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REACH2: Ruxolitinib outperformed control treatment for refractory acute GVHD
Ruxolitinib produced significantly better efficacy outcomes in patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD), compared with investigator’s choice of control therapy, in the phase 3 REACH2 trial.
However, there was a higher incidence of thrombocytopenia with ruxolitinib than with control treatment, according to a report by Robert Zeiser, MD, of University of Freiburg (Germany) and colleagues on behalf of the REACH2 research group. The report was published in the New England Journal of Medicine.
The REACH2 trial (NCT02913261) is a randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with investigator’s choice of therapy for control treatment using a list of nine commonly used options.
Patients were 12 years of age or older with glucocorticoid-refractory acute GVHD after allogeneic stem cell transplant. A total of 154 patients were assigned to the ruxolitinib group, and 155 patients were in the control group.
Most patients – 152 in the ruxolitinib group and 150 in the control group – received at least one dose of trial treatment.
Treatment discontinuation occurred in 72% (111/154) of patients in the ruxolitinib group and in 85% (132/155) of those in the control group. The most common reason for discontinuation was lack of efficacy (in 21% and 44%, respectively).
Outcomes
The overall response at day 28 (the primary endpoint) was significantly higher in the ruxolitinib group than in the control group (62% vs. 39%; odds ratio, 2.64; P < .001). The durable overall response at day 56 was also significantly higher in the ruxolitinib group than in the control group (40% vs. 22%; OR, 2.38; P < .001).
The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group compared with 39% in the control group.
The median failure-free survival was considerably longer with ruxolitinib than with control treatment (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non–relapse-related death, or the use of new systemic therapy for acute GVHD, 0.46).
The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (HR, 0.83).
Overall, 72 patients (47%) in the ruxolitinib group and 77 (51%) in the control group died by the data cutoff date. Most deaths were attributed to acute GVHD (22% in the ruxolitinib group and 25% in the control group).
The most common adverse events at day 28 (in the ruxolitinib and control arms, respectively) were thrombocytopenia (33% and 18%), anemia (30% and 28%), and cytomegalovirus infection (26% and 21%).
Praise for ‘successful’ randomized trial in GVHD
“The authors are to be congratulated for completing this successful randomized trial, which showed convincingly that ruxolitinib was more effective than the investigator’s choice of therapy ... in patients in whom glucocorticoid therapy had failed,” wrote Nelson Chao, MD, of Duke University in Durham, N.C., in his invited editorial.
He went on to speculate on the possible mechanism for ruxolitinib in these patients, discussing the possible role of the STAT3 and STAT1 signaling pathways.
Dr. Chao also found it “interesting that the incidence of infectious complications or relapse was apparently not greater with ruxolitinib than with control therapy,” but he noted that the total follow-up time was short.
“As with all good research, these observations raise important questions and set the stage for further work in this area,” he concluded.
The REACH2 trial was funded by Novartis. The study authors disclosed relationships with a variety of pharmaceutical companies, including Novartis. Dr. Chao reported having no relevant disclosures.
SOURCE: Zeiser R et al. N Engl J Med. 2020. doi: 10.1056/NEJMoa1917635.
Ruxolitinib produced significantly better efficacy outcomes in patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD), compared with investigator’s choice of control therapy, in the phase 3 REACH2 trial.
However, there was a higher incidence of thrombocytopenia with ruxolitinib than with control treatment, according to a report by Robert Zeiser, MD, of University of Freiburg (Germany) and colleagues on behalf of the REACH2 research group. The report was published in the New England Journal of Medicine.
The REACH2 trial (NCT02913261) is a randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with investigator’s choice of therapy for control treatment using a list of nine commonly used options.
Patients were 12 years of age or older with glucocorticoid-refractory acute GVHD after allogeneic stem cell transplant. A total of 154 patients were assigned to the ruxolitinib group, and 155 patients were in the control group.
Most patients – 152 in the ruxolitinib group and 150 in the control group – received at least one dose of trial treatment.
Treatment discontinuation occurred in 72% (111/154) of patients in the ruxolitinib group and in 85% (132/155) of those in the control group. The most common reason for discontinuation was lack of efficacy (in 21% and 44%, respectively).
Outcomes
The overall response at day 28 (the primary endpoint) was significantly higher in the ruxolitinib group than in the control group (62% vs. 39%; odds ratio, 2.64; P < .001). The durable overall response at day 56 was also significantly higher in the ruxolitinib group than in the control group (40% vs. 22%; OR, 2.38; P < .001).
The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group compared with 39% in the control group.
The median failure-free survival was considerably longer with ruxolitinib than with control treatment (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non–relapse-related death, or the use of new systemic therapy for acute GVHD, 0.46).
The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (HR, 0.83).
Overall, 72 patients (47%) in the ruxolitinib group and 77 (51%) in the control group died by the data cutoff date. Most deaths were attributed to acute GVHD (22% in the ruxolitinib group and 25% in the control group).
The most common adverse events at day 28 (in the ruxolitinib and control arms, respectively) were thrombocytopenia (33% and 18%), anemia (30% and 28%), and cytomegalovirus infection (26% and 21%).
Praise for ‘successful’ randomized trial in GVHD
“The authors are to be congratulated for completing this successful randomized trial, which showed convincingly that ruxolitinib was more effective than the investigator’s choice of therapy ... in patients in whom glucocorticoid therapy had failed,” wrote Nelson Chao, MD, of Duke University in Durham, N.C., in his invited editorial.
He went on to speculate on the possible mechanism for ruxolitinib in these patients, discussing the possible role of the STAT3 and STAT1 signaling pathways.
Dr. Chao also found it “interesting that the incidence of infectious complications or relapse was apparently not greater with ruxolitinib than with control therapy,” but he noted that the total follow-up time was short.
“As with all good research, these observations raise important questions and set the stage for further work in this area,” he concluded.
The REACH2 trial was funded by Novartis. The study authors disclosed relationships with a variety of pharmaceutical companies, including Novartis. Dr. Chao reported having no relevant disclosures.
SOURCE: Zeiser R et al. N Engl J Med. 2020. doi: 10.1056/NEJMoa1917635.
Ruxolitinib produced significantly better efficacy outcomes in patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD), compared with investigator’s choice of control therapy, in the phase 3 REACH2 trial.
However, there was a higher incidence of thrombocytopenia with ruxolitinib than with control treatment, according to a report by Robert Zeiser, MD, of University of Freiburg (Germany) and colleagues on behalf of the REACH2 research group. The report was published in the New England Journal of Medicine.
The REACH2 trial (NCT02913261) is a randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with investigator’s choice of therapy for control treatment using a list of nine commonly used options.
Patients were 12 years of age or older with glucocorticoid-refractory acute GVHD after allogeneic stem cell transplant. A total of 154 patients were assigned to the ruxolitinib group, and 155 patients were in the control group.
Most patients – 152 in the ruxolitinib group and 150 in the control group – received at least one dose of trial treatment.
Treatment discontinuation occurred in 72% (111/154) of patients in the ruxolitinib group and in 85% (132/155) of those in the control group. The most common reason for discontinuation was lack of efficacy (in 21% and 44%, respectively).
Outcomes
The overall response at day 28 (the primary endpoint) was significantly higher in the ruxolitinib group than in the control group (62% vs. 39%; odds ratio, 2.64; P < .001). The durable overall response at day 56 was also significantly higher in the ruxolitinib group than in the control group (40% vs. 22%; OR, 2.38; P < .001).
The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group compared with 39% in the control group.
The median failure-free survival was considerably longer with ruxolitinib than with control treatment (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non–relapse-related death, or the use of new systemic therapy for acute GVHD, 0.46).
The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (HR, 0.83).
Overall, 72 patients (47%) in the ruxolitinib group and 77 (51%) in the control group died by the data cutoff date. Most deaths were attributed to acute GVHD (22% in the ruxolitinib group and 25% in the control group).
The most common adverse events at day 28 (in the ruxolitinib and control arms, respectively) were thrombocytopenia (33% and 18%), anemia (30% and 28%), and cytomegalovirus infection (26% and 21%).
Praise for ‘successful’ randomized trial in GVHD
“The authors are to be congratulated for completing this successful randomized trial, which showed convincingly that ruxolitinib was more effective than the investigator’s choice of therapy ... in patients in whom glucocorticoid therapy had failed,” wrote Nelson Chao, MD, of Duke University in Durham, N.C., in his invited editorial.
He went on to speculate on the possible mechanism for ruxolitinib in these patients, discussing the possible role of the STAT3 and STAT1 signaling pathways.
Dr. Chao also found it “interesting that the incidence of infectious complications or relapse was apparently not greater with ruxolitinib than with control therapy,” but he noted that the total follow-up time was short.
“As with all good research, these observations raise important questions and set the stage for further work in this area,” he concluded.
The REACH2 trial was funded by Novartis. The study authors disclosed relationships with a variety of pharmaceutical companies, including Novartis. Dr. Chao reported having no relevant disclosures.
SOURCE: Zeiser R et al. N Engl J Med. 2020. doi: 10.1056/NEJMoa1917635.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Ruxolitinib was significantly more effective against acute graft-versus-host disease than was control treatment.
Major finding: The overall response at day 28 was significantly higher in the ruxolitinib group than in the control group (62% vs. 39%; P < .001).
Study details: Phase 3 trial of 154 patients randomized to ruxolitinib and 155 patients randomized to investigator’s choice of control therapy.
Disclosures: The trial was funded by Novartis. Authors disclosed relationships with a variety of pharmaceutical companies, including Novartis.
Source: Zeiser R et al. N Engl J Med. 2020. doi: 10.1056/NEJMoa1917635.
CLAM trial regimen shown safe, effective for r/r AML
A clofarabine-based treatment was found to be safe and effective in refractory/relapsed acute myeloid leukemia (AML) in the phase 2 CLAM trial.
The CLAM protocol treatment was clofarabine, cytarabine, and mitoxantrone (intravenous infusion, days 1‐5), cytarabine (intravenous infusion starting 4 hours after clofarabine, days 1‐5), and mitoxantrone (intravenous infusion, days 3‐5).
Bone marrow aspiration and trephine biopsy were performed on day 28. A total of 52 patients (16 women), with an age range of 22-65 years and refractory/relapsed AML were treated.
The overall response rate after the first cycle of CLAM was 90.4% (complete remission, 69.2%; CR with incomplete hematologic recovery, 21.2%). In addition, the efficacy of CLAM was not apparently affected by high‐risk karyotypes and genetic mutations among the patients.
Patients with a response (marrow < 5% blasts) received a maximum of two cycles of CLAM consolidation, each at 50% dose reduction, given 6‐8 weeks apart. Responding patients with an HLA‐matched sibling or volunteer‐unrelated donor were offered allogeneic hematopoietic stem cell transplantation (HSCT). Toxicity of CLAM was manageable and did not compromise subsequent allogeneic HSCT, the researchers added.
“In this era of molecular targeting, CLAM might still have a role to play,” according to the researchers. “It offers the advantage of a highly effective regimen that is readily available. It provides a median DOR of 5 months, which is meaningful for organization of HSCT. Delays associated with recruitment into clinical trials or sourcing of targeted drugs are obviated. Precious time is saved, so that patients can quickly be bridged to a potentially curative allogeneic HSCT.”
No disclosures or conflicts of interest were reported.
SOURCE: Gill H et al. Cancer Med. 2020 Mar 20. doi:10.1002/cam4.2865.
A clofarabine-based treatment was found to be safe and effective in refractory/relapsed acute myeloid leukemia (AML) in the phase 2 CLAM trial.
The CLAM protocol treatment was clofarabine, cytarabine, and mitoxantrone (intravenous infusion, days 1‐5), cytarabine (intravenous infusion starting 4 hours after clofarabine, days 1‐5), and mitoxantrone (intravenous infusion, days 3‐5).
Bone marrow aspiration and trephine biopsy were performed on day 28. A total of 52 patients (16 women), with an age range of 22-65 years and refractory/relapsed AML were treated.
The overall response rate after the first cycle of CLAM was 90.4% (complete remission, 69.2%; CR with incomplete hematologic recovery, 21.2%). In addition, the efficacy of CLAM was not apparently affected by high‐risk karyotypes and genetic mutations among the patients.
Patients with a response (marrow < 5% blasts) received a maximum of two cycles of CLAM consolidation, each at 50% dose reduction, given 6‐8 weeks apart. Responding patients with an HLA‐matched sibling or volunteer‐unrelated donor were offered allogeneic hematopoietic stem cell transplantation (HSCT). Toxicity of CLAM was manageable and did not compromise subsequent allogeneic HSCT, the researchers added.
“In this era of molecular targeting, CLAM might still have a role to play,” according to the researchers. “It offers the advantage of a highly effective regimen that is readily available. It provides a median DOR of 5 months, which is meaningful for organization of HSCT. Delays associated with recruitment into clinical trials or sourcing of targeted drugs are obviated. Precious time is saved, so that patients can quickly be bridged to a potentially curative allogeneic HSCT.”
No disclosures or conflicts of interest were reported.
SOURCE: Gill H et al. Cancer Med. 2020 Mar 20. doi:10.1002/cam4.2865.
A clofarabine-based treatment was found to be safe and effective in refractory/relapsed acute myeloid leukemia (AML) in the phase 2 CLAM trial.
The CLAM protocol treatment was clofarabine, cytarabine, and mitoxantrone (intravenous infusion, days 1‐5), cytarabine (intravenous infusion starting 4 hours after clofarabine, days 1‐5), and mitoxantrone (intravenous infusion, days 3‐5).
Bone marrow aspiration and trephine biopsy were performed on day 28. A total of 52 patients (16 women), with an age range of 22-65 years and refractory/relapsed AML were treated.
The overall response rate after the first cycle of CLAM was 90.4% (complete remission, 69.2%; CR with incomplete hematologic recovery, 21.2%). In addition, the efficacy of CLAM was not apparently affected by high‐risk karyotypes and genetic mutations among the patients.
Patients with a response (marrow < 5% blasts) received a maximum of two cycles of CLAM consolidation, each at 50% dose reduction, given 6‐8 weeks apart. Responding patients with an HLA‐matched sibling or volunteer‐unrelated donor were offered allogeneic hematopoietic stem cell transplantation (HSCT). Toxicity of CLAM was manageable and did not compromise subsequent allogeneic HSCT, the researchers added.
“In this era of molecular targeting, CLAM might still have a role to play,” according to the researchers. “It offers the advantage of a highly effective regimen that is readily available. It provides a median DOR of 5 months, which is meaningful for organization of HSCT. Delays associated with recruitment into clinical trials or sourcing of targeted drugs are obviated. Precious time is saved, so that patients can quickly be bridged to a potentially curative allogeneic HSCT.”
No disclosures or conflicts of interest were reported.
SOURCE: Gill H et al. Cancer Med. 2020 Mar 20. doi:10.1002/cam4.2865.
FROM CANCER MEDICINE
Cytokine release syndrome in severe COVID-19: Is tocilizumab effective?
A large amount of data suggest that mild or severe cytokine storms, accompanied by high expression of interleukin-6 (IL-6), occur in patients with severe coronavirus disease and can be an important cause of death. Blocking the signal transduction pathway of IL-6 is expected to become a new method for the treatment of patients with severe COVID-19, with the IL-6 inhibitor, tocilizumab (Actemra), poised to become an effective drug for these patients, according to the authors of a review published online in the International Journal of Antimicrobial Agents.
The reviewers from China detailed the metabolic pathways and regulation of cytokine release syndrome, especially with respect to what is known about severe COVID-19, and discussed the results of recent trials with tocilizumab, which is currently used for treatment of CRS in a variety of cancers and other metabolic disorders.
Tocilizumab is a recombinant humanized monoclonal antibody against human IL-6 receptor of immunoglobulin IgG1 subtype and has been approved for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. The antibody specifically binds soluble- and membrane-bound IL-6 receptors (sIL-6R and mIL-6R) and inhibits sIL-6R– and mIL-6R–mediated signal transduction. It has been shown to be effective in the treatment of severe CRS patients. In 2017, the U.S. Food and Drug Administration approved tocilizumab for the treatment of CRS caused by CAR-T (chimeric antigen receptor T-cell immunotherapy) therapy.
A small clinical trial in China examined the effectiveness of tocilizumab in 21 patients who met the criteria for severe or critical COVID-19, including respiratory failure requiring mechanical ventilation, shock, or admission to the ICU with other organ failure. After a few days of tocilizumab treatment, the body temperatures returned to normal (initially, all 21 patients had fevers), and all other symptoms were significantly improved, according to the authors. A total of 75% (15/20) of the patients reduced their oxygen intake, and 1 patient did not need oxygen. CT scanning showed that 90.5% (19/21) of the patients had absorption of pulmonary lesions, and lab tests showed that the proportion of peripheral blood lymphocytes and C-reactive protein in the patients returned to normal.
The main deficiency of the study was that only the level of IL-6 in peripheral blood before treatment with tocilizumab was reported (mean value, 132.38 ± 278.54 pg/mL), but the level of IL-6 following treatment was not given, according to the reviewers. Serum levels of IL-6 in normal patients are undetectable or very low.
Based upon their analysis of COVID-19’s possible mechanism and the small samples of clinical data available, tocilizumab appeared effective, and “we suggest that it should be used in critically ill COVID-19 patients with significantly elevated IL-6,” the authors stated.
“CRS occurs in a large number of patients with severe COVID-19, which is also an important cause of death. IL-6 is the key molecule of CRS, so IL-6R antagonist tocilizumab may be an important drug to save patients’ lives,” the researchers concluded.
This study was supported by China Mega-Project for Infectious Diseases and the China Mega-Project for Innovative Drugs. The authors reported that they had no conflicts.
SOURCE: Zhang C et al. Int J Antimicrobial Agents. 2020. doi. org/10.1016/j.ijantimicag.2020.105954.
A large amount of data suggest that mild or severe cytokine storms, accompanied by high expression of interleukin-6 (IL-6), occur in patients with severe coronavirus disease and can be an important cause of death. Blocking the signal transduction pathway of IL-6 is expected to become a new method for the treatment of patients with severe COVID-19, with the IL-6 inhibitor, tocilizumab (Actemra), poised to become an effective drug for these patients, according to the authors of a review published online in the International Journal of Antimicrobial Agents.
The reviewers from China detailed the metabolic pathways and regulation of cytokine release syndrome, especially with respect to what is known about severe COVID-19, and discussed the results of recent trials with tocilizumab, which is currently used for treatment of CRS in a variety of cancers and other metabolic disorders.
Tocilizumab is a recombinant humanized monoclonal antibody against human IL-6 receptor of immunoglobulin IgG1 subtype and has been approved for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. The antibody specifically binds soluble- and membrane-bound IL-6 receptors (sIL-6R and mIL-6R) and inhibits sIL-6R– and mIL-6R–mediated signal transduction. It has been shown to be effective in the treatment of severe CRS patients. In 2017, the U.S. Food and Drug Administration approved tocilizumab for the treatment of CRS caused by CAR-T (chimeric antigen receptor T-cell immunotherapy) therapy.
A small clinical trial in China examined the effectiveness of tocilizumab in 21 patients who met the criteria for severe or critical COVID-19, including respiratory failure requiring mechanical ventilation, shock, or admission to the ICU with other organ failure. After a few days of tocilizumab treatment, the body temperatures returned to normal (initially, all 21 patients had fevers), and all other symptoms were significantly improved, according to the authors. A total of 75% (15/20) of the patients reduced their oxygen intake, and 1 patient did not need oxygen. CT scanning showed that 90.5% (19/21) of the patients had absorption of pulmonary lesions, and lab tests showed that the proportion of peripheral blood lymphocytes and C-reactive protein in the patients returned to normal.
The main deficiency of the study was that only the level of IL-6 in peripheral blood before treatment with tocilizumab was reported (mean value, 132.38 ± 278.54 pg/mL), but the level of IL-6 following treatment was not given, according to the reviewers. Serum levels of IL-6 in normal patients are undetectable or very low.
Based upon their analysis of COVID-19’s possible mechanism and the small samples of clinical data available, tocilizumab appeared effective, and “we suggest that it should be used in critically ill COVID-19 patients with significantly elevated IL-6,” the authors stated.
“CRS occurs in a large number of patients with severe COVID-19, which is also an important cause of death. IL-6 is the key molecule of CRS, so IL-6R antagonist tocilizumab may be an important drug to save patients’ lives,” the researchers concluded.
This study was supported by China Mega-Project for Infectious Diseases and the China Mega-Project for Innovative Drugs. The authors reported that they had no conflicts.
SOURCE: Zhang C et al. Int J Antimicrobial Agents. 2020. doi. org/10.1016/j.ijantimicag.2020.105954.
A large amount of data suggest that mild or severe cytokine storms, accompanied by high expression of interleukin-6 (IL-6), occur in patients with severe coronavirus disease and can be an important cause of death. Blocking the signal transduction pathway of IL-6 is expected to become a new method for the treatment of patients with severe COVID-19, with the IL-6 inhibitor, tocilizumab (Actemra), poised to become an effective drug for these patients, according to the authors of a review published online in the International Journal of Antimicrobial Agents.
The reviewers from China detailed the metabolic pathways and regulation of cytokine release syndrome, especially with respect to what is known about severe COVID-19, and discussed the results of recent trials with tocilizumab, which is currently used for treatment of CRS in a variety of cancers and other metabolic disorders.
Tocilizumab is a recombinant humanized monoclonal antibody against human IL-6 receptor of immunoglobulin IgG1 subtype and has been approved for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. The antibody specifically binds soluble- and membrane-bound IL-6 receptors (sIL-6R and mIL-6R) and inhibits sIL-6R– and mIL-6R–mediated signal transduction. It has been shown to be effective in the treatment of severe CRS patients. In 2017, the U.S. Food and Drug Administration approved tocilizumab for the treatment of CRS caused by CAR-T (chimeric antigen receptor T-cell immunotherapy) therapy.
A small clinical trial in China examined the effectiveness of tocilizumab in 21 patients who met the criteria for severe or critical COVID-19, including respiratory failure requiring mechanical ventilation, shock, or admission to the ICU with other organ failure. After a few days of tocilizumab treatment, the body temperatures returned to normal (initially, all 21 patients had fevers), and all other symptoms were significantly improved, according to the authors. A total of 75% (15/20) of the patients reduced their oxygen intake, and 1 patient did not need oxygen. CT scanning showed that 90.5% (19/21) of the patients had absorption of pulmonary lesions, and lab tests showed that the proportion of peripheral blood lymphocytes and C-reactive protein in the patients returned to normal.
The main deficiency of the study was that only the level of IL-6 in peripheral blood before treatment with tocilizumab was reported (mean value, 132.38 ± 278.54 pg/mL), but the level of IL-6 following treatment was not given, according to the reviewers. Serum levels of IL-6 in normal patients are undetectable or very low.
Based upon their analysis of COVID-19’s possible mechanism and the small samples of clinical data available, tocilizumab appeared effective, and “we suggest that it should be used in critically ill COVID-19 patients with significantly elevated IL-6,” the authors stated.
“CRS occurs in a large number of patients with severe COVID-19, which is also an important cause of death. IL-6 is the key molecule of CRS, so IL-6R antagonist tocilizumab may be an important drug to save patients’ lives,” the researchers concluded.
This study was supported by China Mega-Project for Infectious Diseases and the China Mega-Project for Innovative Drugs. The authors reported that they had no conflicts.
SOURCE: Zhang C et al. Int J Antimicrobial Agents. 2020. doi. org/10.1016/j.ijantimicag.2020.105954.
FROM THE INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
AASLD: Liver transplants should proceed despite COVID-19
In liver transplant recipients or patients with autoimmune hepatitis on immunosuppressive therapy, acute cellular rejection or disease flare should not be presumed in the face of active coronavirus disease 2019 (COVID-19), according to the American Association for the Study of Liver Diseases (AASLD).
Signs that would normally be interpreted as flare or rejection need to be considered more cautiously now because the virus attacks the liver, and elevated aspartate aminotransferase, alanine aminotransferase, and slightly elevated bilirubin are common, ranging from a prevalence of 14% to 53% in COVID-19 patients. Acute liver injury is possible, especially in more severe cases, the group said.
The advice comes from a recently released document from AASLD, called “Clinical Insights for Hepatology and Liver Transplant Providers During the Covid-19 Pandemic,” to help hepatologists and liver transplant providers negotiate the pandemic, according to the latest data. It’s a far-ranging work that contains a lot of now familiar steps for providers to take to protect themselves and patients from the virus, but also much advice specific to liver medicine.
For instance, the group said it’s important to keep in mind that experimental treatments for the infection, including statins, remdesivir, and tocilizumab, can be hepatotoxic. Abnormal liver biochemistries are not a contraindication, but liver biochemistries need to be followed regularly in COVID-19 patients, especially those treated with remdesivir or tocilizumab, regardless of baseline values.
Also, lopinavir/ritonavir is a potent inhibitor of cytochrome P450 enzymes involved with calcineurin inhibitor metabolism, so if it’s used, AASLD said to reduce tacrolimus dosages to 1/20–1/50 of baseline.
The group cautioned against anticipatory adjustments to immunosuppressive drugs or dosages in patients without COVID-19, but if immunosuppressed liver disease patients do get the infection, prednisone doses should be reduced but kept above 10 mg/day to avoid adrenal insufficiency. In the setting of lymphopenia, fever, or worsening COVID-19 pneumonia, it advised reduction of azathioprine and mycophenolate dosages and reduction of, but not stopping, calcineurin inhibitors.
Liver transplants should not be postponed. However, to minimize exposure to the hospital environment, AASLD advised to “consider evaluating only patients with HCC [hepatocellular carcinoma] or those patients with severe disease and high MELD [model for end-stage liver disease] scores who are likely to benefit from immediate liver transplant.”
“An argument that has been put forward to justify deferring some transplants is concern about immunosuppressing patients during the COVID-19 pandemic,” the group said, but “data suggest the innate immune response may be the main driver for pulmonary injury due to COVID-19 and [that] immunosuppression may be protective. ... Posttransplant immunosuppression was not a risk factor for mortality associated with” the severe acute respiratory syndrome pandemic in 2003-2004 or the ongoing Middle East respiratory syndrome pandemic, both also caused by coronaviruses.
AASLD advised against reducing immunosuppression or stopping mycophenolate for asymptomatic patients after transplant, but COVID-19 prevention measures should be emphasized, including frequent hand washing and staying away from large crowds.
People who test positive for COVID-19 are ineligible for organ donation. Bronchoalveolar lavage is the most sensitive test (93%), followed by nasal swabs (63%) and pharyngeal swabs (32%).
In general, the group said elective procedures should be postponed, but urgent ones, such as biliary surgery and transjugular intrahepatic portosystemic shunts for bleeding varices, in addition to liver transplants, should not.
Also, HCC patients “should not wait until the pandemic abates to undergo [surveillance] imaging because the prospective duration of the pandemic is unknown. ... An arbitrary delay of 2 months is reasonable” for imaging based on patient and facility circumstances, but otherwise, “proceed with HCC treatments rather than delaying them due to the pandemic,” the group said.
As for who to bring into the office for an initial consult, “consider seeing in person only new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST above 500 U/L, recent onset of hepatic decompensation),” AASLD said.
In liver transplant recipients or patients with autoimmune hepatitis on immunosuppressive therapy, acute cellular rejection or disease flare should not be presumed in the face of active coronavirus disease 2019 (COVID-19), according to the American Association for the Study of Liver Diseases (AASLD).
Signs that would normally be interpreted as flare or rejection need to be considered more cautiously now because the virus attacks the liver, and elevated aspartate aminotransferase, alanine aminotransferase, and slightly elevated bilirubin are common, ranging from a prevalence of 14% to 53% in COVID-19 patients. Acute liver injury is possible, especially in more severe cases, the group said.
The advice comes from a recently released document from AASLD, called “Clinical Insights for Hepatology and Liver Transplant Providers During the Covid-19 Pandemic,” to help hepatologists and liver transplant providers negotiate the pandemic, according to the latest data. It’s a far-ranging work that contains a lot of now familiar steps for providers to take to protect themselves and patients from the virus, but also much advice specific to liver medicine.
For instance, the group said it’s important to keep in mind that experimental treatments for the infection, including statins, remdesivir, and tocilizumab, can be hepatotoxic. Abnormal liver biochemistries are not a contraindication, but liver biochemistries need to be followed regularly in COVID-19 patients, especially those treated with remdesivir or tocilizumab, regardless of baseline values.
Also, lopinavir/ritonavir is a potent inhibitor of cytochrome P450 enzymes involved with calcineurin inhibitor metabolism, so if it’s used, AASLD said to reduce tacrolimus dosages to 1/20–1/50 of baseline.
The group cautioned against anticipatory adjustments to immunosuppressive drugs or dosages in patients without COVID-19, but if immunosuppressed liver disease patients do get the infection, prednisone doses should be reduced but kept above 10 mg/day to avoid adrenal insufficiency. In the setting of lymphopenia, fever, or worsening COVID-19 pneumonia, it advised reduction of azathioprine and mycophenolate dosages and reduction of, but not stopping, calcineurin inhibitors.
Liver transplants should not be postponed. However, to minimize exposure to the hospital environment, AASLD advised to “consider evaluating only patients with HCC [hepatocellular carcinoma] or those patients with severe disease and high MELD [model for end-stage liver disease] scores who are likely to benefit from immediate liver transplant.”
“An argument that has been put forward to justify deferring some transplants is concern about immunosuppressing patients during the COVID-19 pandemic,” the group said, but “data suggest the innate immune response may be the main driver for pulmonary injury due to COVID-19 and [that] immunosuppression may be protective. ... Posttransplant immunosuppression was not a risk factor for mortality associated with” the severe acute respiratory syndrome pandemic in 2003-2004 or the ongoing Middle East respiratory syndrome pandemic, both also caused by coronaviruses.
AASLD advised against reducing immunosuppression or stopping mycophenolate for asymptomatic patients after transplant, but COVID-19 prevention measures should be emphasized, including frequent hand washing and staying away from large crowds.
People who test positive for COVID-19 are ineligible for organ donation. Bronchoalveolar lavage is the most sensitive test (93%), followed by nasal swabs (63%) and pharyngeal swabs (32%).
In general, the group said elective procedures should be postponed, but urgent ones, such as biliary surgery and transjugular intrahepatic portosystemic shunts for bleeding varices, in addition to liver transplants, should not.
Also, HCC patients “should not wait until the pandemic abates to undergo [surveillance] imaging because the prospective duration of the pandemic is unknown. ... An arbitrary delay of 2 months is reasonable” for imaging based on patient and facility circumstances, but otherwise, “proceed with HCC treatments rather than delaying them due to the pandemic,” the group said.
As for who to bring into the office for an initial consult, “consider seeing in person only new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST above 500 U/L, recent onset of hepatic decompensation),” AASLD said.
In liver transplant recipients or patients with autoimmune hepatitis on immunosuppressive therapy, acute cellular rejection or disease flare should not be presumed in the face of active coronavirus disease 2019 (COVID-19), according to the American Association for the Study of Liver Diseases (AASLD).
Signs that would normally be interpreted as flare or rejection need to be considered more cautiously now because the virus attacks the liver, and elevated aspartate aminotransferase, alanine aminotransferase, and slightly elevated bilirubin are common, ranging from a prevalence of 14% to 53% in COVID-19 patients. Acute liver injury is possible, especially in more severe cases, the group said.
The advice comes from a recently released document from AASLD, called “Clinical Insights for Hepatology and Liver Transplant Providers During the Covid-19 Pandemic,” to help hepatologists and liver transplant providers negotiate the pandemic, according to the latest data. It’s a far-ranging work that contains a lot of now familiar steps for providers to take to protect themselves and patients from the virus, but also much advice specific to liver medicine.
For instance, the group said it’s important to keep in mind that experimental treatments for the infection, including statins, remdesivir, and tocilizumab, can be hepatotoxic. Abnormal liver biochemistries are not a contraindication, but liver biochemistries need to be followed regularly in COVID-19 patients, especially those treated with remdesivir or tocilizumab, regardless of baseline values.
Also, lopinavir/ritonavir is a potent inhibitor of cytochrome P450 enzymes involved with calcineurin inhibitor metabolism, so if it’s used, AASLD said to reduce tacrolimus dosages to 1/20–1/50 of baseline.
The group cautioned against anticipatory adjustments to immunosuppressive drugs or dosages in patients without COVID-19, but if immunosuppressed liver disease patients do get the infection, prednisone doses should be reduced but kept above 10 mg/day to avoid adrenal insufficiency. In the setting of lymphopenia, fever, or worsening COVID-19 pneumonia, it advised reduction of azathioprine and mycophenolate dosages and reduction of, but not stopping, calcineurin inhibitors.
Liver transplants should not be postponed. However, to minimize exposure to the hospital environment, AASLD advised to “consider evaluating only patients with HCC [hepatocellular carcinoma] or those patients with severe disease and high MELD [model for end-stage liver disease] scores who are likely to benefit from immediate liver transplant.”
“An argument that has been put forward to justify deferring some transplants is concern about immunosuppressing patients during the COVID-19 pandemic,” the group said, but “data suggest the innate immune response may be the main driver for pulmonary injury due to COVID-19 and [that] immunosuppression may be protective. ... Posttransplant immunosuppression was not a risk factor for mortality associated with” the severe acute respiratory syndrome pandemic in 2003-2004 or the ongoing Middle East respiratory syndrome pandemic, both also caused by coronaviruses.
AASLD advised against reducing immunosuppression or stopping mycophenolate for asymptomatic patients after transplant, but COVID-19 prevention measures should be emphasized, including frequent hand washing and staying away from large crowds.
People who test positive for COVID-19 are ineligible for organ donation. Bronchoalveolar lavage is the most sensitive test (93%), followed by nasal swabs (63%) and pharyngeal swabs (32%).
In general, the group said elective procedures should be postponed, but urgent ones, such as biliary surgery and transjugular intrahepatic portosystemic shunts for bleeding varices, in addition to liver transplants, should not.
Also, HCC patients “should not wait until the pandemic abates to undergo [surveillance] imaging because the prospective duration of the pandemic is unknown. ... An arbitrary delay of 2 months is reasonable” for imaging based on patient and facility circumstances, but otherwise, “proceed with HCC treatments rather than delaying them due to the pandemic,” the group said.
As for who to bring into the office for an initial consult, “consider seeing in person only new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST above 500 U/L, recent onset of hepatic decompensation),” AASLD said.
COVID-19: ASTCT provides interim guidelines for transplantation
The American Society for Transplantation and Cellular Therapy (ASTCT) has released interim guidelines for the care of hematopoietic cell transplantation (HCT) and cellular therapy patients in the light of the global SARS-CoV-2 pandemic.
The guidelines, summarized briefly below, focus on diagnostic and treatment considerations, evaluation of patients prior to initializing HCT and cellular therapy, and cell donor evaluation. Much of the guideline relies upon recommendations developed by the European Society for Blood and Marrow Transplantation (ESBMT). These guidelines were updated on March 16.
The ASTCT document focuses on patient-treatment specifics and does not cover specific infection-prevention policies and procedures, instead suggesting that local and institutional guidelines, such as those from the Centers for Disease Control and Prevention, should be followed. They did recommend that, in the local presence of COVID-19, “clinic visits that are not critical should be either deferred or substituted with telemedicine visits if deemed appropriate and feasible.”
Diagnostic considerations
In any patient with upper or lower respiratory symptoms, obtain polymerase chain reaction (PCR) testing for SARS-CoV-2, where possible, in addition to other respiratory virus PCR testing from any respiratory sample obtained, following CDC recommendations for sample collection and processing, which are continuously being updated on the CDC website.
These recommendations include nasal sampling, rather than oral sampling, and the discouraging of nasal washes where avoidable. If nasal washing is performed, it should be done with appropriate personal protective equipment as described by the CDC. The CDC has also provided additional infection prevention and control information for known and suspected COVID-19 patients in health care settings.
In patients positive for SARS-CoV-2 in an upper respiratory tract sample, chest imaging should be considered.
Preliminary reports suggest that there may be a discrepancy between upper- and lower-tract specimen positivity. Therefore, even when SARS-CoV-2 is not detected in an upper respiratory sample, the ASTCT recommends that chest imaging should be considered for lower respiratory tract infection when clinical symptoms of lower respiratory tract infection are present, including shortness of breath, hypoxia, and tachypnea.
With regard to routine bronchoalveolar lavage, the ASTCT recommends against it if a patient tests positive for SARS-CoV-2 given the risk of transmission among health care workers. The exception is in the case of suspected coinfection based on abnormal chest imaging and in patients for whom it is clinically indicated (for example, those receiving invasive mechanical ventilation). In addition to testing bronchoalveolar lavage samples for SARS-CoV-2, “copathogens should be evaluated and treated.”
Treatment considerations
“At this point no recommendations can be made on specific therapies due to limited data and unknown risk versus benefit; additional recommendations will be forthcoming. Even less data is available for pediatric patients. Treatment for viral, bacterial, and fungal copathogens should be optimized,” according to the ASTCT.
However, the society lists several therapies currently under consideration, which may be available through compassionate-use programs and are being investigated in current clinical trials in several countries, “including lopinavir/ritonavir, ribavirin, hydroxychloroquine, darunavir/cobicistat, and interferons-alpha and -beta.” Remdesivir, in particular, is being evaluated in a National Institutes of Health–sponsored, placebo-controlled clinical trial (NCT04280705).
In case of known or suspected COVID-19 with normal imaging and no or mild symptoms, no therapy is recommended. However, if symptoms progress or imaging is abnormal, an infectious disease specialist or department should be consulted, according to the ASTCT.
Evaluation prior to HCT or cellular therapy
“There is sufficient concern that COVID-19 could have a significant impact on posttransplant or posttherapy outcomes,” according to the guidelines, and the ASTCT provided the following recommendations to be considered in known or suspected COVID-19 patients. In particular, practitioners need to weigh the risk of delaying or altering therapy plans with the risk of progression of underlying disease.
If SARS-CoV-2 is detected in a respiratory specimen, HCT or cellular therapy procedures should be deferred. Therapy should also be deferred in HCT and cellular therapy candidates with close contact with a person infected with SARS-CoV-2 and in those patients who have traveled to a high-risk area or had close contact with a person traveling from an area at high risk for COVID-19.
In the case of a patient in a community with widespread disease, “all HCT and cellular therapy candidates should undergo screening for SARS-CoV-2 infection by PCR in respiratory specimens at the time of initial evaluation and 2 days prior to conditioning/lymphodepletion, regardless of the presence of symptoms, if testing is available.”
Procedures to be deferred include peripheral blood stem cell mobilization, bone marrow harvest, T-cell collections, and conditioning/lymphodepletion. These should not be performed for at least 14 days (preferably 21 days) from the day of last contact, according to the ASTCT. Two consecutive negative PCR tests each approximately 1 week apart (deferral for 14 days minimum), should be obtained, if available.
In areas with high community spread, the guidelines also state that “interim treatment and/or longer deferral of definite therapy should be considered when feasible (for example, multiple myeloma, germ cell tumors, consolidative transplants).”
Similar considerations should be afforded to potential cellular donors. Donors with SARS-CoV-2 detected in a respiratory sample are considered ineligible. Those meeting exposure criteria for patients, as listed above, should be excluded from donation for at least 28 days. “In individual circumstances, a donor may be considered eligible if respiratory samples are negative for SARS-CoV-2 by PCR and donor is asymptomatic. Donor should be closely monitored for COVID-19.”
In the case of unrelated donors, the ASTCT recommends referral to the National Marrow Donor Program (NMDP) guidelines for updated guidance, but points out that, according to the NMDP, the Food and Drug Administration reports that there have been no reported or suspected cases of transfusion-transmitted COVID-19 to date and that “no cases of transfusion-transmission were ever reported for the other two coronaviruses that emerged during the past 2 decades [SARS, the severe acute respiratory syndrome coronavirus, and MERS-CoV, which causes Mideast respiratory syndrome].”
In the updated ESBMT guidelines, this recommendation was made in reference to the greater spread of COVID-19: “It is therefore strongly recommended to have secured stem cell product access by freezing the product before start of conditioning and, in situations when this is not possible, to have an alternative donor as a backup. For low-risk patients, it is recommended to postpone the start of the transplant procedure if deemed to be safe to do so. This includes both allogeneic and autologous transplant procedures.”
In a recent webinar, Pavan Reddy, MD, of the University of Michigan, Ann Arbor, and ASTCT President; Alpana Waghmare, MD, of the Fred Hutchinson Cancer Research Center, Seattle; and Roy Chemaly, MD, of the MD Anderson Cancer Center, Houston, and chair of the ASTCT Transplant Infectious Disease Special Interest Group, discussed the guidelines and provided some updated information.
Dr. Reddy stated that, at the University of Michigan, they were delaying all nonurgent transplants, largely for myeloma, and are postponing even allotransplants. “The transplants we are not delaying are the high-risk AMLs … and in cases where we truly cannot delay transplants because of patient condition or, in some cases, the donor situation.”
Dr. Chemaly and Dr. Waghmare both agreed that their centers were following a similar approach.
With regard to patient testing, all three institution have recently moved to testing everyone a few days before transplant regardless of symptoms.
They also pointed out that essentially all clinical trials were being put on hold during the crisis, except for those few where patients would be put in danger if the trial were interrupted.
The guidelines discuss in depth the rationale, toxicity, and dosages for use of select agents, including remdesivir, chloroquine/hydroxychloroquine, ribavirin, and tocilizumab. There was some concern expressed about shortages developing in these drugs, which serve a number of other patient communities, in particular the possibility of a tocilizumab shortage was of concern.
Steroids and intravenous immunoglobulins are not are not recommended, according to the guidelines, which also stated that adjunctive therapies such as antibiotics should be considered.
Dr. Chemaly, Dr. Reddy, and Dr. Waghmare did not provide disclosure in the webinar.
The ASTCT recommends following the World Health Organization and CDC COVID-19 pages for continued updates and information on other aspects of the pandemic.
This article was updated 3/26/20.
SOURCE: ASTCT Response to COVID-19. 2020. www.astct.org/connect/astct-response-to-covid-19.
There is emerging data regarding coinfection of SARS-CoV-2 with other viruses including infleunza. Immunocompromised hosts, especially transplantation and cellular therapy (TCT) recipients, are known to frequently have more than one pathogen present, especially in pulmonary infections. As the community spread increases, it would be reasonable to obtain concomitant testing for respiratory viruses along with SARS-CoV-2 as recommended. In addition, viral infection can cause secondary bacterial and fungal infections (especially Aspergillus). In the presence of SARS-CoV-2, where it is recommended to avoid bronchoalveolar lavage, we have to keep a high clinical suspicion based on patients’ risk factors.
Acute Respiratory Distress Syndrome (ARDS) caused by an intense inflammatory response is the main cause of death in COVID-19. Early reports on the use of tocilizumab (an IL-6 receptor blocker) for ARDS to block cytokine mediated injury to the lung should be a consideration early in the course of COVID-19 pneumonitis, especially in setting of high risk for ARDS mortality.
We are considering other IL-6–blocking agents like siltuximab in case of a shortage of tocilizumab while centers scramble to get these agents. It is important to note that any such usages for COVID-19 would be considered off-label.
TCT candidates should of course be practicing social distancing in days leading to transplant to reduce their risk of exposure regardless of state or federal recommendations. Household members of TCT candidates should practice similar caution because transmission has been reported by asymptomatic individuals.
Zainab Shahid, MD, is the medical director of Bone Marrow Transplant Infectious Diseases at the Levine Cancer Institute/Atrium Health and a clinical associate professor of medicine at University of North Carolina at Chapel Hill. She reported that she had no relevant disclosures.
There is emerging data regarding coinfection of SARS-CoV-2 with other viruses including infleunza. Immunocompromised hosts, especially transplantation and cellular therapy (TCT) recipients, are known to frequently have more than one pathogen present, especially in pulmonary infections. As the community spread increases, it would be reasonable to obtain concomitant testing for respiratory viruses along with SARS-CoV-2 as recommended. In addition, viral infection can cause secondary bacterial and fungal infections (especially Aspergillus). In the presence of SARS-CoV-2, where it is recommended to avoid bronchoalveolar lavage, we have to keep a high clinical suspicion based on patients’ risk factors.
Acute Respiratory Distress Syndrome (ARDS) caused by an intense inflammatory response is the main cause of death in COVID-19. Early reports on the use of tocilizumab (an IL-6 receptor blocker) for ARDS to block cytokine mediated injury to the lung should be a consideration early in the course of COVID-19 pneumonitis, especially in setting of high risk for ARDS mortality.
We are considering other IL-6–blocking agents like siltuximab in case of a shortage of tocilizumab while centers scramble to get these agents. It is important to note that any such usages for COVID-19 would be considered off-label.
TCT candidates should of course be practicing social distancing in days leading to transplant to reduce their risk of exposure regardless of state or federal recommendations. Household members of TCT candidates should practice similar caution because transmission has been reported by asymptomatic individuals.
Zainab Shahid, MD, is the medical director of Bone Marrow Transplant Infectious Diseases at the Levine Cancer Institute/Atrium Health and a clinical associate professor of medicine at University of North Carolina at Chapel Hill. She reported that she had no relevant disclosures.
There is emerging data regarding coinfection of SARS-CoV-2 with other viruses including infleunza. Immunocompromised hosts, especially transplantation and cellular therapy (TCT) recipients, are known to frequently have more than one pathogen present, especially in pulmonary infections. As the community spread increases, it would be reasonable to obtain concomitant testing for respiratory viruses along with SARS-CoV-2 as recommended. In addition, viral infection can cause secondary bacterial and fungal infections (especially Aspergillus). In the presence of SARS-CoV-2, where it is recommended to avoid bronchoalveolar lavage, we have to keep a high clinical suspicion based on patients’ risk factors.
Acute Respiratory Distress Syndrome (ARDS) caused by an intense inflammatory response is the main cause of death in COVID-19. Early reports on the use of tocilizumab (an IL-6 receptor blocker) for ARDS to block cytokine mediated injury to the lung should be a consideration early in the course of COVID-19 pneumonitis, especially in setting of high risk for ARDS mortality.
We are considering other IL-6–blocking agents like siltuximab in case of a shortage of tocilizumab while centers scramble to get these agents. It is important to note that any such usages for COVID-19 would be considered off-label.
TCT candidates should of course be practicing social distancing in days leading to transplant to reduce their risk of exposure regardless of state or federal recommendations. Household members of TCT candidates should practice similar caution because transmission has been reported by asymptomatic individuals.
Zainab Shahid, MD, is the medical director of Bone Marrow Transplant Infectious Diseases at the Levine Cancer Institute/Atrium Health and a clinical associate professor of medicine at University of North Carolina at Chapel Hill. She reported that she had no relevant disclosures.
The American Society for Transplantation and Cellular Therapy (ASTCT) has released interim guidelines for the care of hematopoietic cell transplantation (HCT) and cellular therapy patients in the light of the global SARS-CoV-2 pandemic.
The guidelines, summarized briefly below, focus on diagnostic and treatment considerations, evaluation of patients prior to initializing HCT and cellular therapy, and cell donor evaluation. Much of the guideline relies upon recommendations developed by the European Society for Blood and Marrow Transplantation (ESBMT). These guidelines were updated on March 16.
The ASTCT document focuses on patient-treatment specifics and does not cover specific infection-prevention policies and procedures, instead suggesting that local and institutional guidelines, such as those from the Centers for Disease Control and Prevention, should be followed. They did recommend that, in the local presence of COVID-19, “clinic visits that are not critical should be either deferred or substituted with telemedicine visits if deemed appropriate and feasible.”
Diagnostic considerations
In any patient with upper or lower respiratory symptoms, obtain polymerase chain reaction (PCR) testing for SARS-CoV-2, where possible, in addition to other respiratory virus PCR testing from any respiratory sample obtained, following CDC recommendations for sample collection and processing, which are continuously being updated on the CDC website.
These recommendations include nasal sampling, rather than oral sampling, and the discouraging of nasal washes where avoidable. If nasal washing is performed, it should be done with appropriate personal protective equipment as described by the CDC. The CDC has also provided additional infection prevention and control information for known and suspected COVID-19 patients in health care settings.
In patients positive for SARS-CoV-2 in an upper respiratory tract sample, chest imaging should be considered.
Preliminary reports suggest that there may be a discrepancy between upper- and lower-tract specimen positivity. Therefore, even when SARS-CoV-2 is not detected in an upper respiratory sample, the ASTCT recommends that chest imaging should be considered for lower respiratory tract infection when clinical symptoms of lower respiratory tract infection are present, including shortness of breath, hypoxia, and tachypnea.
With regard to routine bronchoalveolar lavage, the ASTCT recommends against it if a patient tests positive for SARS-CoV-2 given the risk of transmission among health care workers. The exception is in the case of suspected coinfection based on abnormal chest imaging and in patients for whom it is clinically indicated (for example, those receiving invasive mechanical ventilation). In addition to testing bronchoalveolar lavage samples for SARS-CoV-2, “copathogens should be evaluated and treated.”
Treatment considerations
“At this point no recommendations can be made on specific therapies due to limited data and unknown risk versus benefit; additional recommendations will be forthcoming. Even less data is available for pediatric patients. Treatment for viral, bacterial, and fungal copathogens should be optimized,” according to the ASTCT.
However, the society lists several therapies currently under consideration, which may be available through compassionate-use programs and are being investigated in current clinical trials in several countries, “including lopinavir/ritonavir, ribavirin, hydroxychloroquine, darunavir/cobicistat, and interferons-alpha and -beta.” Remdesivir, in particular, is being evaluated in a National Institutes of Health–sponsored, placebo-controlled clinical trial (NCT04280705).
In case of known or suspected COVID-19 with normal imaging and no or mild symptoms, no therapy is recommended. However, if symptoms progress or imaging is abnormal, an infectious disease specialist or department should be consulted, according to the ASTCT.
Evaluation prior to HCT or cellular therapy
“There is sufficient concern that COVID-19 could have a significant impact on posttransplant or posttherapy outcomes,” according to the guidelines, and the ASTCT provided the following recommendations to be considered in known or suspected COVID-19 patients. In particular, practitioners need to weigh the risk of delaying or altering therapy plans with the risk of progression of underlying disease.
If SARS-CoV-2 is detected in a respiratory specimen, HCT or cellular therapy procedures should be deferred. Therapy should also be deferred in HCT and cellular therapy candidates with close contact with a person infected with SARS-CoV-2 and in those patients who have traveled to a high-risk area or had close contact with a person traveling from an area at high risk for COVID-19.
In the case of a patient in a community with widespread disease, “all HCT and cellular therapy candidates should undergo screening for SARS-CoV-2 infection by PCR in respiratory specimens at the time of initial evaluation and 2 days prior to conditioning/lymphodepletion, regardless of the presence of symptoms, if testing is available.”
Procedures to be deferred include peripheral blood stem cell mobilization, bone marrow harvest, T-cell collections, and conditioning/lymphodepletion. These should not be performed for at least 14 days (preferably 21 days) from the day of last contact, according to the ASTCT. Two consecutive negative PCR tests each approximately 1 week apart (deferral for 14 days minimum), should be obtained, if available.
In areas with high community spread, the guidelines also state that “interim treatment and/or longer deferral of definite therapy should be considered when feasible (for example, multiple myeloma, germ cell tumors, consolidative transplants).”
Similar considerations should be afforded to potential cellular donors. Donors with SARS-CoV-2 detected in a respiratory sample are considered ineligible. Those meeting exposure criteria for patients, as listed above, should be excluded from donation for at least 28 days. “In individual circumstances, a donor may be considered eligible if respiratory samples are negative for SARS-CoV-2 by PCR and donor is asymptomatic. Donor should be closely monitored for COVID-19.”
In the case of unrelated donors, the ASTCT recommends referral to the National Marrow Donor Program (NMDP) guidelines for updated guidance, but points out that, according to the NMDP, the Food and Drug Administration reports that there have been no reported or suspected cases of transfusion-transmitted COVID-19 to date and that “no cases of transfusion-transmission were ever reported for the other two coronaviruses that emerged during the past 2 decades [SARS, the severe acute respiratory syndrome coronavirus, and MERS-CoV, which causes Mideast respiratory syndrome].”
In the updated ESBMT guidelines, this recommendation was made in reference to the greater spread of COVID-19: “It is therefore strongly recommended to have secured stem cell product access by freezing the product before start of conditioning and, in situations when this is not possible, to have an alternative donor as a backup. For low-risk patients, it is recommended to postpone the start of the transplant procedure if deemed to be safe to do so. This includes both allogeneic and autologous transplant procedures.”
In a recent webinar, Pavan Reddy, MD, of the University of Michigan, Ann Arbor, and ASTCT President; Alpana Waghmare, MD, of the Fred Hutchinson Cancer Research Center, Seattle; and Roy Chemaly, MD, of the MD Anderson Cancer Center, Houston, and chair of the ASTCT Transplant Infectious Disease Special Interest Group, discussed the guidelines and provided some updated information.
Dr. Reddy stated that, at the University of Michigan, they were delaying all nonurgent transplants, largely for myeloma, and are postponing even allotransplants. “The transplants we are not delaying are the high-risk AMLs … and in cases where we truly cannot delay transplants because of patient condition or, in some cases, the donor situation.”
Dr. Chemaly and Dr. Waghmare both agreed that their centers were following a similar approach.
With regard to patient testing, all three institution have recently moved to testing everyone a few days before transplant regardless of symptoms.
They also pointed out that essentially all clinical trials were being put on hold during the crisis, except for those few where patients would be put in danger if the trial were interrupted.
The guidelines discuss in depth the rationale, toxicity, and dosages for use of select agents, including remdesivir, chloroquine/hydroxychloroquine, ribavirin, and tocilizumab. There was some concern expressed about shortages developing in these drugs, which serve a number of other patient communities, in particular the possibility of a tocilizumab shortage was of concern.
Steroids and intravenous immunoglobulins are not are not recommended, according to the guidelines, which also stated that adjunctive therapies such as antibiotics should be considered.
Dr. Chemaly, Dr. Reddy, and Dr. Waghmare did not provide disclosure in the webinar.
The ASTCT recommends following the World Health Organization and CDC COVID-19 pages for continued updates and information on other aspects of the pandemic.
This article was updated 3/26/20.
SOURCE: ASTCT Response to COVID-19. 2020. www.astct.org/connect/astct-response-to-covid-19.
The American Society for Transplantation and Cellular Therapy (ASTCT) has released interim guidelines for the care of hematopoietic cell transplantation (HCT) and cellular therapy patients in the light of the global SARS-CoV-2 pandemic.
The guidelines, summarized briefly below, focus on diagnostic and treatment considerations, evaluation of patients prior to initializing HCT and cellular therapy, and cell donor evaluation. Much of the guideline relies upon recommendations developed by the European Society for Blood and Marrow Transplantation (ESBMT). These guidelines were updated on March 16.
The ASTCT document focuses on patient-treatment specifics and does not cover specific infection-prevention policies and procedures, instead suggesting that local and institutional guidelines, such as those from the Centers for Disease Control and Prevention, should be followed. They did recommend that, in the local presence of COVID-19, “clinic visits that are not critical should be either deferred or substituted with telemedicine visits if deemed appropriate and feasible.”
Diagnostic considerations
In any patient with upper or lower respiratory symptoms, obtain polymerase chain reaction (PCR) testing for SARS-CoV-2, where possible, in addition to other respiratory virus PCR testing from any respiratory sample obtained, following CDC recommendations for sample collection and processing, which are continuously being updated on the CDC website.
These recommendations include nasal sampling, rather than oral sampling, and the discouraging of nasal washes where avoidable. If nasal washing is performed, it should be done with appropriate personal protective equipment as described by the CDC. The CDC has also provided additional infection prevention and control information for known and suspected COVID-19 patients in health care settings.
In patients positive for SARS-CoV-2 in an upper respiratory tract sample, chest imaging should be considered.
Preliminary reports suggest that there may be a discrepancy between upper- and lower-tract specimen positivity. Therefore, even when SARS-CoV-2 is not detected in an upper respiratory sample, the ASTCT recommends that chest imaging should be considered for lower respiratory tract infection when clinical symptoms of lower respiratory tract infection are present, including shortness of breath, hypoxia, and tachypnea.
With regard to routine bronchoalveolar lavage, the ASTCT recommends against it if a patient tests positive for SARS-CoV-2 given the risk of transmission among health care workers. The exception is in the case of suspected coinfection based on abnormal chest imaging and in patients for whom it is clinically indicated (for example, those receiving invasive mechanical ventilation). In addition to testing bronchoalveolar lavage samples for SARS-CoV-2, “copathogens should be evaluated and treated.”
Treatment considerations
“At this point no recommendations can be made on specific therapies due to limited data and unknown risk versus benefit; additional recommendations will be forthcoming. Even less data is available for pediatric patients. Treatment for viral, bacterial, and fungal copathogens should be optimized,” according to the ASTCT.
However, the society lists several therapies currently under consideration, which may be available through compassionate-use programs and are being investigated in current clinical trials in several countries, “including lopinavir/ritonavir, ribavirin, hydroxychloroquine, darunavir/cobicistat, and interferons-alpha and -beta.” Remdesivir, in particular, is being evaluated in a National Institutes of Health–sponsored, placebo-controlled clinical trial (NCT04280705).
In case of known or suspected COVID-19 with normal imaging and no or mild symptoms, no therapy is recommended. However, if symptoms progress or imaging is abnormal, an infectious disease specialist or department should be consulted, according to the ASTCT.
Evaluation prior to HCT or cellular therapy
“There is sufficient concern that COVID-19 could have a significant impact on posttransplant or posttherapy outcomes,” according to the guidelines, and the ASTCT provided the following recommendations to be considered in known or suspected COVID-19 patients. In particular, practitioners need to weigh the risk of delaying or altering therapy plans with the risk of progression of underlying disease.
If SARS-CoV-2 is detected in a respiratory specimen, HCT or cellular therapy procedures should be deferred. Therapy should also be deferred in HCT and cellular therapy candidates with close contact with a person infected with SARS-CoV-2 and in those patients who have traveled to a high-risk area or had close contact with a person traveling from an area at high risk for COVID-19.
In the case of a patient in a community with widespread disease, “all HCT and cellular therapy candidates should undergo screening for SARS-CoV-2 infection by PCR in respiratory specimens at the time of initial evaluation and 2 days prior to conditioning/lymphodepletion, regardless of the presence of symptoms, if testing is available.”
Procedures to be deferred include peripheral blood stem cell mobilization, bone marrow harvest, T-cell collections, and conditioning/lymphodepletion. These should not be performed for at least 14 days (preferably 21 days) from the day of last contact, according to the ASTCT. Two consecutive negative PCR tests each approximately 1 week apart (deferral for 14 days minimum), should be obtained, if available.
In areas with high community spread, the guidelines also state that “interim treatment and/or longer deferral of definite therapy should be considered when feasible (for example, multiple myeloma, germ cell tumors, consolidative transplants).”
Similar considerations should be afforded to potential cellular donors. Donors with SARS-CoV-2 detected in a respiratory sample are considered ineligible. Those meeting exposure criteria for patients, as listed above, should be excluded from donation for at least 28 days. “In individual circumstances, a donor may be considered eligible if respiratory samples are negative for SARS-CoV-2 by PCR and donor is asymptomatic. Donor should be closely monitored for COVID-19.”
In the case of unrelated donors, the ASTCT recommends referral to the National Marrow Donor Program (NMDP) guidelines for updated guidance, but points out that, according to the NMDP, the Food and Drug Administration reports that there have been no reported or suspected cases of transfusion-transmitted COVID-19 to date and that “no cases of transfusion-transmission were ever reported for the other two coronaviruses that emerged during the past 2 decades [SARS, the severe acute respiratory syndrome coronavirus, and MERS-CoV, which causes Mideast respiratory syndrome].”
In the updated ESBMT guidelines, this recommendation was made in reference to the greater spread of COVID-19: “It is therefore strongly recommended to have secured stem cell product access by freezing the product before start of conditioning and, in situations when this is not possible, to have an alternative donor as a backup. For low-risk patients, it is recommended to postpone the start of the transplant procedure if deemed to be safe to do so. This includes both allogeneic and autologous transplant procedures.”
In a recent webinar, Pavan Reddy, MD, of the University of Michigan, Ann Arbor, and ASTCT President; Alpana Waghmare, MD, of the Fred Hutchinson Cancer Research Center, Seattle; and Roy Chemaly, MD, of the MD Anderson Cancer Center, Houston, and chair of the ASTCT Transplant Infectious Disease Special Interest Group, discussed the guidelines and provided some updated information.
Dr. Reddy stated that, at the University of Michigan, they were delaying all nonurgent transplants, largely for myeloma, and are postponing even allotransplants. “The transplants we are not delaying are the high-risk AMLs … and in cases where we truly cannot delay transplants because of patient condition or, in some cases, the donor situation.”
Dr. Chemaly and Dr. Waghmare both agreed that their centers were following a similar approach.
With regard to patient testing, all three institution have recently moved to testing everyone a few days before transplant regardless of symptoms.
They also pointed out that essentially all clinical trials were being put on hold during the crisis, except for those few where patients would be put in danger if the trial were interrupted.
The guidelines discuss in depth the rationale, toxicity, and dosages for use of select agents, including remdesivir, chloroquine/hydroxychloroquine, ribavirin, and tocilizumab. There was some concern expressed about shortages developing in these drugs, which serve a number of other patient communities, in particular the possibility of a tocilizumab shortage was of concern.
Steroids and intravenous immunoglobulins are not are not recommended, according to the guidelines, which also stated that adjunctive therapies such as antibiotics should be considered.
Dr. Chemaly, Dr. Reddy, and Dr. Waghmare did not provide disclosure in the webinar.
The ASTCT recommends following the World Health Organization and CDC COVID-19 pages for continued updates and information on other aspects of the pandemic.
This article was updated 3/26/20.
SOURCE: ASTCT Response to COVID-19. 2020. www.astct.org/connect/astct-response-to-covid-19.
Second transplant a good salvage option for children with ALL, AML, or MDS
ORLANDO – A second hematopoietic stem cell transplant can be a successful salvage therapy for a child who has experienced a relapse following a first allogeneic transplant, investigators report.
A retrospective study of 221 children who experienced a relapse after a first hematopoietic stem cell transplant (HSCT) showed that 3-year overall survival (OS) was six times higher among those who had second HSCT, compared with those who did not, reported Akshay Sharma, MBBS, from St. Jude’s Children’s Research Hospital in Memphis.
“We found that factors that are typically associated with poor outcomes after transplant such as disease status at the time of first transplantation – being in remission or not, type of transplant – myeloablative or reduced intensity, and choice of donor were generally not significantly predictive of outcomes following posttransplant relapse in our multivariable model,” he said at the Transplantation and Cellular Therapy Meetings.
Relapse is the most common cause of death after HSCT, and 20%-30% of children who undergo allogeneic HSCT will experience a relapse.
To study this issue, Dr. Sharma and colleagues took a retrospective look at 703 patients 21 and younger who received a first alloHSCT at St. Jude’s for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or myelodysplastic syndrome from 1990 through 2018. Of this cohort, 211 patients (31%) experienced a relapse after transplant.
There were no significant differences between patients who had a relapse and those who did not in sex, race, conditioning-regimen intensity, performance status, donor type, or graft type (peripheral blood stem cell, umbilical cord blood, bone marrow), or in the incidence of acute graft-versus-host disease GVHD.
The investigators found that, as expected, outcomes were poor for patients who experienced a posttransplant relapse, with 3-year overall survival from relapse for the 221 patients of just 10%.
In multivariable analysis controlling for sex, disease status at the time of first transplant, interval from first transplant to relapse, management after relapse, chronic GVHD and year of relapse, factors significantly associated with worse overall survival were relapse within 6 months of transplant vs. later than 6 months (hazard ratio, 4.6; P < .001) and decade of transplant (HR, 2.6 for 1990-2000 and 1.6 for 2001-2010 vs. 2011-2018; P < .001).
In contrast, both second HSCT and donor lymphocyte infusion were associated with better overall survival, compared with postrelapse chemotherapy or supportive care (HR, 0.04 and 0.6, respectively; P < .001 for both comparisons).
A longer interval from first transplant to relapse was the strongest predictor of long-term survival, Dr. Sharma said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Among the 221 patients who had a relapse, 61 (28%) had a second HSCT, 28 (13%) received only donor lymphocyte infusions, without second transplant, and 132 (62%) received either chemotherapy or supportive care.
The 3-year overall survival rate for patients who received a second transplant was 28%, compared with 4% for those who did not have a repeat HSCT. The most important independent predictors for getting a second transplant were longer time to relapse after first transplant, first transplantation from a matched sibling donor instead of from a haploidentical donor, some degree of acute GVHD, and decade of first transplant (current decade vs. earlier decades).
The investigators also looked at guideline recommendations from both the American Society of Hematology and UK National Health Service regarding second allogenenic transplant after relapse.
ASH guidelines say that “patients with chemo-sensitive disease in remission who had a long initial remission (> 6-12 months) after first transplant and who never developed any GVHD” are most likely to benefit from a second transplant.
NHS guidelines say that a second transplant can be considered for patients who experience relapse more than 12 months after first alloHSCT. But as Dr. Sharma and colleagues discovered, patients who had a second transplant had better overall survival regardless of time from first to second transplant, compared with patients who had later relapses but no second transplant.
“With these data in mind, we submit that these ASH and NHS guidelines, which are based on older data from the 1900s and 2000 and are mostly based on adult data and do not include much pediatric data should be reconsidered, at least in the context of pediatric patients as we approach them,” he said.
Jaap-Jan Boelens, MD, PhD, a pediatric transplant specialist at Memorial Sloan Kettering Cancer Center in New York City, who was not involved in the study, said that the use of second transplant as salvage therapy is becoming more common at his center.
“But there is a little nuance,” he said in an interview. “If someone relapses a month after transplant, let’s say, it doesn’t make sense to go for another allo transplant. But if the interval between transplant is longer, more than half a year, we usually consider going for a second allo transplant.”
The decision to attempt a second transplant may also hinge on the disease the patient is being treated for, and on the depth of remission prior to relapse, he said.
Reggie E. Duerst, MD, director of the Stem Cell Transplant Program at Ann & Robert H. Lurie Children’s Hospital of Chicago, said that trying to replicate the conditions of the first transplant may not work.
“It’s also a function of who was the donor for the first transplant – was it a matched sibling? And then for the second one do you go to an unrelated donor, or a half-matched relative, banking on the fact that the donor’s immune system for the second transplant is going to be able to mediate some kind of graft-versus-leukemia effect that wasn’t there the first time around?” he said.
Dr. Duerst, who was not involved in the study, noted that, for some patients with lymphoid malignancies, chimeric antigen receptor (CAR) T-cell therapy may be a more effective salvage strategy than second transplant, but added that it’s still too soon to know which strategy will be more effective.
The study was supported by St. Jude’s, the American Society of Hematology, and the American Society for Transplantation and Cellular Therapy. Dr. Sharma, Dr. Boelens, and Dr. Duerst reported having no relevant disclosures.
SOURCE: Sharma A et al. TCT 2020, Abstract 116.
ORLANDO – A second hematopoietic stem cell transplant can be a successful salvage therapy for a child who has experienced a relapse following a first allogeneic transplant, investigators report.
A retrospective study of 221 children who experienced a relapse after a first hematopoietic stem cell transplant (HSCT) showed that 3-year overall survival (OS) was six times higher among those who had second HSCT, compared with those who did not, reported Akshay Sharma, MBBS, from St. Jude’s Children’s Research Hospital in Memphis.
“We found that factors that are typically associated with poor outcomes after transplant such as disease status at the time of first transplantation – being in remission or not, type of transplant – myeloablative or reduced intensity, and choice of donor were generally not significantly predictive of outcomes following posttransplant relapse in our multivariable model,” he said at the Transplantation and Cellular Therapy Meetings.
Relapse is the most common cause of death after HSCT, and 20%-30% of children who undergo allogeneic HSCT will experience a relapse.
To study this issue, Dr. Sharma and colleagues took a retrospective look at 703 patients 21 and younger who received a first alloHSCT at St. Jude’s for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or myelodysplastic syndrome from 1990 through 2018. Of this cohort, 211 patients (31%) experienced a relapse after transplant.
There were no significant differences between patients who had a relapse and those who did not in sex, race, conditioning-regimen intensity, performance status, donor type, or graft type (peripheral blood stem cell, umbilical cord blood, bone marrow), or in the incidence of acute graft-versus-host disease GVHD.
The investigators found that, as expected, outcomes were poor for patients who experienced a posttransplant relapse, with 3-year overall survival from relapse for the 221 patients of just 10%.
In multivariable analysis controlling for sex, disease status at the time of first transplant, interval from first transplant to relapse, management after relapse, chronic GVHD and year of relapse, factors significantly associated with worse overall survival were relapse within 6 months of transplant vs. later than 6 months (hazard ratio, 4.6; P < .001) and decade of transplant (HR, 2.6 for 1990-2000 and 1.6 for 2001-2010 vs. 2011-2018; P < .001).
In contrast, both second HSCT and donor lymphocyte infusion were associated with better overall survival, compared with postrelapse chemotherapy or supportive care (HR, 0.04 and 0.6, respectively; P < .001 for both comparisons).
A longer interval from first transplant to relapse was the strongest predictor of long-term survival, Dr. Sharma said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Among the 221 patients who had a relapse, 61 (28%) had a second HSCT, 28 (13%) received only donor lymphocyte infusions, without second transplant, and 132 (62%) received either chemotherapy or supportive care.
The 3-year overall survival rate for patients who received a second transplant was 28%, compared with 4% for those who did not have a repeat HSCT. The most important independent predictors for getting a second transplant were longer time to relapse after first transplant, first transplantation from a matched sibling donor instead of from a haploidentical donor, some degree of acute GVHD, and decade of first transplant (current decade vs. earlier decades).
The investigators also looked at guideline recommendations from both the American Society of Hematology and UK National Health Service regarding second allogenenic transplant after relapse.
ASH guidelines say that “patients with chemo-sensitive disease in remission who had a long initial remission (> 6-12 months) after first transplant and who never developed any GVHD” are most likely to benefit from a second transplant.
NHS guidelines say that a second transplant can be considered for patients who experience relapse more than 12 months after first alloHSCT. But as Dr. Sharma and colleagues discovered, patients who had a second transplant had better overall survival regardless of time from first to second transplant, compared with patients who had later relapses but no second transplant.
“With these data in mind, we submit that these ASH and NHS guidelines, which are based on older data from the 1900s and 2000 and are mostly based on adult data and do not include much pediatric data should be reconsidered, at least in the context of pediatric patients as we approach them,” he said.
Jaap-Jan Boelens, MD, PhD, a pediatric transplant specialist at Memorial Sloan Kettering Cancer Center in New York City, who was not involved in the study, said that the use of second transplant as salvage therapy is becoming more common at his center.
“But there is a little nuance,” he said in an interview. “If someone relapses a month after transplant, let’s say, it doesn’t make sense to go for another allo transplant. But if the interval between transplant is longer, more than half a year, we usually consider going for a second allo transplant.”
The decision to attempt a second transplant may also hinge on the disease the patient is being treated for, and on the depth of remission prior to relapse, he said.
Reggie E. Duerst, MD, director of the Stem Cell Transplant Program at Ann & Robert H. Lurie Children’s Hospital of Chicago, said that trying to replicate the conditions of the first transplant may not work.
“It’s also a function of who was the donor for the first transplant – was it a matched sibling? And then for the second one do you go to an unrelated donor, or a half-matched relative, banking on the fact that the donor’s immune system for the second transplant is going to be able to mediate some kind of graft-versus-leukemia effect that wasn’t there the first time around?” he said.
Dr. Duerst, who was not involved in the study, noted that, for some patients with lymphoid malignancies, chimeric antigen receptor (CAR) T-cell therapy may be a more effective salvage strategy than second transplant, but added that it’s still too soon to know which strategy will be more effective.
The study was supported by St. Jude’s, the American Society of Hematology, and the American Society for Transplantation and Cellular Therapy. Dr. Sharma, Dr. Boelens, and Dr. Duerst reported having no relevant disclosures.
SOURCE: Sharma A et al. TCT 2020, Abstract 116.
ORLANDO – A second hematopoietic stem cell transplant can be a successful salvage therapy for a child who has experienced a relapse following a first allogeneic transplant, investigators report.
A retrospective study of 221 children who experienced a relapse after a first hematopoietic stem cell transplant (HSCT) showed that 3-year overall survival (OS) was six times higher among those who had second HSCT, compared with those who did not, reported Akshay Sharma, MBBS, from St. Jude’s Children’s Research Hospital in Memphis.
“We found that factors that are typically associated with poor outcomes after transplant such as disease status at the time of first transplantation – being in remission or not, type of transplant – myeloablative or reduced intensity, and choice of donor were generally not significantly predictive of outcomes following posttransplant relapse in our multivariable model,” he said at the Transplantation and Cellular Therapy Meetings.
Relapse is the most common cause of death after HSCT, and 20%-30% of children who undergo allogeneic HSCT will experience a relapse.
To study this issue, Dr. Sharma and colleagues took a retrospective look at 703 patients 21 and younger who received a first alloHSCT at St. Jude’s for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or myelodysplastic syndrome from 1990 through 2018. Of this cohort, 211 patients (31%) experienced a relapse after transplant.
There were no significant differences between patients who had a relapse and those who did not in sex, race, conditioning-regimen intensity, performance status, donor type, or graft type (peripheral blood stem cell, umbilical cord blood, bone marrow), or in the incidence of acute graft-versus-host disease GVHD.
The investigators found that, as expected, outcomes were poor for patients who experienced a posttransplant relapse, with 3-year overall survival from relapse for the 221 patients of just 10%.
In multivariable analysis controlling for sex, disease status at the time of first transplant, interval from first transplant to relapse, management after relapse, chronic GVHD and year of relapse, factors significantly associated with worse overall survival were relapse within 6 months of transplant vs. later than 6 months (hazard ratio, 4.6; P < .001) and decade of transplant (HR, 2.6 for 1990-2000 and 1.6 for 2001-2010 vs. 2011-2018; P < .001).
In contrast, both second HSCT and donor lymphocyte infusion were associated with better overall survival, compared with postrelapse chemotherapy or supportive care (HR, 0.04 and 0.6, respectively; P < .001 for both comparisons).
A longer interval from first transplant to relapse was the strongest predictor of long-term survival, Dr. Sharma said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
Among the 221 patients who had a relapse, 61 (28%) had a second HSCT, 28 (13%) received only donor lymphocyte infusions, without second transplant, and 132 (62%) received either chemotherapy or supportive care.
The 3-year overall survival rate for patients who received a second transplant was 28%, compared with 4% for those who did not have a repeat HSCT. The most important independent predictors for getting a second transplant were longer time to relapse after first transplant, first transplantation from a matched sibling donor instead of from a haploidentical donor, some degree of acute GVHD, and decade of first transplant (current decade vs. earlier decades).
The investigators also looked at guideline recommendations from both the American Society of Hematology and UK National Health Service regarding second allogenenic transplant after relapse.
ASH guidelines say that “patients with chemo-sensitive disease in remission who had a long initial remission (> 6-12 months) after first transplant and who never developed any GVHD” are most likely to benefit from a second transplant.
NHS guidelines say that a second transplant can be considered for patients who experience relapse more than 12 months after first alloHSCT. But as Dr. Sharma and colleagues discovered, patients who had a second transplant had better overall survival regardless of time from first to second transplant, compared with patients who had later relapses but no second transplant.
“With these data in mind, we submit that these ASH and NHS guidelines, which are based on older data from the 1900s and 2000 and are mostly based on adult data and do not include much pediatric data should be reconsidered, at least in the context of pediatric patients as we approach them,” he said.
Jaap-Jan Boelens, MD, PhD, a pediatric transplant specialist at Memorial Sloan Kettering Cancer Center in New York City, who was not involved in the study, said that the use of second transplant as salvage therapy is becoming more common at his center.
“But there is a little nuance,” he said in an interview. “If someone relapses a month after transplant, let’s say, it doesn’t make sense to go for another allo transplant. But if the interval between transplant is longer, more than half a year, we usually consider going for a second allo transplant.”
The decision to attempt a second transplant may also hinge on the disease the patient is being treated for, and on the depth of remission prior to relapse, he said.
Reggie E. Duerst, MD, director of the Stem Cell Transplant Program at Ann & Robert H. Lurie Children’s Hospital of Chicago, said that trying to replicate the conditions of the first transplant may not work.
“It’s also a function of who was the donor for the first transplant – was it a matched sibling? And then for the second one do you go to an unrelated donor, or a half-matched relative, banking on the fact that the donor’s immune system for the second transplant is going to be able to mediate some kind of graft-versus-leukemia effect that wasn’t there the first time around?” he said.
Dr. Duerst, who was not involved in the study, noted that, for some patients with lymphoid malignancies, chimeric antigen receptor (CAR) T-cell therapy may be a more effective salvage strategy than second transplant, but added that it’s still too soon to know which strategy will be more effective.
The study was supported by St. Jude’s, the American Society of Hematology, and the American Society for Transplantation and Cellular Therapy. Dr. Sharma, Dr. Boelens, and Dr. Duerst reported having no relevant disclosures.
SOURCE: Sharma A et al. TCT 2020, Abstract 116.
REPORTING FROM TCT 2020
NMA haploidentical allo-BMT plus post-transplant cyclophosphamide deemed safe, effective for CLL
for patients with chronic lymphocytic leukemia (CLL), according to a study published in Biology of Blood and Marrow Transplantation.
The number of patients undergoing haploidentical allo-BMT has increased substantially, with the advent of new graft-versus-host disease (GVHD) prophylaxis strategies, such as posttransplantation cyclophosphamide (PTCy), that reduce the risk of GVHD complications; however there have been few studies assessing the results of this treatment regimen, according to the authors.
The study assessed 64 consecutive patients with CLL between Jan. 2005 and Aug. 2018 who underwent haploidentical allo-BMT. The median age was 59 years; 4 patients (6.2%) underwent allo-BMT after first-line treatment; 20 patients (31.2%) underwent allo-BMT after second-line treatment, and 40 patients (62.5%) underwent allo-BMT after three or more lines of treatment for relapsed and/or refractory disease.
All patients received a nonmyeloablative (NMA) conditioning regimen consisting of fludarabine, cyclophosphamide, and 200 cGy total body irradiation. Patients received PTCy (i.v. 50 mg/kg per day) on days +3 and +4, along with additional GVHD prophylaxis with mycophenolate mofetil between days +5 and +35 and tacrolimus or sirolimus between days +5 and +180.
For all 64 patients, the median duration of follow-up was 4.4 years based on the reverse Kaplan-Meier method. The 4-year overall survival (OS) was 52%, and the 4-year progression-free survival (PFS) was 37%. The 56 patients with less than 20% marrow CLL involvement before undergoing allo-BMT had a 4-year OS of 61%, a 4-year PFS of 43%, and a median OS of 4.8 years, according to the authors.
Regression analysis demonstrated that donor age, stem cell source, IGHV mutation status, or grade II-III acute GVHD did not affect risk of progression or survival.
“The majority of our patients had unfavorable risk factors, and collectively our data show that haploidentical allo-BMT with PTCy in CLL with less than 20% marrow involvement is a safe treatment option carrying a low risk of serious GVHD and other toxicities,” the researchers concluded.
The study was supported by National Institutes of Health, National Cancer Institute grants. The authors reported that they had no disclosures.
SOURCE: Suman P et al. Biol Blood Marrow Transplant. 2020 Mar 1;26:502-8. doi: 10.1016/j.bbmt.2019.11.008
for patients with chronic lymphocytic leukemia (CLL), according to a study published in Biology of Blood and Marrow Transplantation.
The number of patients undergoing haploidentical allo-BMT has increased substantially, with the advent of new graft-versus-host disease (GVHD) prophylaxis strategies, such as posttransplantation cyclophosphamide (PTCy), that reduce the risk of GVHD complications; however there have been few studies assessing the results of this treatment regimen, according to the authors.
The study assessed 64 consecutive patients with CLL between Jan. 2005 and Aug. 2018 who underwent haploidentical allo-BMT. The median age was 59 years; 4 patients (6.2%) underwent allo-BMT after first-line treatment; 20 patients (31.2%) underwent allo-BMT after second-line treatment, and 40 patients (62.5%) underwent allo-BMT after three or more lines of treatment for relapsed and/or refractory disease.
All patients received a nonmyeloablative (NMA) conditioning regimen consisting of fludarabine, cyclophosphamide, and 200 cGy total body irradiation. Patients received PTCy (i.v. 50 mg/kg per day) on days +3 and +4, along with additional GVHD prophylaxis with mycophenolate mofetil between days +5 and +35 and tacrolimus or sirolimus between days +5 and +180.
For all 64 patients, the median duration of follow-up was 4.4 years based on the reverse Kaplan-Meier method. The 4-year overall survival (OS) was 52%, and the 4-year progression-free survival (PFS) was 37%. The 56 patients with less than 20% marrow CLL involvement before undergoing allo-BMT had a 4-year OS of 61%, a 4-year PFS of 43%, and a median OS of 4.8 years, according to the authors.
Regression analysis demonstrated that donor age, stem cell source, IGHV mutation status, or grade II-III acute GVHD did not affect risk of progression or survival.
“The majority of our patients had unfavorable risk factors, and collectively our data show that haploidentical allo-BMT with PTCy in CLL with less than 20% marrow involvement is a safe treatment option carrying a low risk of serious GVHD and other toxicities,” the researchers concluded.
The study was supported by National Institutes of Health, National Cancer Institute grants. The authors reported that they had no disclosures.
SOURCE: Suman P et al. Biol Blood Marrow Transplant. 2020 Mar 1;26:502-8. doi: 10.1016/j.bbmt.2019.11.008
for patients with chronic lymphocytic leukemia (CLL), according to a study published in Biology of Blood and Marrow Transplantation.
The number of patients undergoing haploidentical allo-BMT has increased substantially, with the advent of new graft-versus-host disease (GVHD) prophylaxis strategies, such as posttransplantation cyclophosphamide (PTCy), that reduce the risk of GVHD complications; however there have been few studies assessing the results of this treatment regimen, according to the authors.
The study assessed 64 consecutive patients with CLL between Jan. 2005 and Aug. 2018 who underwent haploidentical allo-BMT. The median age was 59 years; 4 patients (6.2%) underwent allo-BMT after first-line treatment; 20 patients (31.2%) underwent allo-BMT after second-line treatment, and 40 patients (62.5%) underwent allo-BMT after three or more lines of treatment for relapsed and/or refractory disease.
All patients received a nonmyeloablative (NMA) conditioning regimen consisting of fludarabine, cyclophosphamide, and 200 cGy total body irradiation. Patients received PTCy (i.v. 50 mg/kg per day) on days +3 and +4, along with additional GVHD prophylaxis with mycophenolate mofetil between days +5 and +35 and tacrolimus or sirolimus between days +5 and +180.
For all 64 patients, the median duration of follow-up was 4.4 years based on the reverse Kaplan-Meier method. The 4-year overall survival (OS) was 52%, and the 4-year progression-free survival (PFS) was 37%. The 56 patients with less than 20% marrow CLL involvement before undergoing allo-BMT had a 4-year OS of 61%, a 4-year PFS of 43%, and a median OS of 4.8 years, according to the authors.
Regression analysis demonstrated that donor age, stem cell source, IGHV mutation status, or grade II-III acute GVHD did not affect risk of progression or survival.
“The majority of our patients had unfavorable risk factors, and collectively our data show that haploidentical allo-BMT with PTCy in CLL with less than 20% marrow involvement is a safe treatment option carrying a low risk of serious GVHD and other toxicities,” the researchers concluded.
The study was supported by National Institutes of Health, National Cancer Institute grants. The authors reported that they had no disclosures.
SOURCE: Suman P et al. Biol Blood Marrow Transplant. 2020 Mar 1;26:502-8. doi: 10.1016/j.bbmt.2019.11.008
FROM BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
Younger children can safely visit HSCT recipients (sometimes)
ORLANDO – For visits to hematopoietic stem cell transplant recipients, the kids are alright – assuming that they’re not sniffling, coughing, or running a fever, that is.
Since their blood and marrow transplant (BMT) unit began allowing child visits to patients in 2018, there have been no increases in either health care–associated infections or average length of stay, and patient satisfaction has markedly improved, reported Mylene R. de Vera, RN, and colleagues from the Greenbaum Cancer Center at the University of Maryland Medical Center in Baltimore.
Although her center had previously had a policy restricting child visitors out of concerns about transmission of infections, “we did a literature search and found that child visitor restriction is really neither evidence based nor recommended by any professional organization,” she said in an interview at the annual Transplantation & Cellular Therapy Meetings.
“At the same time, I also informally surveyed 10 hospitals and BMT centers nationally, and found that 70% of them allow child visitation,” she added at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
An informal survey by this reporter found wide variations in practice. For example, Massachusetts General Hospital Cancer Center policy allows only children 12 and older to visit, but other hospitals have somewhat less stringent policies.
“Our policy is that for children under 12, they need to A) be screened, and B) need to get approval from the attending stem-cell physician,” said Reggie E. Duerst, MD, director of the Stem Cell Transplant Program at Ann & Robert H. Lurie Children’s Hospital of Chicago.
Dr. Duerst, who was not involved in the study, said in an interview seeking objective commentary that his center doesn’t especially encourage visits from younger children, on the understanding that, as every parent knows, the odds are higher that children under 12 may be carrying a respiratory virus, compared with adolescents.
He added that visits from children might be beneficial for patients who are more critically ill or at high risk for dying, but again, only if the child has been carefully screened.
At Memorial Sloan Kettering Cancer Center in New York, children are allowed to visit transplant recipients strictly on a case-by-case basis, and only after consultation with and approval from transplant unit staff, an MSKCC spokesman said.
In an interview, Ms. de Vera cited a 2016 study in the American Journal of Critical Care by Mini Jacob, RN, and colleagues from Emory University in Atlanta, who reported that, among family members visiting patients in an intensive care unit with a continuous visitation policy, open visitation was ranked as the second-most important need.
Beginning in 2018, Ms. de Vera and colleagues sought to promote a patient-centered policy by implementing guidelines that would allow safe visitation by children to BMT recipients.
The process included the aforementioned literature search, survey of other centers, and a staff survey, which showed that 70% of staff said they believed that allowing child visitation would support the goal of patient-centered care. The survey also showed, however, that 40% of staff thought that healthy children presented a higher risk of infection to immunocompromised patients, and 50% agreed with the statement that having children on the unit would be disruptive to care.
In August of 2019, all BMT unit staff members took part in an in-service training session designed “to align perception with evidence-based practice.” The training included detailed information and procedures for screening would-be child visitors for potential risks prior to allowing them on the unit.
The one-page screening tool asks about current or recent infections; coughing, sneezing, etc.; and other health-related issues, including whether the child is up to date on vaccinations.
The following month, the BMT unit implemented its new child visitation policy, and by the end of 2019 the unit had logged a total of 71 child visits.
As noted, there were no increases in either health care–associated infections or in the average length of stay, In fact, from April to September 2019 the average length of stay was 13 days, compared with 18 days during the 6-month period in 2018, before child visits were allowed.
In addition, a Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) patient-satisfaction survey showed that the scores on “taking preferences into account” increased to 92% during October through December 2018, compared with 33% from July through September of the same year.
Interestingly, patient-reported satisfaction also fell by half from January to March 2019, when child visits were suspended as part of hospital-wide restrictions during the influenza season.
A survey of staff conducted a year after the child visitation policy was implemented showed a relative 37% increase in reported awareness that the visits promote patient-centered care, a 35% drop in the reported belief that healthy child visitors pose higher risk of infection, and a more than 100% relative decline in the perception that child visitors would upset BMT unit routine.
“I just wanted to prove to my coworkers that child visitation really did not affect length of stay or health care–associated infections, and at the same time may have a positive effect on patient satisfaction,” Ms. de Vera said.
The study was internally supported. All persons interviewed reported no conflicts of interest to disclose.
SOURCE: de Vera MR et al. TCT 2020, Abstract 588.
ORLANDO – For visits to hematopoietic stem cell transplant recipients, the kids are alright – assuming that they’re not sniffling, coughing, or running a fever, that is.
Since their blood and marrow transplant (BMT) unit began allowing child visits to patients in 2018, there have been no increases in either health care–associated infections or average length of stay, and patient satisfaction has markedly improved, reported Mylene R. de Vera, RN, and colleagues from the Greenbaum Cancer Center at the University of Maryland Medical Center in Baltimore.
Although her center had previously had a policy restricting child visitors out of concerns about transmission of infections, “we did a literature search and found that child visitor restriction is really neither evidence based nor recommended by any professional organization,” she said in an interview at the annual Transplantation & Cellular Therapy Meetings.
“At the same time, I also informally surveyed 10 hospitals and BMT centers nationally, and found that 70% of them allow child visitation,” she added at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
An informal survey by this reporter found wide variations in practice. For example, Massachusetts General Hospital Cancer Center policy allows only children 12 and older to visit, but other hospitals have somewhat less stringent policies.
“Our policy is that for children under 12, they need to A) be screened, and B) need to get approval from the attending stem-cell physician,” said Reggie E. Duerst, MD, director of the Stem Cell Transplant Program at Ann & Robert H. Lurie Children’s Hospital of Chicago.
Dr. Duerst, who was not involved in the study, said in an interview seeking objective commentary that his center doesn’t especially encourage visits from younger children, on the understanding that, as every parent knows, the odds are higher that children under 12 may be carrying a respiratory virus, compared with adolescents.
He added that visits from children might be beneficial for patients who are more critically ill or at high risk for dying, but again, only if the child has been carefully screened.
At Memorial Sloan Kettering Cancer Center in New York, children are allowed to visit transplant recipients strictly on a case-by-case basis, and only after consultation with and approval from transplant unit staff, an MSKCC spokesman said.
In an interview, Ms. de Vera cited a 2016 study in the American Journal of Critical Care by Mini Jacob, RN, and colleagues from Emory University in Atlanta, who reported that, among family members visiting patients in an intensive care unit with a continuous visitation policy, open visitation was ranked as the second-most important need.
Beginning in 2018, Ms. de Vera and colleagues sought to promote a patient-centered policy by implementing guidelines that would allow safe visitation by children to BMT recipients.
The process included the aforementioned literature search, survey of other centers, and a staff survey, which showed that 70% of staff said they believed that allowing child visitation would support the goal of patient-centered care. The survey also showed, however, that 40% of staff thought that healthy children presented a higher risk of infection to immunocompromised patients, and 50% agreed with the statement that having children on the unit would be disruptive to care.
In August of 2019, all BMT unit staff members took part in an in-service training session designed “to align perception with evidence-based practice.” The training included detailed information and procedures for screening would-be child visitors for potential risks prior to allowing them on the unit.
The one-page screening tool asks about current or recent infections; coughing, sneezing, etc.; and other health-related issues, including whether the child is up to date on vaccinations.
The following month, the BMT unit implemented its new child visitation policy, and by the end of 2019 the unit had logged a total of 71 child visits.
As noted, there were no increases in either health care–associated infections or in the average length of stay, In fact, from April to September 2019 the average length of stay was 13 days, compared with 18 days during the 6-month period in 2018, before child visits were allowed.
In addition, a Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) patient-satisfaction survey showed that the scores on “taking preferences into account” increased to 92% during October through December 2018, compared with 33% from July through September of the same year.
Interestingly, patient-reported satisfaction also fell by half from January to March 2019, when child visits were suspended as part of hospital-wide restrictions during the influenza season.
A survey of staff conducted a year after the child visitation policy was implemented showed a relative 37% increase in reported awareness that the visits promote patient-centered care, a 35% drop in the reported belief that healthy child visitors pose higher risk of infection, and a more than 100% relative decline in the perception that child visitors would upset BMT unit routine.
“I just wanted to prove to my coworkers that child visitation really did not affect length of stay or health care–associated infections, and at the same time may have a positive effect on patient satisfaction,” Ms. de Vera said.
The study was internally supported. All persons interviewed reported no conflicts of interest to disclose.
SOURCE: de Vera MR et al. TCT 2020, Abstract 588.
ORLANDO – For visits to hematopoietic stem cell transplant recipients, the kids are alright – assuming that they’re not sniffling, coughing, or running a fever, that is.
Since their blood and marrow transplant (BMT) unit began allowing child visits to patients in 2018, there have been no increases in either health care–associated infections or average length of stay, and patient satisfaction has markedly improved, reported Mylene R. de Vera, RN, and colleagues from the Greenbaum Cancer Center at the University of Maryland Medical Center in Baltimore.
Although her center had previously had a policy restricting child visitors out of concerns about transmission of infections, “we did a literature search and found that child visitor restriction is really neither evidence based nor recommended by any professional organization,” she said in an interview at the annual Transplantation & Cellular Therapy Meetings.
“At the same time, I also informally surveyed 10 hospitals and BMT centers nationally, and found that 70% of them allow child visitation,” she added at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
An informal survey by this reporter found wide variations in practice. For example, Massachusetts General Hospital Cancer Center policy allows only children 12 and older to visit, but other hospitals have somewhat less stringent policies.
“Our policy is that for children under 12, they need to A) be screened, and B) need to get approval from the attending stem-cell physician,” said Reggie E. Duerst, MD, director of the Stem Cell Transplant Program at Ann & Robert H. Lurie Children’s Hospital of Chicago.
Dr. Duerst, who was not involved in the study, said in an interview seeking objective commentary that his center doesn’t especially encourage visits from younger children, on the understanding that, as every parent knows, the odds are higher that children under 12 may be carrying a respiratory virus, compared with adolescents.
He added that visits from children might be beneficial for patients who are more critically ill or at high risk for dying, but again, only if the child has been carefully screened.
At Memorial Sloan Kettering Cancer Center in New York, children are allowed to visit transplant recipients strictly on a case-by-case basis, and only after consultation with and approval from transplant unit staff, an MSKCC spokesman said.
In an interview, Ms. de Vera cited a 2016 study in the American Journal of Critical Care by Mini Jacob, RN, and colleagues from Emory University in Atlanta, who reported that, among family members visiting patients in an intensive care unit with a continuous visitation policy, open visitation was ranked as the second-most important need.
Beginning in 2018, Ms. de Vera and colleagues sought to promote a patient-centered policy by implementing guidelines that would allow safe visitation by children to BMT recipients.
The process included the aforementioned literature search, survey of other centers, and a staff survey, which showed that 70% of staff said they believed that allowing child visitation would support the goal of patient-centered care. The survey also showed, however, that 40% of staff thought that healthy children presented a higher risk of infection to immunocompromised patients, and 50% agreed with the statement that having children on the unit would be disruptive to care.
In August of 2019, all BMT unit staff members took part in an in-service training session designed “to align perception with evidence-based practice.” The training included detailed information and procedures for screening would-be child visitors for potential risks prior to allowing them on the unit.
The one-page screening tool asks about current or recent infections; coughing, sneezing, etc.; and other health-related issues, including whether the child is up to date on vaccinations.
The following month, the BMT unit implemented its new child visitation policy, and by the end of 2019 the unit had logged a total of 71 child visits.
As noted, there were no increases in either health care–associated infections or in the average length of stay, In fact, from April to September 2019 the average length of stay was 13 days, compared with 18 days during the 6-month period in 2018, before child visits were allowed.
In addition, a Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) patient-satisfaction survey showed that the scores on “taking preferences into account” increased to 92% during October through December 2018, compared with 33% from July through September of the same year.
Interestingly, patient-reported satisfaction also fell by half from January to March 2019, when child visits were suspended as part of hospital-wide restrictions during the influenza season.
A survey of staff conducted a year after the child visitation policy was implemented showed a relative 37% increase in reported awareness that the visits promote patient-centered care, a 35% drop in the reported belief that healthy child visitors pose higher risk of infection, and a more than 100% relative decline in the perception that child visitors would upset BMT unit routine.
“I just wanted to prove to my coworkers that child visitation really did not affect length of stay or health care–associated infections, and at the same time may have a positive effect on patient satisfaction,” Ms. de Vera said.
The study was internally supported. All persons interviewed reported no conflicts of interest to disclose.
SOURCE: de Vera MR et al. TCT 2020, Abstract 588.
REPORTING FROM TCT 2020
HIV free 30 months after stem cell transplant, is the London patient cured?
A patient with HIV remission induced by stem cell transplantation continues to be disease free at the 30-month mark.
The individual, referred to as the London patient, received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for stage IVB Hodgkin lymphoma. The transplant donor was homozygous for the CCR5 delta-32 mutation, which confers immunity to HIV because there’s no point of entry for the virus into immune cells.
After extensive sampling of various tissues, including gut, lymph node, blood, semen, and cerebrospinal fluid (CSF), Ravindra Kumar Gupta, MD, PhD, and colleagues found no detectable virus that was competent to replicate. However, they reported that the testing did detect some “fossilized” remnants of HIV DNA persisting in certain tissues.
The results were shared in a video presentation of the research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
The London patient’s HIV status had been reported the previous year at CROI 2019, but only blood samples were used in that analysis.
In a commentary accompanying the simultaneously published study in the Lancet, Jennifer Zerbato, PhD, and Sharon Lewin, FRACP, PHD, FAAHMS, asked: “A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV?
“We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication,” continued Dr. Zerbato, of the University of Melbourne, and Dr. Lewin, of the Royal Melbourne Hospital and Monash University, also in Melbourne.
In their ongoing analysis of data from the London patient, Dr. Gupta, a virologist at the University of Cambridge (England), and associates constructed a mathematical model that maps the probability for lifetime remission or cure of HIV against several factors, including the degree of chimerism achieved with the stem cell transplant.
In this model, when chimerism reaches 80% in total HIV target cells, the probability of remission for life is 98%; when donor chimerism reaches 90%, the probability of lifetime remission is greater than 99%. Peripheral T-cell chimerism in the London patient has held steady at 99%.
Dr. Gupta and associates obtained some testing opportunistically: A PET-CT scan revealed an axillary lymph node that was biopsied after it was found to have avid radiotracer uptake. Similarly, the CSF sample was obtained in the course of a work-up for some neurologic symptoms that the London patient was having.
In contrast to the first patient who achieved ongoing HIV remission from a pair of stem cell transplants received over 13 years ago – the Berlin patient – the London patient did not receive whole-body radiation, but rather underwent a reduced-intensity conditioning regimen. The London patient experienced a bout of gut graft-versus-host disease (GVHD) about 2 months after his transplant, but has been free of GVHD in the interval. He hasn’t taken cytotoxic agents or any GVHD prophylaxis since 6 months post transplant.
Though there’s no sign of HIV that’s competent to replicate, “the London patient has shown somewhat slow CD4 reconstitution,” said Dr. Gupta and coauthors in discussing the results.
The patient had a reactivation of Epstein-Barr virus (EBV) about 21 months after analytic treatment interruption (ATI) of antiretroviral therapy that was managed without any specific treatment, but he hasn’t experienced any opportunistic infections. However, his CD4 count didn’t rebound to pretransplant levels until 28 months after ATI. At that point, his CD4 count was 430 cells per mcL, or 23.5% of total T cells. The CD4:CD8 ratio was 0.86; normal range is 1.5-2.5.
The researchers used quantitative real-time polymerase chain reaction (rt-PCR) to look for packaging site and envelope (env) DNA fragments, and droplet digital PCR to quantify HIV-1 DNA.
The patient’s HIV-1 plasma load measured at 30 months post ATI on an ultrasensitive assay was below the lower limit of detection (less than 1 copy per mL). Semen viremia measured at 21 months was also below the lower limit of detection, as was CSF measured at 25 months.
Samples were taken from the patient’s rectum, cecum, sigmoid colon, and terminal ileum during a colonoscopy conducted 22 months post ATI; all tested negative for HIV DNA via droplet digital PCR.
The lymph node had large numbers of EBV-positive cells and was positive for HIV-1 env and long-terminal repeat by double-drop PCR, but no integrase DNA was detected. Additionally, no intact proviral DNA was found on assay.
Dr. Gupta and associates speculated that “EBV reactivation could have triggered EBV-specific CD4 and CD8 T-cell responses and proliferation, potentially including CD4 T cells containing HIV-1 DNA.” Supporting this hypothesis, EBV-specific CD8 T-cell responses in peripheral blood were “robust,” and the researchers also saw some CD4 response.
“Similar to the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient. Residual HIV-1 DNA and axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the lymph note sampled,” noted Dr. Gupta and coauthors.
Responses of CD4 and CD8 T cells to HIV have also remained below the limit of detection, though cytomegalovirus-specific responses persist in the London patient.
As with the Berlin patient, standard enzyme-linked immunosorbent assay (ELISA) testing has remained positive in the London patient. “Standard ELISA testing, therefore, cannot be used as a marker for cure, although more work needs to be done to assess the role of detuned low-avidity antibody assays in defining cure,” noted Dr. Gupta and associates.
The ongoing follow-up plan for the London patient is to obtain viral load testing twice yearly up to 5 years post ATI, and then obtain yearly tests for a total of 10 years. Ongoing testing will confirm the investigators’ belief that “these findings probably represent the second recorded HIV-1 cure after CCR5 delta-32/delta-32 allo-HSCT, with evidence of residual low-level HIV-1 DNA.”
Dr. Zerbato and Dr. Lewin advised cautious optimism and ongoing surveillance: “In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell.”
Dr. Gupta reported being a consultant for ViiV Healthcare and Gilead Sciences; several coauthors also reported financial relationships with pharmaceutical companies. The work was funded by amfAR, the American Foundation for AIDS Research, and the Wellcome Trust. Dr. Lewin reported grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium. Dr. Zerbato reported grants from the Melbourne HIV Cure Consortium,
SOURCE: Gupta R et al. Lancet. 2020 Mar 10. doi: 10.1016/ S2352-3018(20)30069-2.
A patient with HIV remission induced by stem cell transplantation continues to be disease free at the 30-month mark.
The individual, referred to as the London patient, received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for stage IVB Hodgkin lymphoma. The transplant donor was homozygous for the CCR5 delta-32 mutation, which confers immunity to HIV because there’s no point of entry for the virus into immune cells.
After extensive sampling of various tissues, including gut, lymph node, blood, semen, and cerebrospinal fluid (CSF), Ravindra Kumar Gupta, MD, PhD, and colleagues found no detectable virus that was competent to replicate. However, they reported that the testing did detect some “fossilized” remnants of HIV DNA persisting in certain tissues.
The results were shared in a video presentation of the research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
The London patient’s HIV status had been reported the previous year at CROI 2019, but only blood samples were used in that analysis.
In a commentary accompanying the simultaneously published study in the Lancet, Jennifer Zerbato, PhD, and Sharon Lewin, FRACP, PHD, FAAHMS, asked: “A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV?
“We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication,” continued Dr. Zerbato, of the University of Melbourne, and Dr. Lewin, of the Royal Melbourne Hospital and Monash University, also in Melbourne.
In their ongoing analysis of data from the London patient, Dr. Gupta, a virologist at the University of Cambridge (England), and associates constructed a mathematical model that maps the probability for lifetime remission or cure of HIV against several factors, including the degree of chimerism achieved with the stem cell transplant.
In this model, when chimerism reaches 80% in total HIV target cells, the probability of remission for life is 98%; when donor chimerism reaches 90%, the probability of lifetime remission is greater than 99%. Peripheral T-cell chimerism in the London patient has held steady at 99%.
Dr. Gupta and associates obtained some testing opportunistically: A PET-CT scan revealed an axillary lymph node that was biopsied after it was found to have avid radiotracer uptake. Similarly, the CSF sample was obtained in the course of a work-up for some neurologic symptoms that the London patient was having.
In contrast to the first patient who achieved ongoing HIV remission from a pair of stem cell transplants received over 13 years ago – the Berlin patient – the London patient did not receive whole-body radiation, but rather underwent a reduced-intensity conditioning regimen. The London patient experienced a bout of gut graft-versus-host disease (GVHD) about 2 months after his transplant, but has been free of GVHD in the interval. He hasn’t taken cytotoxic agents or any GVHD prophylaxis since 6 months post transplant.
Though there’s no sign of HIV that’s competent to replicate, “the London patient has shown somewhat slow CD4 reconstitution,” said Dr. Gupta and coauthors in discussing the results.
The patient had a reactivation of Epstein-Barr virus (EBV) about 21 months after analytic treatment interruption (ATI) of antiretroviral therapy that was managed without any specific treatment, but he hasn’t experienced any opportunistic infections. However, his CD4 count didn’t rebound to pretransplant levels until 28 months after ATI. At that point, his CD4 count was 430 cells per mcL, or 23.5% of total T cells. The CD4:CD8 ratio was 0.86; normal range is 1.5-2.5.
The researchers used quantitative real-time polymerase chain reaction (rt-PCR) to look for packaging site and envelope (env) DNA fragments, and droplet digital PCR to quantify HIV-1 DNA.
The patient’s HIV-1 plasma load measured at 30 months post ATI on an ultrasensitive assay was below the lower limit of detection (less than 1 copy per mL). Semen viremia measured at 21 months was also below the lower limit of detection, as was CSF measured at 25 months.
Samples were taken from the patient’s rectum, cecum, sigmoid colon, and terminal ileum during a colonoscopy conducted 22 months post ATI; all tested negative for HIV DNA via droplet digital PCR.
The lymph node had large numbers of EBV-positive cells and was positive for HIV-1 env and long-terminal repeat by double-drop PCR, but no integrase DNA was detected. Additionally, no intact proviral DNA was found on assay.
Dr. Gupta and associates speculated that “EBV reactivation could have triggered EBV-specific CD4 and CD8 T-cell responses and proliferation, potentially including CD4 T cells containing HIV-1 DNA.” Supporting this hypothesis, EBV-specific CD8 T-cell responses in peripheral blood were “robust,” and the researchers also saw some CD4 response.
“Similar to the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient. Residual HIV-1 DNA and axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the lymph note sampled,” noted Dr. Gupta and coauthors.
Responses of CD4 and CD8 T cells to HIV have also remained below the limit of detection, though cytomegalovirus-specific responses persist in the London patient.
As with the Berlin patient, standard enzyme-linked immunosorbent assay (ELISA) testing has remained positive in the London patient. “Standard ELISA testing, therefore, cannot be used as a marker for cure, although more work needs to be done to assess the role of detuned low-avidity antibody assays in defining cure,” noted Dr. Gupta and associates.
The ongoing follow-up plan for the London patient is to obtain viral load testing twice yearly up to 5 years post ATI, and then obtain yearly tests for a total of 10 years. Ongoing testing will confirm the investigators’ belief that “these findings probably represent the second recorded HIV-1 cure after CCR5 delta-32/delta-32 allo-HSCT, with evidence of residual low-level HIV-1 DNA.”
Dr. Zerbato and Dr. Lewin advised cautious optimism and ongoing surveillance: “In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell.”
Dr. Gupta reported being a consultant for ViiV Healthcare and Gilead Sciences; several coauthors also reported financial relationships with pharmaceutical companies. The work was funded by amfAR, the American Foundation for AIDS Research, and the Wellcome Trust. Dr. Lewin reported grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium. Dr. Zerbato reported grants from the Melbourne HIV Cure Consortium,
SOURCE: Gupta R et al. Lancet. 2020 Mar 10. doi: 10.1016/ S2352-3018(20)30069-2.
A patient with HIV remission induced by stem cell transplantation continues to be disease free at the 30-month mark.
The individual, referred to as the London patient, received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for stage IVB Hodgkin lymphoma. The transplant donor was homozygous for the CCR5 delta-32 mutation, which confers immunity to HIV because there’s no point of entry for the virus into immune cells.
After extensive sampling of various tissues, including gut, lymph node, blood, semen, and cerebrospinal fluid (CSF), Ravindra Kumar Gupta, MD, PhD, and colleagues found no detectable virus that was competent to replicate. However, they reported that the testing did detect some “fossilized” remnants of HIV DNA persisting in certain tissues.
The results were shared in a video presentation of the research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.
The London patient’s HIV status had been reported the previous year at CROI 2019, but only blood samples were used in that analysis.
In a commentary accompanying the simultaneously published study in the Lancet, Jennifer Zerbato, PhD, and Sharon Lewin, FRACP, PHD, FAAHMS, asked: “A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV?
“We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication,” continued Dr. Zerbato, of the University of Melbourne, and Dr. Lewin, of the Royal Melbourne Hospital and Monash University, also in Melbourne.
In their ongoing analysis of data from the London patient, Dr. Gupta, a virologist at the University of Cambridge (England), and associates constructed a mathematical model that maps the probability for lifetime remission or cure of HIV against several factors, including the degree of chimerism achieved with the stem cell transplant.
In this model, when chimerism reaches 80% in total HIV target cells, the probability of remission for life is 98%; when donor chimerism reaches 90%, the probability of lifetime remission is greater than 99%. Peripheral T-cell chimerism in the London patient has held steady at 99%.
Dr. Gupta and associates obtained some testing opportunistically: A PET-CT scan revealed an axillary lymph node that was biopsied after it was found to have avid radiotracer uptake. Similarly, the CSF sample was obtained in the course of a work-up for some neurologic symptoms that the London patient was having.
In contrast to the first patient who achieved ongoing HIV remission from a pair of stem cell transplants received over 13 years ago – the Berlin patient – the London patient did not receive whole-body radiation, but rather underwent a reduced-intensity conditioning regimen. The London patient experienced a bout of gut graft-versus-host disease (GVHD) about 2 months after his transplant, but has been free of GVHD in the interval. He hasn’t taken cytotoxic agents or any GVHD prophylaxis since 6 months post transplant.
Though there’s no sign of HIV that’s competent to replicate, “the London patient has shown somewhat slow CD4 reconstitution,” said Dr. Gupta and coauthors in discussing the results.
The patient had a reactivation of Epstein-Barr virus (EBV) about 21 months after analytic treatment interruption (ATI) of antiretroviral therapy that was managed without any specific treatment, but he hasn’t experienced any opportunistic infections. However, his CD4 count didn’t rebound to pretransplant levels until 28 months after ATI. At that point, his CD4 count was 430 cells per mcL, or 23.5% of total T cells. The CD4:CD8 ratio was 0.86; normal range is 1.5-2.5.
The researchers used quantitative real-time polymerase chain reaction (rt-PCR) to look for packaging site and envelope (env) DNA fragments, and droplet digital PCR to quantify HIV-1 DNA.
The patient’s HIV-1 plasma load measured at 30 months post ATI on an ultrasensitive assay was below the lower limit of detection (less than 1 copy per mL). Semen viremia measured at 21 months was also below the lower limit of detection, as was CSF measured at 25 months.
Samples were taken from the patient’s rectum, cecum, sigmoid colon, and terminal ileum during a colonoscopy conducted 22 months post ATI; all tested negative for HIV DNA via droplet digital PCR.
The lymph node had large numbers of EBV-positive cells and was positive for HIV-1 env and long-terminal repeat by double-drop PCR, but no integrase DNA was detected. Additionally, no intact proviral DNA was found on assay.
Dr. Gupta and associates speculated that “EBV reactivation could have triggered EBV-specific CD4 and CD8 T-cell responses and proliferation, potentially including CD4 T cells containing HIV-1 DNA.” Supporting this hypothesis, EBV-specific CD8 T-cell responses in peripheral blood were “robust,” and the researchers also saw some CD4 response.
“Similar to the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient. Residual HIV-1 DNA and axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the lymph note sampled,” noted Dr. Gupta and coauthors.
Responses of CD4 and CD8 T cells to HIV have also remained below the limit of detection, though cytomegalovirus-specific responses persist in the London patient.
As with the Berlin patient, standard enzyme-linked immunosorbent assay (ELISA) testing has remained positive in the London patient. “Standard ELISA testing, therefore, cannot be used as a marker for cure, although more work needs to be done to assess the role of detuned low-avidity antibody assays in defining cure,” noted Dr. Gupta and associates.
The ongoing follow-up plan for the London patient is to obtain viral load testing twice yearly up to 5 years post ATI, and then obtain yearly tests for a total of 10 years. Ongoing testing will confirm the investigators’ belief that “these findings probably represent the second recorded HIV-1 cure after CCR5 delta-32/delta-32 allo-HSCT, with evidence of residual low-level HIV-1 DNA.”
Dr. Zerbato and Dr. Lewin advised cautious optimism and ongoing surveillance: “In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell.”
Dr. Gupta reported being a consultant for ViiV Healthcare and Gilead Sciences; several coauthors also reported financial relationships with pharmaceutical companies. The work was funded by amfAR, the American Foundation for AIDS Research, and the Wellcome Trust. Dr. Lewin reported grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium. Dr. Zerbato reported grants from the Melbourne HIV Cure Consortium,
SOURCE: Gupta R et al. Lancet. 2020 Mar 10. doi: 10.1016/ S2352-3018(20)30069-2.
FROM CROI 2020
Stored CD34 cells for multiple myeloma patients largely unused
ORLANDO – Collecting and storing extra stem cells on the off chance that a patient with multiple myeloma will need a salvage autologous stem cell transplant may not be worth the money or effort, investigators say.
Among patients with multiple myeloma who had adequate collection of mobilized and stored cells, only 3 of 146 eligible patients were given the stored cells in a second autologous stem cell transplant (ASCT), reported Nausheen Ahmed, MD, from the Case Western Reserve Cancer Center and University Hospitals Seidman Cancer Center, both in Cleveland.
“We found overall low utilization of salvage transplants and storage stem cells at our institution, which may not justify the strategy of early collection for all patients fit for transplant,” she said at the Transplantation and Cellular Therapy Meetings.
But Sergio Giralt, MD, a transplant specialist from Memorial Sloan Kettering Cancer Center, New York, who was not involved in the study, warned against changing practice “for the wrong reason, because it’s just a financial reason.”
Get them while they’re fresh
The rationale for collecting and storing extra cells is the risk that mobilization will fail in the future following prolonged maintenance with immunomodulatory agents such as lenalidomide (Revlimid), and the risk for genetic or epigenetic damage to cells from high-dose melphalan used in transplant-conditioning regimens, Dr. Ahmed noted at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
“However, there are potential issues with early mobilization and storage, including cost, resources, apheresis scheduling, uncertainty of cell viability, and liability. There’s also risk of side effects with filgrastim and plerixafor use [for mobilization],” she said.
Dr. Ahmed and colleagues conducted a study to determine how stored stem cells for second ASCT were used, describe how second ASCTs are used in patients who meet the Mayo Consensus Stratification for Myeloma & Risk-Adapted Therapy (mSMART) criteria, and the costs of mobilizing and storing stem cells for a second ASCT.
They took a retrospective look at all adults aged 18 years and older with a diagnosis of multiple myeloma who received a first ASCT at their institution from 2009 to 2017. They excluded patients who had amyloidosis without myeloma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) syndrome.
Patients were considered eligible for a second ASCT based on mSMART recommendations if they had a relapse either 18 or more months without maintenance therapy or after at least 36 months on maintenance. The investigators defined an extra day of collection as an additional day of apheresis to obtain 2 million or more CD34 cells/kg for storage only.
They estimated costs from the institution’s charge master as the sum of cell processing, leukapheresis costs, additional plerixafor costs, and storage costs, and calculated the total duration of storage as months from the date of collection until the last follow-up.
The median age of the total study population of 179 patients was 61 years, with a majority of male and white patients. Of this group, 98% had an Eastern Cooperative Oncology Group performance score of 0-1. In all, 63.7% of the patients had standard-risk cytogenetics, 22.4% had high-risk disease, and the remainder had unknown cytogenetic risk.
At a median follow-up of 56.5 months, 95 patients (53.1%) had experienced a relapse after transplant with a median time to progression of 47.5 months. The majority of patients (166; 92.7%) had received a single transplant, 10 (5.6%) had received tandem transplants, and only 3 (1.6%) had a second transplant at relapse.
Looking at the use of second transplant in patients who met the criteria for salvage transplant based on mSMART (excluding patients who had undergone tandem transplant) and whose maintenance status was known, they identified 61 patients on maintenance therapy and 24 with no maintenance. A total of 31 patients (18 in the maintenance group and 13 in the no-maintenance group) met mSMART criteria for salvage ASCT.
Dr. Ahmed and colleagues next looked at the 146 patients who had at least 2 million stored cells/kg, and found that the stored cells were used for only three patients. Of the 146 patients, 66 had 1 extra collection day, 17 had 2 extra days, and 4 had 3 extra days, for an average additional cost per patient of $16,859.
‘Woefully underutilized’
Discussing the study, Dr. Giralt asked: “How valid are the SMART criteria of 36 months? And the answer is there is no data to support it, and if we actually go back to our oncology, any patient who has had more than 18 months without exposure to a drug can continue to have sensitivity to that drug, and that’s why if we used the ASBMT criteria of greater than 18 months you’d have a larger population” of patients eligible for salvage transplant.
He stated that, “we know these patients exist, we know they have cells in the freezer, but we’re not using those cells. Second transplant is woefully underutilized in myeloma patients,” and he added that stored cells could also be used to support those patients who develop cytopenias following chimeric antigen receptor (CAR) T-cell therapy.
Yago Nieto, MD, from the University of Texas MD Anderson Cancer Center, Houston, who comoderated the session where the data were presented, agreed with Dr. Giralt that stored stem cells are underutilized in the treatment of patients with multiple myeloma.
“I don’t think that the experience from Case Western, where the percentage of patients who are eligible for salvage transplant and actually got it was less than 10%, can be extrapolated to many other centers. I think that in most centers the actual percentage is higher than that,” he said in an interview.
“There are going to be therapies like CAR T that will compete with salvage transplants, but I think more patients should be considered for this salvage procedure,” he added.
No funding source for the story was disclosed. Dr. Ahmed reported no financial disclosures. Dr. Giralt reported consulting/advisory activities and receiving research funding from multiple companies. Dr. Nieto disclosed research funding from, and consultancy for, several companies.
SOURCE: Ahmed N et al. TCT 2020, Abstract 28.
ORLANDO – Collecting and storing extra stem cells on the off chance that a patient with multiple myeloma will need a salvage autologous stem cell transplant may not be worth the money or effort, investigators say.
Among patients with multiple myeloma who had adequate collection of mobilized and stored cells, only 3 of 146 eligible patients were given the stored cells in a second autologous stem cell transplant (ASCT), reported Nausheen Ahmed, MD, from the Case Western Reserve Cancer Center and University Hospitals Seidman Cancer Center, both in Cleveland.
“We found overall low utilization of salvage transplants and storage stem cells at our institution, which may not justify the strategy of early collection for all patients fit for transplant,” she said at the Transplantation and Cellular Therapy Meetings.
But Sergio Giralt, MD, a transplant specialist from Memorial Sloan Kettering Cancer Center, New York, who was not involved in the study, warned against changing practice “for the wrong reason, because it’s just a financial reason.”
Get them while they’re fresh
The rationale for collecting and storing extra cells is the risk that mobilization will fail in the future following prolonged maintenance with immunomodulatory agents such as lenalidomide (Revlimid), and the risk for genetic or epigenetic damage to cells from high-dose melphalan used in transplant-conditioning regimens, Dr. Ahmed noted at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
“However, there are potential issues with early mobilization and storage, including cost, resources, apheresis scheduling, uncertainty of cell viability, and liability. There’s also risk of side effects with filgrastim and plerixafor use [for mobilization],” she said.
Dr. Ahmed and colleagues conducted a study to determine how stored stem cells for second ASCT were used, describe how second ASCTs are used in patients who meet the Mayo Consensus Stratification for Myeloma & Risk-Adapted Therapy (mSMART) criteria, and the costs of mobilizing and storing stem cells for a second ASCT.
They took a retrospective look at all adults aged 18 years and older with a diagnosis of multiple myeloma who received a first ASCT at their institution from 2009 to 2017. They excluded patients who had amyloidosis without myeloma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) syndrome.
Patients were considered eligible for a second ASCT based on mSMART recommendations if they had a relapse either 18 or more months without maintenance therapy or after at least 36 months on maintenance. The investigators defined an extra day of collection as an additional day of apheresis to obtain 2 million or more CD34 cells/kg for storage only.
They estimated costs from the institution’s charge master as the sum of cell processing, leukapheresis costs, additional plerixafor costs, and storage costs, and calculated the total duration of storage as months from the date of collection until the last follow-up.
The median age of the total study population of 179 patients was 61 years, with a majority of male and white patients. Of this group, 98% had an Eastern Cooperative Oncology Group performance score of 0-1. In all, 63.7% of the patients had standard-risk cytogenetics, 22.4% had high-risk disease, and the remainder had unknown cytogenetic risk.
At a median follow-up of 56.5 months, 95 patients (53.1%) had experienced a relapse after transplant with a median time to progression of 47.5 months. The majority of patients (166; 92.7%) had received a single transplant, 10 (5.6%) had received tandem transplants, and only 3 (1.6%) had a second transplant at relapse.
Looking at the use of second transplant in patients who met the criteria for salvage transplant based on mSMART (excluding patients who had undergone tandem transplant) and whose maintenance status was known, they identified 61 patients on maintenance therapy and 24 with no maintenance. A total of 31 patients (18 in the maintenance group and 13 in the no-maintenance group) met mSMART criteria for salvage ASCT.
Dr. Ahmed and colleagues next looked at the 146 patients who had at least 2 million stored cells/kg, and found that the stored cells were used for only three patients. Of the 146 patients, 66 had 1 extra collection day, 17 had 2 extra days, and 4 had 3 extra days, for an average additional cost per patient of $16,859.
‘Woefully underutilized’
Discussing the study, Dr. Giralt asked: “How valid are the SMART criteria of 36 months? And the answer is there is no data to support it, and if we actually go back to our oncology, any patient who has had more than 18 months without exposure to a drug can continue to have sensitivity to that drug, and that’s why if we used the ASBMT criteria of greater than 18 months you’d have a larger population” of patients eligible for salvage transplant.
He stated that, “we know these patients exist, we know they have cells in the freezer, but we’re not using those cells. Second transplant is woefully underutilized in myeloma patients,” and he added that stored cells could also be used to support those patients who develop cytopenias following chimeric antigen receptor (CAR) T-cell therapy.
Yago Nieto, MD, from the University of Texas MD Anderson Cancer Center, Houston, who comoderated the session where the data were presented, agreed with Dr. Giralt that stored stem cells are underutilized in the treatment of patients with multiple myeloma.
“I don’t think that the experience from Case Western, where the percentage of patients who are eligible for salvage transplant and actually got it was less than 10%, can be extrapolated to many other centers. I think that in most centers the actual percentage is higher than that,” he said in an interview.
“There are going to be therapies like CAR T that will compete with salvage transplants, but I think more patients should be considered for this salvage procedure,” he added.
No funding source for the story was disclosed. Dr. Ahmed reported no financial disclosures. Dr. Giralt reported consulting/advisory activities and receiving research funding from multiple companies. Dr. Nieto disclosed research funding from, and consultancy for, several companies.
SOURCE: Ahmed N et al. TCT 2020, Abstract 28.
ORLANDO – Collecting and storing extra stem cells on the off chance that a patient with multiple myeloma will need a salvage autologous stem cell transplant may not be worth the money or effort, investigators say.
Among patients with multiple myeloma who had adequate collection of mobilized and stored cells, only 3 of 146 eligible patients were given the stored cells in a second autologous stem cell transplant (ASCT), reported Nausheen Ahmed, MD, from the Case Western Reserve Cancer Center and University Hospitals Seidman Cancer Center, both in Cleveland.
“We found overall low utilization of salvage transplants and storage stem cells at our institution, which may not justify the strategy of early collection for all patients fit for transplant,” she said at the Transplantation and Cellular Therapy Meetings.
But Sergio Giralt, MD, a transplant specialist from Memorial Sloan Kettering Cancer Center, New York, who was not involved in the study, warned against changing practice “for the wrong reason, because it’s just a financial reason.”
Get them while they’re fresh
The rationale for collecting and storing extra cells is the risk that mobilization will fail in the future following prolonged maintenance with immunomodulatory agents such as lenalidomide (Revlimid), and the risk for genetic or epigenetic damage to cells from high-dose melphalan used in transplant-conditioning regimens, Dr. Ahmed noted at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.
“However, there are potential issues with early mobilization and storage, including cost, resources, apheresis scheduling, uncertainty of cell viability, and liability. There’s also risk of side effects with filgrastim and plerixafor use [for mobilization],” she said.
Dr. Ahmed and colleagues conducted a study to determine how stored stem cells for second ASCT were used, describe how second ASCTs are used in patients who meet the Mayo Consensus Stratification for Myeloma & Risk-Adapted Therapy (mSMART) criteria, and the costs of mobilizing and storing stem cells for a second ASCT.
They took a retrospective look at all adults aged 18 years and older with a diagnosis of multiple myeloma who received a first ASCT at their institution from 2009 to 2017. They excluded patients who had amyloidosis without myeloma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) syndrome.
Patients were considered eligible for a second ASCT based on mSMART recommendations if they had a relapse either 18 or more months without maintenance therapy or after at least 36 months on maintenance. The investigators defined an extra day of collection as an additional day of apheresis to obtain 2 million or more CD34 cells/kg for storage only.
They estimated costs from the institution’s charge master as the sum of cell processing, leukapheresis costs, additional plerixafor costs, and storage costs, and calculated the total duration of storage as months from the date of collection until the last follow-up.
The median age of the total study population of 179 patients was 61 years, with a majority of male and white patients. Of this group, 98% had an Eastern Cooperative Oncology Group performance score of 0-1. In all, 63.7% of the patients had standard-risk cytogenetics, 22.4% had high-risk disease, and the remainder had unknown cytogenetic risk.
At a median follow-up of 56.5 months, 95 patients (53.1%) had experienced a relapse after transplant with a median time to progression of 47.5 months. The majority of patients (166; 92.7%) had received a single transplant, 10 (5.6%) had received tandem transplants, and only 3 (1.6%) had a second transplant at relapse.
Looking at the use of second transplant in patients who met the criteria for salvage transplant based on mSMART (excluding patients who had undergone tandem transplant) and whose maintenance status was known, they identified 61 patients on maintenance therapy and 24 with no maintenance. A total of 31 patients (18 in the maintenance group and 13 in the no-maintenance group) met mSMART criteria for salvage ASCT.
Dr. Ahmed and colleagues next looked at the 146 patients who had at least 2 million stored cells/kg, and found that the stored cells were used for only three patients. Of the 146 patients, 66 had 1 extra collection day, 17 had 2 extra days, and 4 had 3 extra days, for an average additional cost per patient of $16,859.
‘Woefully underutilized’
Discussing the study, Dr. Giralt asked: “How valid are the SMART criteria of 36 months? And the answer is there is no data to support it, and if we actually go back to our oncology, any patient who has had more than 18 months without exposure to a drug can continue to have sensitivity to that drug, and that’s why if we used the ASBMT criteria of greater than 18 months you’d have a larger population” of patients eligible for salvage transplant.
He stated that, “we know these patients exist, we know they have cells in the freezer, but we’re not using those cells. Second transplant is woefully underutilized in myeloma patients,” and he added that stored cells could also be used to support those patients who develop cytopenias following chimeric antigen receptor (CAR) T-cell therapy.
Yago Nieto, MD, from the University of Texas MD Anderson Cancer Center, Houston, who comoderated the session where the data were presented, agreed with Dr. Giralt that stored stem cells are underutilized in the treatment of patients with multiple myeloma.
“I don’t think that the experience from Case Western, where the percentage of patients who are eligible for salvage transplant and actually got it was less than 10%, can be extrapolated to many other centers. I think that in most centers the actual percentage is higher than that,” he said in an interview.
“There are going to be therapies like CAR T that will compete with salvage transplants, but I think more patients should be considered for this salvage procedure,” he added.
No funding source for the story was disclosed. Dr. Ahmed reported no financial disclosures. Dr. Giralt reported consulting/advisory activities and receiving research funding from multiple companies. Dr. Nieto disclosed research funding from, and consultancy for, several companies.
SOURCE: Ahmed N et al. TCT 2020, Abstract 28.
REPORTING FROM TCT 2020