial fibrillation should continue their therapy unless the platelet count is less than 30-50x109/L or if the fibrinogen is less than 1.0 g/L.16
Conclusion
Coagulopathies associated with COVID-19 infections have been documented in several studies around the world, and it has been shown to be fatal in some cases. Despite documentation, the mechanism behind this coagulopathy is not well understood. Because of the potentially lethal complications associated with coagulopathies, early recognition and anticoagulation is imperative to improve clinical outcomes. These results are very preliminary: More studies are required to understand the role of anticoagulation and its effect on the morbidity and mortality associated with COVID-19–associated coagulopathy.
Dr. Yeruva is a board-certified hematologist/medical oncologist with WellSpan Health and clinical assistant professor of internal medicine, Penn State University, Hershey. Mr. Henderson is a third-year graduate-entry medical student at the Royal College of Surgeons in Ireland with interests in family medicine, dermatology, and tropical diseases. Dr. Al-Tawfiq is a consultant of internal medicine & infectious diseases, and the director of quality at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia, an adjunct associate professor of infectious diseases, molecular medicine and clinical pharmacology at Johns Hopkins University School of Medicine, and adjunct associate professor at Indiana University School of Medicine, Indianapolis. Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals.
References
1. World Health Organization. Coronavirus disease (COVID-2019) situation reports.
2. Lippi G et al. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020 Mar 13. 506:145-8. doi: 10.1016/j.cca.2020.03.022.
3. Klok FA et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Throm Res. 2020;18(4):844-7. doi: 10.1016/j.thromres.2020.04.013.
4. Fox S et al. Pulmonary and cardiac pathology in Covid-19: The first autopsy series from New Orleans. MedRxiv. 2020 Apr 10. doi: 10.1101/2020.04.06.20050575.
5. Yang M et al. Thrombocytopenia in patients with severe acute respiratory syndrome (review). Hematology 2013 Sep 4. doi: 10.1080/1024533040002617.
6. Giannis D et al. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. 2020 June. doi: 10.1016/j.jcv.2020.104362.
7. Guo W et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020 Mar 31. doi: 10.1002/dmrr.3319.
8. Manalo IF et al. A dermatologic manifestation of COVID-19: Transient livedo reticularis. J Am Acad Dermat. 2020 Apr. doi: 10.1016/j.jaad.2020.04.018.
9. Tang N et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Feb 19. doi: 10.1111/jth.14768, 18: 844-847.
10. Huang C et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020 Jan 24. doi: 10.1016/S0140-6736(20)30183-5.
11. Thachil J et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 Mar 25. doi: 10.1111/JTH.14810.
12. Tang N et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 Mar 27. doi: 10.1111/JTH.14817.
13. Zhang Y et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020 Mar 28. doi: 10.3760/cma.j.issn.0253-2727.2020.0006.
14. Poterucha TJ et al. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017. doi: 10.1160/TH16-08-0620.
15. Mousavi S et al. Anti-inflammatory effects of heparin and its derivatives: A systematic review. Adv Pharmacol Pharm Sci. 2015 May 12. doi: 10.1155/2015/507151.
16. Kreuziger L et al. COVID-19 and VTE/anticoagulation: Frequently asked questions. American Society of Hematology. 2020 Apr 17.
Coronavirus disease 2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), currently causing a pandemic affecting many countries around the world, beginning in December 2019 and spreading rapidly on a global scale since. Globally, its burden has been increasing rapidly, with more than 1.2 million people testing positive for the illness and 123,000 people losing their lives, as per April 15th’s WHO COVID-19 Situation Report.1 These numbers are increasing with each passing day. Clinically, SARS-CoV-2 has a highly variable course, ranging from mild disease manifested as a self-limited illness (seen in younger and healthier patients) to severe pneumonia/ARDS and multiorgan failure with intravascular coagulopathy.2
In this article, we intend to investigate and establish a comprehensive review of COVID-19–associated coagulopathy mechanisms, laboratory findings, and current management guidelines put forth by various societies globally.
Mechanism of coagulopathy
COVID-19–associated coagulopathy has been shown to predispose to both arterial and venous thrombosis through excessive inflammation and hypoxia, leading to activation of the coagulation cascade and consumption of coagulation factors, resulting in microvascular thrombosis.3 Though the exact pathophysiology for the activation of this cascade is not known, the proposed mechanism has been: endothelial damage triggering platelet activation within the lung, leading to aggregation, thrombosis, and consumption of platelets in the lung.2,5,6
Fox et al. noted similar coagulopathy findings of four deceased COVID-19 patients. Autopsy results concluded that the dominant process was diffuse alveolar damage, notable CD4+ aggregates around thrombosed small vessels, significant associated hemorrhage, and thrombotic microangiopathy restricted to the lungs. The proposed mechanism was the activation of megakaryocytes, possibly native to the lung, with platelet aggregation, formation of platelet-rich clots, and fibrin deposition playing a major role.4
It has been noted that diabetic patients are at an increased risk of vascular events and hypercoagulability with COVID-19.7 COVID-19 can also cause livedo reticularis and acrocyanosis because of the microthrombosis in the cutaneous vasculature secondary to underlying coagulopathy, as reported in a case report of two U.S. patients with COVID-19.8
Clinical and laboratory abnormalities
A recent study reported from Netherlands by Klok et al. analyzed 184 ICU patients with COVID-19 pneumonia and concluded that the cumulative incidence of acute pulmonary embolism (PE), deep vein thrombosis (DVT), ischemic stroke, MI, or systemic arterial embolism was 31% (95% confidence interval, 20%-41%). PE was the most frequent thrombotic complication and was noted in 81% of patients. Coagulopathy, defined as spontaneous prolongation of prothrombin time (PT) > 3s or activated partial thromboplastin time (aPTT) > 5s, was reported as an independent predictor of thrombotic complications.3
Hematologic abnormalities that were noted in COVID-19 coagulopathy include: decreased platelet counts, decreased fibrinogen levels, elevated PT/INR, elevated partial thromboplastin time (PTT), and elevated d-dimer.9,10 In a retrospective analysis9 by Tang et al., 71.4% of nonsurvivors and 0.6% of survivors had met the criteria of disseminated intravascular coagulation (DIC) during their hospital stay. Nonsurvivors of COVID-19 had statistically significant elevation of d-dimer levels, FDP levels, PT, and aPTT, when compared to survivors (P < .05). The overall mortality in this study was reported as 11.5%.9 In addition, elevated d-dimer, fibrin and fibrinogen degradation product (FDP) levels and longer PT and aPTT were associated with poor prognosis.
Thus, d-dimer, PT, and platelet count should be measured in all patients who present with COVID-19 infection. We can also suggest that in patients with markedly elevated d-dimer (three- to fourfold increase), admission to hospital should be considered even in the absence of severe clinical symptoms.11
COVID-19 coagulopathy management
In a retrospective study9 of 449 patients with severe COVID-19 from Wuhan, China, by Tang et al., 99 patients mainly received low-weight molecular heparin (LMWH) for 7 days or longer. No difference in 28-day mortality was noted between heparin users and nonusers (30.3% vs. 29.7%; P = .910). A lower 28-day mortality rate was noted in heparin patients with sepsis-induced coagulopathy score of ≥4.0 (40.0% vs. 64.2%; P = .029) or a d-dimer level greater than sixfold of upper limit of normal, compared with nonusers of heparin.12
Another small study of seven COVID-19 patients with acroischemia in China demonstrated that administering LMWH was successful at decreasing the d-dimer and fibrinogen degradation product levels but noted no significant improvement in clinical symptoms.13
Recently, the International Society of Thrombosis and Hemostasis and American Society of Hematology published recommendations and guidelines regarding the recognition and management of coagulopathy in COVID-19.11 Prophylactic anticoagulation therapy with LMWH was recommended in all hospitalized patients with COVID-19, provided there was an absence of any contraindications (active bleeding, platelet count less than 25 x 109/L and fibrinogen less than 0.5 g/dL). Anticoagulation with LMWH was associated with better prognosis in severe COVID-19 patients and in COVID-19 patients with markedly elevated d-dimer, as it also has anti-inflammatory effects.12 This anti-inflammatory property of heparin has been documented in previous studies but the underlying mechanism is unknown and more research is required.14,15
Despite coagulopathy being noticed with cases of COVID-19, bleeding has been a rare finding in COVID-19 infections. If bleeding is noted, recommendations were made to keep platelet levels greater than 50 x109/L, fibrinogen less than 2.0 g/L, and INR [international normalized ratio] greater than 1.5.11 Mechanical thromboprophylaxis should be used when pharmacologic thromboprophylaxis is contraindicated.16
COVID-19 patients with new diagnoses of venous thromboembolism (VTE) or atrial fibrillation should be prescribed therapeutic anticoagulation. Patients who are already on anticoagulation for VTE or atrial fibrillation should continue their therapy unless the platelet count is less than 30-50x109/L or if the fibrinogen is less than 1.0 g/L.16
Conclusion
Coagulopathies associated with COVID-19 infections have been documented in several studies around the world, and it has been shown to be fatal in some cases. Despite documentation, the mechanism behind this coagulopathy is not well understood. Because of the potentially lethal complications associated with coagulopathies, early recognition and anticoagulation is imperative to improve clinical outcomes. These results are very preliminary: More studies are required to understand the role of anticoagulation and its effect on the morbidity and mortality associated with COVID-19–associated coagulopathy.
Dr. Yeruva is a board-certified hematologist/medical oncologist with WellSpan Health and clinical assistant professor of internal medicine, Penn State University, Hershey. Mr. Henderson is a third-year graduate-entry medical student at the Royal College of Surgeons in Ireland with interests in family medicine, dermatology, and tropical diseases. Dr. Al-Tawfiq is a consultant of internal medicine & infectious diseases, and the director of quality at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia, an adjunct associate professor of infectious diseases, molecular medicine and clinical pharmacology at Johns Hopkins University School of Medicine, and adjunct associate professor at Indiana University School of Medicine, Indianapolis. Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals.
References
1. World Health Organization. Coronavirus disease (COVID-2019) situation reports.
2. Lippi G et al. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020 Mar 13. 506:145-8. doi: 10.1016/j.cca.2020.03.022.
3. Klok FA et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Throm Res. 2020;18(4):844-7. doi: 10.1016/j.thromres.2020.04.013.
4. Fox S et al. Pulmonary and cardiac pathology in Covid-19: The first autopsy series from New Orleans. MedRxiv. 2020 Apr 10. doi: 10.1101/2020.04.06.20050575.
5. Yang M et al. Thrombocytopenia in patients with severe acute respiratory syndrome (review). Hematology 2013 Sep 4. doi: 10.1080/1024533040002617.
6. Giannis D et al. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. 2020 June. doi: 10.1016/j.jcv.2020.104362.
7. Guo W et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020 Mar 31. doi: 10.1002/dmrr.3319.
8. Manalo IF et al. A dermatologic manifestation of COVID-19: Transient livedo reticularis. J Am Acad Dermat. 2020 Apr. doi: 10.1016/j.jaad.2020.04.018.
9. Tang N et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Feb 19. doi: 10.1111/jth.14768, 18: 844-847.
10. Huang C et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020 Jan 24. doi: 10.1016/S0140-6736(20)30183-5.
11. Thachil J et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 Mar 25. doi: 10.1111/JTH.14810.
12. Tang N et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 Mar 27. doi: 10.1111/JTH.14817.
13. Zhang Y et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020 Mar 28. doi: 10.3760/cma.j.issn.0253-2727.2020.0006.
14. Poterucha TJ et al. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017. doi: 10.1160/TH16-08-0620.
15. Mousavi S et al. Anti-inflammatory effects of heparin and its derivatives: A systematic review. Adv Pharmacol Pharm Sci. 2015 May 12. doi: 10.1155/2015/507151.
16. Kreuziger L et al. COVID-19 and VTE/anticoagulation: Frequently asked questions. American Society of Hematology. 2020 Apr 17.
Coronavirus disease 2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), currently causing a pandemic affecting many countries around the world, beginning in December 2019 and spreading rapidly on a global scale since. Globally, its burden has been increasing rapidly, with more than 1.2 million people testing positive for the illness and 123,000 people losing their lives, as per April 15th’s WHO COVID-19 Situation Report.1 These numbers are increasing with each passing day. Clinically, SARS-CoV-2 has a highly variable course, ranging from mild disease manifested as a self-limited illness (seen in younger and healthier patients) to severe pneumonia/ARDS and multiorgan failure with intravascular coagulopathy.2
In this article, we intend to investigate and establish a comprehensive review of COVID-19–associated coagulopathy mechanisms, laboratory findings, and current management guidelines put forth by various societies globally.
Mechanism of coagulopathy
COVID-19–associated coagulopathy has been shown to predispose to both arterial and venous thrombosis through excessive inflammation and hypoxia, leading to activation of the coagulation cascade and consumption of coagulation factors, resulting in microvascular thrombosis.3 Though the exact pathophysiology for the activation of this cascade is not known, the proposed mechanism has been: endothelial damage triggering platelet activation within the lung, leading to aggregation, thrombosis, and consumption of platelets in the lung.2,5,6
Fox et al. noted similar coagulopathy findings of four deceased COVID-19 patients. Autopsy results concluded that the dominant process was diffuse alveolar damage, notable CD4+ aggregates around thrombosed small vessels, significant associated hemorrhage, and thrombotic microangiopathy restricted to the lungs. The proposed mechanism was the activation of megakaryocytes, possibly native to the lung, with platelet aggregation, formation of platelet-rich clots, and fibrin deposition playing a major role.4
It has been noted that diabetic patients are at an increased risk of vascular events and hypercoagulability with COVID-19.7 COVID-19 can also cause livedo reticularis and acrocyanosis because of the microthrombosis in the cutaneous vasculature secondary to underlying coagulopathy, as reported in a case report of two U.S. patients with COVID-19.8
Clinical and laboratory abnormalities
A recent study reported from Netherlands by Klok et al. analyzed 184 ICU patients with COVID-19 pneumonia and concluded that the cumulative incidence of acute pulmonary embolism (PE), deep vein thrombosis (DVT), ischemic stroke, MI, or systemic arterial embolism was 31% (95% confidence interval, 20%-41%). PE was the most frequent thrombotic complication and was noted in 81% of patients. Coagulopathy, defined as spontaneous prolongation of prothrombin time (PT) > 3s or activated partial thromboplastin time (aPTT) > 5s, was reported as an independent predictor of thrombotic complications.3
Hematologic abnormalities that were noted in COVID-19 coagulopathy include: decreased platelet counts, decreased fibrinogen levels, elevated PT/INR, elevated partial thromboplastin time (PTT), and elevated d-dimer.9,10 In a retrospective analysis9 by Tang et al., 71.4% of nonsurvivors and 0.6% of survivors had met the criteria of disseminated intravascular coagulation (DIC) during their hospital stay. Nonsurvivors of COVID-19 had statistically significant elevation of d-dimer levels, FDP levels, PT, and aPTT, when compared to survivors (P < .05). The overall mortality in this study was reported as 11.5%.9 In addition, elevated d-dimer, fibrin and fibrinogen degradation product (FDP) levels and longer PT and aPTT were associated with poor prognosis.
Thus, d-dimer, PT, and platelet count should be measured in all patients who present with COVID-19 infection. We can also suggest that in patients with markedly elevated d-dimer (three- to fourfold increase), admission to hospital should be considered even in the absence of severe clinical symptoms.11
COVID-19 coagulopathy management
In a retrospective study9 of 449 patients with severe COVID-19 from Wuhan, China, by Tang et al., 99 patients mainly received low-weight molecular heparin (LMWH) for 7 days or longer. No difference in 28-day mortality was noted between heparin users and nonusers (30.3% vs. 29.7%; P = .910). A lower 28-day mortality rate was noted in heparin patients with sepsis-induced coagulopathy score of ≥4.0 (40.0% vs. 64.2%; P = .029) or a d-dimer level greater than sixfold of upper limit of normal, compared with nonusers of heparin.12
Another small study of seven COVID-19 patients with acroischemia in China demonstrated that administering LMWH was successful at decreasing the d-dimer and fibrinogen degradation product levels but noted no significant improvement in clinical symptoms.13
Recently, the International Society of Thrombosis and Hemostasis and American Society of Hematology published recommendations and guidelines regarding the recognition and management of coagulopathy in COVID-19.11 Prophylactic anticoagulation therapy with LMWH was recommended in all hospitalized patients with COVID-19, provided there was an absence of any contraindications (active bleeding, platelet count less than 25 x 109/L and fibrinogen less than 0.5 g/dL). Anticoagulation with LMWH was associated with better prognosis in severe COVID-19 patients and in COVID-19 patients with markedly elevated d-dimer, as it also has anti-inflammatory effects.12 This anti-inflammatory property of heparin has been documented in previous studies but the underlying mechanism is unknown and more research is required.14,15
Despite coagulopathy being noticed with cases of COVID-19, bleeding has been a rare finding in COVID-19 infections. If bleeding is noted, recommendations were made to keep platelet levels greater than 50 x109/L, fibrinogen less than 2.0 g/L, and INR [international normalized ratio] greater than 1.5.11 Mechanical thromboprophylaxis should be used when pharmacologic thromboprophylaxis is contraindicated.16
COVID-19 patients with new diagnoses of venous thromboembolism (VTE) or atrial fibrillation should be prescribed therapeutic anticoagulation. Patients who are already on anticoagulation for VTE or atrial fibrillation should continue their therapy unless the platelet count is less than 30-50x109/L or if the fibrinogen is less than 1.0 g/L.16
Conclusion
Coagulopathies associated with COVID-19 infections have been documented in several studies around the world, and it has been shown to be fatal in some cases. Despite documentation, the mechanism behind this coagulopathy is not well understood. Because of the potentially lethal complications associated with coagulopathies, early recognition and anticoagulation is imperative to improve clinical outcomes. These results are very preliminary: More studies are required to understand the role of anticoagulation and its effect on the morbidity and mortality associated with COVID-19–associated coagulopathy.
Dr. Yeruva is a board-certified hematologist/medical oncologist with WellSpan Health and clinical assistant professor of internal medicine, Penn State University, Hershey. Mr. Henderson is a third-year graduate-entry medical student at the Royal College of Surgeons in Ireland with interests in family medicine, dermatology, and tropical diseases. Dr. Al-Tawfiq is a consultant of internal medicine & infectious diseases, and the director of quality at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia, an adjunct associate professor of infectious diseases, molecular medicine and clinical pharmacology at Johns Hopkins University School of Medicine, and adjunct associate professor at Indiana University School of Medicine, Indianapolis. Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals.
References
1. World Health Organization. Coronavirus disease (COVID-2019) situation reports.
2. Lippi G et al. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020 Mar 13. 506:145-8. doi: 10.1016/j.cca.2020.03.022.
3. Klok FA et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Throm Res. 2020;18(4):844-7. doi: 10.1016/j.thromres.2020.04.013.
4. Fox S et al. Pulmonary and cardiac pathology in Covid-19: The first autopsy series from New Orleans. MedRxiv. 2020 Apr 10. doi: 10.1101/2020.04.06.20050575.
5. Yang M et al. Thrombocytopenia in patients with severe acute respiratory syndrome (review). Hematology 2013 Sep 4. doi: 10.1080/1024533040002617.
6. Giannis D et al. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. 2020 June. doi: 10.1016/j.jcv.2020.104362.
7. Guo W et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev. 2020 Mar 31. doi: 10.1002/dmrr.3319.
8. Manalo IF et al. A dermatologic manifestation of COVID-19: Transient livedo reticularis. J Am Acad Dermat. 2020 Apr. doi: 10.1016/j.jaad.2020.04.018.
9. Tang N et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Feb 19. doi: 10.1111/jth.14768, 18: 844-847.
10. Huang C et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020 Jan 24. doi: 10.1016/S0140-6736(20)30183-5.
11. Thachil J et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 Mar 25. doi: 10.1111/JTH.14810.
12. Tang N et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 Mar 27. doi: 10.1111/JTH.14817.
13. Zhang Y et al. Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za Zhi. 2020 Mar 28. doi: 10.3760/cma.j.issn.0253-2727.2020.0006.
14. Poterucha TJ et al. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017. doi: 10.1160/TH16-08-0620.
15. Mousavi S et al. Anti-inflammatory effects of heparin and its derivatives: A systematic review. Adv Pharmacol Pharm Sci. 2015 May 12. doi: 10.1155/2015/507151.
16. Kreuziger L et al. COVID-19 and VTE/anticoagulation: Frequently asked questions. American Society of Hematology. 2020 Apr 17.
COVID-19 pulmonary severity ascribed to coagulation differences
Differences in COVID-19-related death rates between people of white and Asian ancestry may be partly explained by documented ethnic/racial differences in risk for blood clotting and pulmonary thrombotic events, investigators propose.
“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MB, PhD, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland.
Dr. O’Donnell and colleagues studied pulmonary effects and outcomes of 83 patients admitted to St. James Hospital in Dublin, and found evidence to suggest that the diffuse, bilateral pulmonary inflammation seen in many patients with severe COVID-19 infections may be caused by a pulmonary-specific vasculopathy they label “pulmonary intravascular coagulopathy” (PIC), an entity distinct from disseminated intravascular coagulopathy (DIC).
“Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they wrote in a study published online in the British Journal of Haematology.
Study flaws harm conclusions
But critical care specialists who agreed to review and comment on the study for MDedge News said that it has significant flaws that affect the ability to interpret the findings and “undermine the conclusions reached by the authors.”
“The underlying premise of the study is that there are racial and ethnic differences in the development of venous thromboembolism that may explain the racial and ethnic differences in outcomes from COVID-19,” J. Daryl Thornton, MD, MPH, a fellow of the American Thoracic Society and associate professor of pulmonary, critical care, and sleep medicine at Case Western Reserve University, Cleveland, said in an interview. “This is an interesting hypothesis and one that could be easily tested in a well-designed study with sufficient representation from the relevant racial and ethnic groups. However, this study is neither well designed nor does it have sufficient racial and ethnic representation.”
Elliott R. Haut, MD, PhD, associate professor of surgery, anesthesiology and critical care medicine at Johns Hopkins Medicine, Baltimore, said in an interview that the study is “mediocre” and has the feel of a paper rushed to press.
“It talks about their theory that race, ethnicity, have an effect on venous thromboembolism, and that’s a pretty well-known fact. No one’s a hundred percent sure why that is, but certainly there are tons and tons of papers that show that there are groups that are at higher risk than others,” he said. “Their idea that this is caused by this pulmonary inflammation, that is totally a guess; there is no data in this paper to support that.”
Dr. Thornton and Dr. Haut both noted that the authors don’t define how race and ethnicity were determined and whether patients were asked to provide it, and although they mention the racial/ethnic breakdown once, subsequent references are to entire cohort are as “Caucasian.”
They also called into question the value of comparing laboratory data across continents in centers with different testing methods and parameters, especially in a time when the clinical picture changes so rapidly.
Coagulation differences
Dr. O’Donnell and colleagues noted that most studies of COVID-19-associated coagulopathy published to date have been with Chinese patients.
“This is important because race and ethnicity have major effects upon thrombotic risk. In particular, epidemiological studies have shown that the incidence of venous thromboembolism (VTE) is approximately three to fourfold lower in Chinese compared to Caucasian individuals. Conversely, VTE risk is significantly higher in African-Americans compared to Caucasians,” they wrote.
Because of the lower risk of VTE in the Chinese population, thromboprophylaxis with low-molecular-weight heparin (LMWH) or other agents is less frequently used in Chinese hospitals than in hospitals with predominantly non-Asian patients, they noted.
To see whether the were differences in coagulopathy between Chinese and white patients, the researchers enrolled 55 men and 28 women, median age 64, who were admitted to St. James Hospital with COVID-19 infections from March 13 through April 10, 2020. The cohort included 67 patients of white background, 10 of Asian ancestry, 5 of African ethnicity, and 1 of Latino/Hispanic ancestry.
Of the 83 patients, 67 had comorbidities at admission. At the time of the report, 50 patients had fully recovered and were discharged, 20 remained in the hospital, and 13 had died. In all, 50 patients were discharged without needing ICU care, 23 were admitted to the ICU, and 10 required ICU but were deemed “clinically unsuitable” for ICU admission.
Although the patients had normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT), plasma d-dimer levels were significantly elevated and were above the range of normal in two-thirds of patients on admission.
Despite the increased d-dimer levels, however, there was no evidence of DIC as defined by the International Society of Thrombosis and Hemostasis Scientific and Standardization committee (ISTH SSC) guidelines. Platelet counts were in the normal range in 83.1% of patients, and only five had counts less than 100 x 109/L at admission. Fibrinogen levels were also elevated, as were C-reactive protein levels, both likely indicating an acute phase response.
“Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of d-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission. Nevertheless, our data confirm that severe COVID-19 infection is associated with a significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the original Chinese cohorts,” they wrote.
When they compared patients who required ICU admission for ventilator support and those who died with patients who were discharged without needing ICU support, they found that survivors were younger (median age 60.2 vs. 75.2 years), and that more critically ill patients were more likely to have comorbidities.
They also found that patients with abnormal coagulation parameters on admission were significantly more likely to have poor prognosis (P = .018), and that patients in the adverse outcomes group had significantly higher fibrinogen and CRP levels (P = .045 and .0005, respectively).
There was no significant difference in PT between the prognosis groups at admission, but by day 4 and beyond PT was a median of 13.1 vs. 12.5 seconds in the favorable outcomes groups (P = .007), and patients with poor prognosis continued to have significantly higher d-dimer levels. (P = .003)
“Cumulatively, these data support the hypothesis that COVID-19–associated coagulopathy probably contributes to the underlying pulmonary pathogenesis,” the researchers wrote.
They noted that the angiotensin converting enzyme 2 (ACE-2) receptor that COVID-19 uses to enter cells is expressed on both type II pneumocytes and vascular endothelial cells within the lung, suggesting that the coagulopathy may be related to direct pulmonary endothelial cell infection , activation, and/or damage, and to the documented cytokine storm that can affect thrombin generation and fibrin deposition within the lungs.
“In the context of this lung-centric vasculopathy, we hypothesize that the refractory acute respiratory distress syndrome phenotype observed in severe COVID-19 is due to concurrent ‘double-hit’ pathologies targeting both ventilation (V) and perfusion (Q) within the lungs where alveoli and pulmonary microvasculature exist in close anatomical juxtaposition,” they wrote.
The investigators noted that larger randomized trials will be needed to determine whether more aggressive anti-coagulation and/or targeted anti-inflammatory therapies could effectively treated PIC in patients with severe COVID-19.
The study was supported by the Wellcome Trust and the Health Research Board Health Service and the Research and Development Division, Northern Ireland. Dr. O’Donnell disclosed speakers bureau activities, advisory board participation, and research grants from multiple companies. The other doctors had no relevant conflicts of interest to disclose.
SOURCE: Fogarty H et al. Br J Haematol. 2020 Apr 24. doi: 10.1111/bjh.16749.
Differences in COVID-19-related death rates between people of white and Asian ancestry may be partly explained by documented ethnic/racial differences in risk for blood clotting and pulmonary thrombotic events, investigators propose.
“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MB, PhD, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland.
Dr. O’Donnell and colleagues studied pulmonary effects and outcomes of 83 patients admitted to St. James Hospital in Dublin, and found evidence to suggest that the diffuse, bilateral pulmonary inflammation seen in many patients with severe COVID-19 infections may be caused by a pulmonary-specific vasculopathy they label “pulmonary intravascular coagulopathy” (PIC), an entity distinct from disseminated intravascular coagulopathy (DIC).
“Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they wrote in a study published online in the British Journal of Haematology.
Study flaws harm conclusions
But critical care specialists who agreed to review and comment on the study for MDedge News said that it has significant flaws that affect the ability to interpret the findings and “undermine the conclusions reached by the authors.”
“The underlying premise of the study is that there are racial and ethnic differences in the development of venous thromboembolism that may explain the racial and ethnic differences in outcomes from COVID-19,” J. Daryl Thornton, MD, MPH, a fellow of the American Thoracic Society and associate professor of pulmonary, critical care, and sleep medicine at Case Western Reserve University, Cleveland, said in an interview. “This is an interesting hypothesis and one that could be easily tested in a well-designed study with sufficient representation from the relevant racial and ethnic groups. However, this study is neither well designed nor does it have sufficient racial and ethnic representation.”
Elliott R. Haut, MD, PhD, associate professor of surgery, anesthesiology and critical care medicine at Johns Hopkins Medicine, Baltimore, said in an interview that the study is “mediocre” and has the feel of a paper rushed to press.
“It talks about their theory that race, ethnicity, have an effect on venous thromboembolism, and that’s a pretty well-known fact. No one’s a hundred percent sure why that is, but certainly there are tons and tons of papers that show that there are groups that are at higher risk than others,” he said. “Their idea that this is caused by this pulmonary inflammation, that is totally a guess; there is no data in this paper to support that.”
Dr. Thornton and Dr. Haut both noted that the authors don’t define how race and ethnicity were determined and whether patients were asked to provide it, and although they mention the racial/ethnic breakdown once, subsequent references are to entire cohort are as “Caucasian.”
They also called into question the value of comparing laboratory data across continents in centers with different testing methods and parameters, especially in a time when the clinical picture changes so rapidly.
Coagulation differences
Dr. O’Donnell and colleagues noted that most studies of COVID-19-associated coagulopathy published to date have been with Chinese patients.
“This is important because race and ethnicity have major effects upon thrombotic risk. In particular, epidemiological studies have shown that the incidence of venous thromboembolism (VTE) is approximately three to fourfold lower in Chinese compared to Caucasian individuals. Conversely, VTE risk is significantly higher in African-Americans compared to Caucasians,” they wrote.
Because of the lower risk of VTE in the Chinese population, thromboprophylaxis with low-molecular-weight heparin (LMWH) or other agents is less frequently used in Chinese hospitals than in hospitals with predominantly non-Asian patients, they noted.
To see whether the were differences in coagulopathy between Chinese and white patients, the researchers enrolled 55 men and 28 women, median age 64, who were admitted to St. James Hospital with COVID-19 infections from March 13 through April 10, 2020. The cohort included 67 patients of white background, 10 of Asian ancestry, 5 of African ethnicity, and 1 of Latino/Hispanic ancestry.
Of the 83 patients, 67 had comorbidities at admission. At the time of the report, 50 patients had fully recovered and were discharged, 20 remained in the hospital, and 13 had died. In all, 50 patients were discharged without needing ICU care, 23 were admitted to the ICU, and 10 required ICU but were deemed “clinically unsuitable” for ICU admission.
Although the patients had normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT), plasma d-dimer levels were significantly elevated and were above the range of normal in two-thirds of patients on admission.
Despite the increased d-dimer levels, however, there was no evidence of DIC as defined by the International Society of Thrombosis and Hemostasis Scientific and Standardization committee (ISTH SSC) guidelines. Platelet counts were in the normal range in 83.1% of patients, and only five had counts less than 100 x 109/L at admission. Fibrinogen levels were also elevated, as were C-reactive protein levels, both likely indicating an acute phase response.
“Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of d-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission. Nevertheless, our data confirm that severe COVID-19 infection is associated with a significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the original Chinese cohorts,” they wrote.
When they compared patients who required ICU admission for ventilator support and those who died with patients who were discharged without needing ICU support, they found that survivors were younger (median age 60.2 vs. 75.2 years), and that more critically ill patients were more likely to have comorbidities.
They also found that patients with abnormal coagulation parameters on admission were significantly more likely to have poor prognosis (P = .018), and that patients in the adverse outcomes group had significantly higher fibrinogen and CRP levels (P = .045 and .0005, respectively).
There was no significant difference in PT between the prognosis groups at admission, but by day 4 and beyond PT was a median of 13.1 vs. 12.5 seconds in the favorable outcomes groups (P = .007), and patients with poor prognosis continued to have significantly higher d-dimer levels. (P = .003)
“Cumulatively, these data support the hypothesis that COVID-19–associated coagulopathy probably contributes to the underlying pulmonary pathogenesis,” the researchers wrote.
They noted that the angiotensin converting enzyme 2 (ACE-2) receptor that COVID-19 uses to enter cells is expressed on both type II pneumocytes and vascular endothelial cells within the lung, suggesting that the coagulopathy may be related to direct pulmonary endothelial cell infection , activation, and/or damage, and to the documented cytokine storm that can affect thrombin generation and fibrin deposition within the lungs.
“In the context of this lung-centric vasculopathy, we hypothesize that the refractory acute respiratory distress syndrome phenotype observed in severe COVID-19 is due to concurrent ‘double-hit’ pathologies targeting both ventilation (V) and perfusion (Q) within the lungs where alveoli and pulmonary microvasculature exist in close anatomical juxtaposition,” they wrote.
The investigators noted that larger randomized trials will be needed to determine whether more aggressive anti-coagulation and/or targeted anti-inflammatory therapies could effectively treated PIC in patients with severe COVID-19.
The study was supported by the Wellcome Trust and the Health Research Board Health Service and the Research and Development Division, Northern Ireland. Dr. O’Donnell disclosed speakers bureau activities, advisory board participation, and research grants from multiple companies. The other doctors had no relevant conflicts of interest to disclose.
SOURCE: Fogarty H et al. Br J Haematol. 2020 Apr 24. doi: 10.1111/bjh.16749.
Differences in COVID-19-related death rates between people of white and Asian ancestry may be partly explained by documented ethnic/racial differences in risk for blood clotting and pulmonary thrombotic events, investigators propose.
“Our novel findings demonstrate that COVID-19 is associated with a unique type of blood clotting disorder that is primarily focused within the lungs and which undoubtedly contributes to the high levels of mortality being seen in patients with COVID-19,” said James O’Donnell, MB, PhD, director of the Irish Centre for Vascular Biology at the Royal College of Surgeons in Ireland.
Dr. O’Donnell and colleagues studied pulmonary effects and outcomes of 83 patients admitted to St. James Hospital in Dublin, and found evidence to suggest that the diffuse, bilateral pulmonary inflammation seen in many patients with severe COVID-19 infections may be caused by a pulmonary-specific vasculopathy they label “pulmonary intravascular coagulopathy” (PIC), an entity distinct from disseminated intravascular coagulopathy (DIC).
“Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID-19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID-19 mortality,” they wrote in a study published online in the British Journal of Haematology.
Study flaws harm conclusions
But critical care specialists who agreed to review and comment on the study for MDedge News said that it has significant flaws that affect the ability to interpret the findings and “undermine the conclusions reached by the authors.”
“The underlying premise of the study is that there are racial and ethnic differences in the development of venous thromboembolism that may explain the racial and ethnic differences in outcomes from COVID-19,” J. Daryl Thornton, MD, MPH, a fellow of the American Thoracic Society and associate professor of pulmonary, critical care, and sleep medicine at Case Western Reserve University, Cleveland, said in an interview. “This is an interesting hypothesis and one that could be easily tested in a well-designed study with sufficient representation from the relevant racial and ethnic groups. However, this study is neither well designed nor does it have sufficient racial and ethnic representation.”
Elliott R. Haut, MD, PhD, associate professor of surgery, anesthesiology and critical care medicine at Johns Hopkins Medicine, Baltimore, said in an interview that the study is “mediocre” and has the feel of a paper rushed to press.
“It talks about their theory that race, ethnicity, have an effect on venous thromboembolism, and that’s a pretty well-known fact. No one’s a hundred percent sure why that is, but certainly there are tons and tons of papers that show that there are groups that are at higher risk than others,” he said. “Their idea that this is caused by this pulmonary inflammation, that is totally a guess; there is no data in this paper to support that.”
Dr. Thornton and Dr. Haut both noted that the authors don’t define how race and ethnicity were determined and whether patients were asked to provide it, and although they mention the racial/ethnic breakdown once, subsequent references are to entire cohort are as “Caucasian.”
They also called into question the value of comparing laboratory data across continents in centers with different testing methods and parameters, especially in a time when the clinical picture changes so rapidly.
Coagulation differences
Dr. O’Donnell and colleagues noted that most studies of COVID-19-associated coagulopathy published to date have been with Chinese patients.
“This is important because race and ethnicity have major effects upon thrombotic risk. In particular, epidemiological studies have shown that the incidence of venous thromboembolism (VTE) is approximately three to fourfold lower in Chinese compared to Caucasian individuals. Conversely, VTE risk is significantly higher in African-Americans compared to Caucasians,” they wrote.
Because of the lower risk of VTE in the Chinese population, thromboprophylaxis with low-molecular-weight heparin (LMWH) or other agents is less frequently used in Chinese hospitals than in hospitals with predominantly non-Asian patients, they noted.
To see whether the were differences in coagulopathy between Chinese and white patients, the researchers enrolled 55 men and 28 women, median age 64, who were admitted to St. James Hospital with COVID-19 infections from March 13 through April 10, 2020. The cohort included 67 patients of white background, 10 of Asian ancestry, 5 of African ethnicity, and 1 of Latino/Hispanic ancestry.
Of the 83 patients, 67 had comorbidities at admission. At the time of the report, 50 patients had fully recovered and were discharged, 20 remained in the hospital, and 13 had died. In all, 50 patients were discharged without needing ICU care, 23 were admitted to the ICU, and 10 required ICU but were deemed “clinically unsuitable” for ICU admission.
Although the patients had normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT), plasma d-dimer levels were significantly elevated and were above the range of normal in two-thirds of patients on admission.
Despite the increased d-dimer levels, however, there was no evidence of DIC as defined by the International Society of Thrombosis and Hemostasis Scientific and Standardization committee (ISTH SSC) guidelines. Platelet counts were in the normal range in 83.1% of patients, and only five had counts less than 100 x 109/L at admission. Fibrinogen levels were also elevated, as were C-reactive protein levels, both likely indicating an acute phase response.
“Thus, despite the fact that thrombotic risk is much higher in Caucasian patients and the significant elevated levels of d-dimers observed, overt DIC as defined according to the ISTH SSC DIC score was present in none of our COVID-19 patients at time of admission. Nevertheless, our data confirm that severe COVID-19 infection is associated with a significant coagulopathy in Caucasian patients that appears to be similar in magnitude to that previously reported in the original Chinese cohorts,” they wrote.
When they compared patients who required ICU admission for ventilator support and those who died with patients who were discharged without needing ICU support, they found that survivors were younger (median age 60.2 vs. 75.2 years), and that more critically ill patients were more likely to have comorbidities.
They also found that patients with abnormal coagulation parameters on admission were significantly more likely to have poor prognosis (P = .018), and that patients in the adverse outcomes group had significantly higher fibrinogen and CRP levels (P = .045 and .0005, respectively).
There was no significant difference in PT between the prognosis groups at admission, but by day 4 and beyond PT was a median of 13.1 vs. 12.5 seconds in the favorable outcomes groups (P = .007), and patients with poor prognosis continued to have significantly higher d-dimer levels. (P = .003)
“Cumulatively, these data support the hypothesis that COVID-19–associated coagulopathy probably contributes to the underlying pulmonary pathogenesis,” the researchers wrote.
They noted that the angiotensin converting enzyme 2 (ACE-2) receptor that COVID-19 uses to enter cells is expressed on both type II pneumocytes and vascular endothelial cells within the lung, suggesting that the coagulopathy may be related to direct pulmonary endothelial cell infection , activation, and/or damage, and to the documented cytokine storm that can affect thrombin generation and fibrin deposition within the lungs.
“In the context of this lung-centric vasculopathy, we hypothesize that the refractory acute respiratory distress syndrome phenotype observed in severe COVID-19 is due to concurrent ‘double-hit’ pathologies targeting both ventilation (V) and perfusion (Q) within the lungs where alveoli and pulmonary microvasculature exist in close anatomical juxtaposition,” they wrote.
The investigators noted that larger randomized trials will be needed to determine whether more aggressive anti-coagulation and/or targeted anti-inflammatory therapies could effectively treated PIC in patients with severe COVID-19.
The study was supported by the Wellcome Trust and the Health Research Board Health Service and the Research and Development Division, Northern Ireland. Dr. O’Donnell disclosed speakers bureau activities, advisory board participation, and research grants from multiple companies. The other doctors had no relevant conflicts of interest to disclose.
SOURCE: Fogarty H et al. Br J Haematol. 2020 Apr 24. doi: 10.1111/bjh.16749.
FROM THE BRITISH JOURNAL OF HEMATOLOGY
Advances in Hematology and Oncology (May 2020)
Click here to access May 2020 Advances in Hematology and Oncology
Table of Contents
- Distress and Factors Associated with Suicidal Ideation in Veterans Living with Cancer
- Incidental Findings of Pulmonary and Hilar Malignancy by Low-Resolution Computed Tomography Used in Perfusion Imaging
- Applying a Text-Search Algorithm to Radiology Reports Can Find More Patients With Pulmonary Nodules Than Radiology Coding Alone
- Radiotherapeutic Care of Patients With Stage IV Lung Cancer and Thoracic Symptoms in the Veterans Health Administration
- Atrial Fibrillation and Bleeding in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib in the Veterans Health Administration
Click here to access May 2020 Advances in Hematology and Oncology
Table of Contents
- Distress and Factors Associated with Suicidal Ideation in Veterans Living with Cancer
- Incidental Findings of Pulmonary and Hilar Malignancy by Low-Resolution Computed Tomography Used in Perfusion Imaging
- Applying a Text-Search Algorithm to Radiology Reports Can Find More Patients With Pulmonary Nodules Than Radiology Coding Alone
- Radiotherapeutic Care of Patients With Stage IV Lung Cancer and Thoracic Symptoms in the Veterans Health Administration
- Atrial Fibrillation and Bleeding in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib in the Veterans Health Administration
Click here to access May 2020 Advances in Hematology and Oncology
Table of Contents
- Distress and Factors Associated with Suicidal Ideation in Veterans Living with Cancer
- Incidental Findings of Pulmonary and Hilar Malignancy by Low-Resolution Computed Tomography Used in Perfusion Imaging
- Applying a Text-Search Algorithm to Radiology Reports Can Find More Patients With Pulmonary Nodules Than Radiology Coding Alone
- Radiotherapeutic Care of Patients With Stage IV Lung Cancer and Thoracic Symptoms in the Veterans Health Administration
- Atrial Fibrillation and Bleeding in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib in the Veterans Health Administration
Metastatic cancer linked to worse outcomes of COVID-19
Cancer type, stage, and recent treatment may affect outcomes of COVID-19 in cancer patients, according to a study of patients from China.
The data showed that patients with hematologic malignancies and those with metastatic cancers had higher risks of developing severe or critical COVID-19 symptoms, being admitted to the ICU, requiring ventilation, and dying.
On the other hand, patients with nonmetastatic cancer had outcomes comparable to those of noncancer patients with COVID-19.
Similarly, cancer patients who had recently undergone surgery or received immunotherapy were more likely to have poor outcomes, whereas cancer patients treated with radiotherapy had outcomes similar to those of noncancer COVID-19 patients.
Hongbing Cai, MD, of Zhongnan Hospital of Wuhan University in China, presented these results at the AACR virtual meeting I. The results also were published in Cancer Discovery.
Cancer vs. noncancer patients
The study included 105 cancer patients with COVID-19 who were treated from Jan. 1 to Feb. 24, 2020, at 14 hospitals in Wuhan, China. Patients had lung (20.95%), gastrointestinal (12.38%), breast (10.48%), and thyroid cancers (10.48%) as well as hematologic malignancies (8.57%). Dr. Cai and colleagues matched the COVID-19 cancer patients to 536 COVID-19 patients without cancer. Patients were matched by hospital, duration of hospitalization, and age.
“COVID-19 patients with cancer had higher risks of all severe outcomes,” Dr. Cai noted.
Compared with noncancer patients, the cancer patients had a higher risk of:
- Severe or critical COVID-19 symptoms – odds ratio, 2.79 (P < .01).
- Being admitted to the ICU – OR, 2.84 (P < .01).
- Requiring invasive mechanical ventilation – OR, 14 (P < .01).
- Death – OR, 2.34 (P = .03).
Cancer type and stage
Dr. Cai noted that outcomes were the worst among patients with hematologic malignancies and those with metastatic cancer (stage IV).
Compared with patients without cancer, those with hematologic malignancies had a higher risk of:
- Severe/critical symptoms – OR, 10.61 (P < .01).
- ICU admission – OR, 9.66 (P < .01).
- Invasive mechanical ventilation – OR, 38 (P < .01).
- Death – OR, 9.07 (P = .01).
Compared with patients without cancer, those with metastatic cancer had a higher risk of:
- Severe/critical symptoms – OR, 5.97 (P < .01).
- ICU admission – OR, 6.59 (P < 0.01).
- Invasive mechanical ventilation – OR, 55.42 (P < .01).
- Death – OR, 5.58 (P = .01).
On the other hand, outcomes in patients with nonmetastatic cancer were not significantly different from outcomes in patients without cancer (P > .05 for all outcomes).
Cancer treatment
The treatments cancer patients received within 40 days before the onset of COVID-19 symptoms were radiotherapy (12.26%), chemotherapy (14.15%), surgery (7.62%), targeted therapies (3.81%), and immunotherapy (5.71%).
Compared with patients without cancer, those who received immunotherapy had a higher risk of:
- Severe/critical symptoms – OR, 10.61 (P < .01).
- Death – OR, 9.07 (P = .04).
Patients who underwent surgery had a higher risk of:
- Severe/critical symptoms – OR, 8.84 (P < .01).
- ICU admission – OR, 7.24 (P = .02).
- Invasive mechanical ventilation – OR, 44.33 (P < .01).
Conversely, outcomes in cancer patients who received radiotherapy were not significantly different from outcomes in patients without cancer (P > .10 for all).
These results suggest that “postponing surgery should be considered in outbreak areas,” Dr. Cai said, adding that scheduled radiotherapy can go ahead but with “intensive protection and surveillance.”
Dr. Cai said it remains to be seen whether patients with early-stage cancer need to postpone their treatments during the COVID-19 pandemic or whether immunotherapy aggravates severe outcomes in cancer patients with COVID-19. For now, she said, cancer patients should have individualized treatment plans based on their tumor type and stage.
Dr. Cai disclosed no conflicts of interest. This study was supported by the National Natural Science Foundation of China, the Singapore Ministry of Health’s National Medical Research Council, the National Institutes of Health/National Heart, Lung, and Blood Institute, and the Xiu Research Fund.
SOURCE: Cai H. AACR 2020. Patients with cancer appear more vulnerable to SARS-COV-2: A multicenter study during the COVID-19 outbreak; Dai M et al. Cancer Discov. 2020 Apr 28. doi: 10.1158/2159-8290.CD-20-0422.
Cancer type, stage, and recent treatment may affect outcomes of COVID-19 in cancer patients, according to a study of patients from China.
The data showed that patients with hematologic malignancies and those with metastatic cancers had higher risks of developing severe or critical COVID-19 symptoms, being admitted to the ICU, requiring ventilation, and dying.
On the other hand, patients with nonmetastatic cancer had outcomes comparable to those of noncancer patients with COVID-19.
Similarly, cancer patients who had recently undergone surgery or received immunotherapy were more likely to have poor outcomes, whereas cancer patients treated with radiotherapy had outcomes similar to those of noncancer COVID-19 patients.
Hongbing Cai, MD, of Zhongnan Hospital of Wuhan University in China, presented these results at the AACR virtual meeting I. The results also were published in Cancer Discovery.
Cancer vs. noncancer patients
The study included 105 cancer patients with COVID-19 who were treated from Jan. 1 to Feb. 24, 2020, at 14 hospitals in Wuhan, China. Patients had lung (20.95%), gastrointestinal (12.38%), breast (10.48%), and thyroid cancers (10.48%) as well as hematologic malignancies (8.57%). Dr. Cai and colleagues matched the COVID-19 cancer patients to 536 COVID-19 patients without cancer. Patients were matched by hospital, duration of hospitalization, and age.
“COVID-19 patients with cancer had higher risks of all severe outcomes,” Dr. Cai noted.
Compared with noncancer patients, the cancer patients had a higher risk of:
- Severe or critical COVID-19 symptoms – odds ratio, 2.79 (P < .01).
- Being admitted to the ICU – OR, 2.84 (P < .01).
- Requiring invasive mechanical ventilation – OR, 14 (P < .01).
- Death – OR, 2.34 (P = .03).
Cancer type and stage
Dr. Cai noted that outcomes were the worst among patients with hematologic malignancies and those with metastatic cancer (stage IV).
Compared with patients without cancer, those with hematologic malignancies had a higher risk of:
- Severe/critical symptoms – OR, 10.61 (P < .01).
- ICU admission – OR, 9.66 (P < .01).
- Invasive mechanical ventilation – OR, 38 (P < .01).
- Death – OR, 9.07 (P = .01).
Compared with patients without cancer, those with metastatic cancer had a higher risk of:
- Severe/critical symptoms – OR, 5.97 (P < .01).
- ICU admission – OR, 6.59 (P < 0.01).
- Invasive mechanical ventilation – OR, 55.42 (P < .01).
- Death – OR, 5.58 (P = .01).
On the other hand, outcomes in patients with nonmetastatic cancer were not significantly different from outcomes in patients without cancer (P > .05 for all outcomes).
Cancer treatment
The treatments cancer patients received within 40 days before the onset of COVID-19 symptoms were radiotherapy (12.26%), chemotherapy (14.15%), surgery (7.62%), targeted therapies (3.81%), and immunotherapy (5.71%).
Compared with patients without cancer, those who received immunotherapy had a higher risk of:
- Severe/critical symptoms – OR, 10.61 (P < .01).
- Death – OR, 9.07 (P = .04).
Patients who underwent surgery had a higher risk of:
- Severe/critical symptoms – OR, 8.84 (P < .01).
- ICU admission – OR, 7.24 (P = .02).
- Invasive mechanical ventilation – OR, 44.33 (P < .01).
Conversely, outcomes in cancer patients who received radiotherapy were not significantly different from outcomes in patients without cancer (P > .10 for all).
These results suggest that “postponing surgery should be considered in outbreak areas,” Dr. Cai said, adding that scheduled radiotherapy can go ahead but with “intensive protection and surveillance.”
Dr. Cai said it remains to be seen whether patients with early-stage cancer need to postpone their treatments during the COVID-19 pandemic or whether immunotherapy aggravates severe outcomes in cancer patients with COVID-19. For now, she said, cancer patients should have individualized treatment plans based on their tumor type and stage.
Dr. Cai disclosed no conflicts of interest. This study was supported by the National Natural Science Foundation of China, the Singapore Ministry of Health’s National Medical Research Council, the National Institutes of Health/National Heart, Lung, and Blood Institute, and the Xiu Research Fund.
SOURCE: Cai H. AACR 2020. Patients with cancer appear more vulnerable to SARS-COV-2: A multicenter study during the COVID-19 outbreak; Dai M et al. Cancer Discov. 2020 Apr 28. doi: 10.1158/2159-8290.CD-20-0422.
Cancer type, stage, and recent treatment may affect outcomes of COVID-19 in cancer patients, according to a study of patients from China.
The data showed that patients with hematologic malignancies and those with metastatic cancers had higher risks of developing severe or critical COVID-19 symptoms, being admitted to the ICU, requiring ventilation, and dying.
On the other hand, patients with nonmetastatic cancer had outcomes comparable to those of noncancer patients with COVID-19.
Similarly, cancer patients who had recently undergone surgery or received immunotherapy were more likely to have poor outcomes, whereas cancer patients treated with radiotherapy had outcomes similar to those of noncancer COVID-19 patients.
Hongbing Cai, MD, of Zhongnan Hospital of Wuhan University in China, presented these results at the AACR virtual meeting I. The results also were published in Cancer Discovery.
Cancer vs. noncancer patients
The study included 105 cancer patients with COVID-19 who were treated from Jan. 1 to Feb. 24, 2020, at 14 hospitals in Wuhan, China. Patients had lung (20.95%), gastrointestinal (12.38%), breast (10.48%), and thyroid cancers (10.48%) as well as hematologic malignancies (8.57%). Dr. Cai and colleagues matched the COVID-19 cancer patients to 536 COVID-19 patients without cancer. Patients were matched by hospital, duration of hospitalization, and age.
“COVID-19 patients with cancer had higher risks of all severe outcomes,” Dr. Cai noted.
Compared with noncancer patients, the cancer patients had a higher risk of:
- Severe or critical COVID-19 symptoms – odds ratio, 2.79 (P < .01).
- Being admitted to the ICU – OR, 2.84 (P < .01).
- Requiring invasive mechanical ventilation – OR, 14 (P < .01).
- Death – OR, 2.34 (P = .03).
Cancer type and stage
Dr. Cai noted that outcomes were the worst among patients with hematologic malignancies and those with metastatic cancer (stage IV).
Compared with patients without cancer, those with hematologic malignancies had a higher risk of:
- Severe/critical symptoms – OR, 10.61 (P < .01).
- ICU admission – OR, 9.66 (P < .01).
- Invasive mechanical ventilation – OR, 38 (P < .01).
- Death – OR, 9.07 (P = .01).
Compared with patients without cancer, those with metastatic cancer had a higher risk of:
- Severe/critical symptoms – OR, 5.97 (P < .01).
- ICU admission – OR, 6.59 (P < 0.01).
- Invasive mechanical ventilation – OR, 55.42 (P < .01).
- Death – OR, 5.58 (P = .01).
On the other hand, outcomes in patients with nonmetastatic cancer were not significantly different from outcomes in patients without cancer (P > .05 for all outcomes).
Cancer treatment
The treatments cancer patients received within 40 days before the onset of COVID-19 symptoms were radiotherapy (12.26%), chemotherapy (14.15%), surgery (7.62%), targeted therapies (3.81%), and immunotherapy (5.71%).
Compared with patients without cancer, those who received immunotherapy had a higher risk of:
- Severe/critical symptoms – OR, 10.61 (P < .01).
- Death – OR, 9.07 (P = .04).
Patients who underwent surgery had a higher risk of:
- Severe/critical symptoms – OR, 8.84 (P < .01).
- ICU admission – OR, 7.24 (P = .02).
- Invasive mechanical ventilation – OR, 44.33 (P < .01).
Conversely, outcomes in cancer patients who received radiotherapy were not significantly different from outcomes in patients without cancer (P > .10 for all).
These results suggest that “postponing surgery should be considered in outbreak areas,” Dr. Cai said, adding that scheduled radiotherapy can go ahead but with “intensive protection and surveillance.”
Dr. Cai said it remains to be seen whether patients with early-stage cancer need to postpone their treatments during the COVID-19 pandemic or whether immunotherapy aggravates severe outcomes in cancer patients with COVID-19. For now, she said, cancer patients should have individualized treatment plans based on their tumor type and stage.
Dr. Cai disclosed no conflicts of interest. This study was supported by the National Natural Science Foundation of China, the Singapore Ministry of Health’s National Medical Research Council, the National Institutes of Health/National Heart, Lung, and Blood Institute, and the Xiu Research Fund.
SOURCE: Cai H. AACR 2020. Patients with cancer appear more vulnerable to SARS-COV-2: A multicenter study during the COVID-19 outbreak; Dai M et al. Cancer Discov. 2020 Apr 28. doi: 10.1158/2159-8290.CD-20-0422.
FROM AACR 2020
Six million childhood cancer deaths could be prevented over the next 30 years
Unless global investments are made to improve care worldwide, 11.1 million children will die from cancer over the next 30 years; 9.3 million of them (84%) will be in low- and lower-middle–income countries, according to a report in Lancet Oncology.
The report suggests that one in two new cases of childhood cancer are undiagnosed in low- and middle-income countries. If that trend continues, the number of children with cancer who are never diagnosed over the next 3 decades will exceed the number of those who are diagnosed.
Childhood cancer “is not complex, expensive, difficult to diagnose, or complicated to treat,” yet there’s a “worldwide inequity and a bleak picture for children with cancer” in low-income and middle-income countries, according to the report authors. The authors are 44 oncologists, pediatricians, and global health experts from around the world, led by Rifat Atun, MD, a professor of global health systems at Harvard University in Boston.
“For too long, there has been a widespread misconception that caring for children with cancer in low- and middle-income countries is expensive, unattainable, and inappropriate because of competing health priorities. Nothing could be further from the truth,” Dr. Atun said in a statement.
Dr. Atun and colleagues argued that the burden of childhood cancer “could be vastly reduced with new funding to scale up cost-effective interventions.” In fact, the authors estimated that scaling up interventions could prevent 6.2 million childhood cancer deaths between 2020 and 2050.
The reduction in deaths would translate to 318.4 million life-years gained, which would, in turn, translate to a global lifetime productivity gain of $2,580 billion, four times greater than the cumulative cost of $594 billion. This would mean a net return of $3 for every $1 spent.
Potential funders include governments, professional organizations, philanthropic groups, and industry, according to the authors. They also laid out the following six-pronged framework on how to proceed:
- Include childhood cancer in universal health coverage.
- Develop national cancer control plans for low-income and middle-income countries.
- End out-of-pocket costs for childhood cancer.
- Establish national and regional cancer networks to increase access to care.
- Expand population-based cancer registries to include children.
- Invest in research and innovations in low-income and middle-income countries.
“Success will be attained through political leadership, global solidarity, collective action, inclusive participation of all major stakeholders, and alignment of national and global efforts to expand access to effective and sustainable care for children with cancer,” the authors wrote.
No funding sources were reported. The authors didn’t have any disclosures.
SOURCE: Atun R et al. Lancet Oncol. 2020 Apr;21(4):e185-224.
Unless global investments are made to improve care worldwide, 11.1 million children will die from cancer over the next 30 years; 9.3 million of them (84%) will be in low- and lower-middle–income countries, according to a report in Lancet Oncology.
The report suggests that one in two new cases of childhood cancer are undiagnosed in low- and middle-income countries. If that trend continues, the number of children with cancer who are never diagnosed over the next 3 decades will exceed the number of those who are diagnosed.
Childhood cancer “is not complex, expensive, difficult to diagnose, or complicated to treat,” yet there’s a “worldwide inequity and a bleak picture for children with cancer” in low-income and middle-income countries, according to the report authors. The authors are 44 oncologists, pediatricians, and global health experts from around the world, led by Rifat Atun, MD, a professor of global health systems at Harvard University in Boston.
“For too long, there has been a widespread misconception that caring for children with cancer in low- and middle-income countries is expensive, unattainable, and inappropriate because of competing health priorities. Nothing could be further from the truth,” Dr. Atun said in a statement.
Dr. Atun and colleagues argued that the burden of childhood cancer “could be vastly reduced with new funding to scale up cost-effective interventions.” In fact, the authors estimated that scaling up interventions could prevent 6.2 million childhood cancer deaths between 2020 and 2050.
The reduction in deaths would translate to 318.4 million life-years gained, which would, in turn, translate to a global lifetime productivity gain of $2,580 billion, four times greater than the cumulative cost of $594 billion. This would mean a net return of $3 for every $1 spent.
Potential funders include governments, professional organizations, philanthropic groups, and industry, according to the authors. They also laid out the following six-pronged framework on how to proceed:
- Include childhood cancer in universal health coverage.
- Develop national cancer control plans for low-income and middle-income countries.
- End out-of-pocket costs for childhood cancer.
- Establish national and regional cancer networks to increase access to care.
- Expand population-based cancer registries to include children.
- Invest in research and innovations in low-income and middle-income countries.
“Success will be attained through political leadership, global solidarity, collective action, inclusive participation of all major stakeholders, and alignment of national and global efforts to expand access to effective and sustainable care for children with cancer,” the authors wrote.
No funding sources were reported. The authors didn’t have any disclosures.
SOURCE: Atun R et al. Lancet Oncol. 2020 Apr;21(4):e185-224.
Unless global investments are made to improve care worldwide, 11.1 million children will die from cancer over the next 30 years; 9.3 million of them (84%) will be in low- and lower-middle–income countries, according to a report in Lancet Oncology.
The report suggests that one in two new cases of childhood cancer are undiagnosed in low- and middle-income countries. If that trend continues, the number of children with cancer who are never diagnosed over the next 3 decades will exceed the number of those who are diagnosed.
Childhood cancer “is not complex, expensive, difficult to diagnose, or complicated to treat,” yet there’s a “worldwide inequity and a bleak picture for children with cancer” in low-income and middle-income countries, according to the report authors. The authors are 44 oncologists, pediatricians, and global health experts from around the world, led by Rifat Atun, MD, a professor of global health systems at Harvard University in Boston.
“For too long, there has been a widespread misconception that caring for children with cancer in low- and middle-income countries is expensive, unattainable, and inappropriate because of competing health priorities. Nothing could be further from the truth,” Dr. Atun said in a statement.
Dr. Atun and colleagues argued that the burden of childhood cancer “could be vastly reduced with new funding to scale up cost-effective interventions.” In fact, the authors estimated that scaling up interventions could prevent 6.2 million childhood cancer deaths between 2020 and 2050.
The reduction in deaths would translate to 318.4 million life-years gained, which would, in turn, translate to a global lifetime productivity gain of $2,580 billion, four times greater than the cumulative cost of $594 billion. This would mean a net return of $3 for every $1 spent.
Potential funders include governments, professional organizations, philanthropic groups, and industry, according to the authors. They also laid out the following six-pronged framework on how to proceed:
- Include childhood cancer in universal health coverage.
- Develop national cancer control plans for low-income and middle-income countries.
- End out-of-pocket costs for childhood cancer.
- Establish national and regional cancer networks to increase access to care.
- Expand population-based cancer registries to include children.
- Invest in research and innovations in low-income and middle-income countries.
“Success will be attained through political leadership, global solidarity, collective action, inclusive participation of all major stakeholders, and alignment of national and global efforts to expand access to effective and sustainable care for children with cancer,” the authors wrote.
No funding sources were reported. The authors didn’t have any disclosures.
SOURCE: Atun R et al. Lancet Oncol. 2020 Apr;21(4):e185-224.
FROM LANCET ONCOLOGY