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COVID-19: Adjusting practice in acute leukemia care
The SARS-CoV-2 pandemic poses significant risks to leukemia patients and their providers, impacting every aspect of care from diagnosis through therapy, according to an editorial letter published online in Leukemia Research.
One key concern to be considered is the risk of missed or delayed diagnosis due to the pandemic conditions. An estimated 50%-75% of patients with acute leukemia are febrile at diagnosis and this puts them at high risk of a misdiagnosis of COVID-19 upon initial evaluation. As with other oncological conditions (primary mediastinal lymphoma or lung cancer, for example), which often present with a cough with or without fever, their symptoms “are likely to be considered trivial after a negative SARS-CoV-2 test,” with patients then being sent home without further assessment. In a rapidly progressing disease such as acute leukemia, this could lead to critical delays in therapeutic intervention.
The authors, from the Service and Central Laboratory of Hematology, Lausanne (Switzerland) University Hospital, also discussed the problems that might occur with regard to most standard forms of therapy. In particular, they addressed potential impacts of the pandemic on chemotherapy, bone marrow transplantation, maintenance treatments, supportive measures, and targeted therapies.
Of particular concern, “most patients may suffer from postponed chemotherapy, due to a shortage of isolation beds and blood products or the wish to avoid immunosuppressive treatments,” the authors noted, warning that “delay in chemotherapy initiation may negatively affect prognosis, [particularly in patients under age 60] with favorable- or intermediate-risk disease.”
With regard to stem cell transplantation, the authors detail the many potential difficulties with regard to procedures involving both donors and recipients, and warn that in some cases, delay in transplant could result in the reappearance of a significant minimal residual disease, which has a well-established negative impact on survival.
The authors also noted that blood product shortages have already begun in most affected countries, and how, in response, transfusion societies have called for conservative transfusion policies in strict adherence to evidence-based guidelines for patient’s blood management.
“COVID-19 will result in numerous casualties. Acute leukemia patients are at a higher risk of severe complications,” the authors stated. In particular, physicians should especially be aware of how treatment for acute leukemia may have “interactions with other drugs used to treat SARS-CoV-2–related infections/complications such as antibiotics, antiviral drugs, and various other drugs that prolong QTc or impact targeted-therapy pharmacokinetics,” they concluded.
The authors reported that they received no government or private funding for this research, and that they had no conflicts of interest.
SOURCE: Gavillet M et al. Leuk. Res. 2020. doi.org/10.1016/j.leukres.2020.106353.
The SARS-CoV-2 pandemic poses significant risks to leukemia patients and their providers, impacting every aspect of care from diagnosis through therapy, according to an editorial letter published online in Leukemia Research.
One key concern to be considered is the risk of missed or delayed diagnosis due to the pandemic conditions. An estimated 50%-75% of patients with acute leukemia are febrile at diagnosis and this puts them at high risk of a misdiagnosis of COVID-19 upon initial evaluation. As with other oncological conditions (primary mediastinal lymphoma or lung cancer, for example), which often present with a cough with or without fever, their symptoms “are likely to be considered trivial after a negative SARS-CoV-2 test,” with patients then being sent home without further assessment. In a rapidly progressing disease such as acute leukemia, this could lead to critical delays in therapeutic intervention.
The authors, from the Service and Central Laboratory of Hematology, Lausanne (Switzerland) University Hospital, also discussed the problems that might occur with regard to most standard forms of therapy. In particular, they addressed potential impacts of the pandemic on chemotherapy, bone marrow transplantation, maintenance treatments, supportive measures, and targeted therapies.
Of particular concern, “most patients may suffer from postponed chemotherapy, due to a shortage of isolation beds and blood products or the wish to avoid immunosuppressive treatments,” the authors noted, warning that “delay in chemotherapy initiation may negatively affect prognosis, [particularly in patients under age 60] with favorable- or intermediate-risk disease.”
With regard to stem cell transplantation, the authors detail the many potential difficulties with regard to procedures involving both donors and recipients, and warn that in some cases, delay in transplant could result in the reappearance of a significant minimal residual disease, which has a well-established negative impact on survival.
The authors also noted that blood product shortages have already begun in most affected countries, and how, in response, transfusion societies have called for conservative transfusion policies in strict adherence to evidence-based guidelines for patient’s blood management.
“COVID-19 will result in numerous casualties. Acute leukemia patients are at a higher risk of severe complications,” the authors stated. In particular, physicians should especially be aware of how treatment for acute leukemia may have “interactions with other drugs used to treat SARS-CoV-2–related infections/complications such as antibiotics, antiviral drugs, and various other drugs that prolong QTc or impact targeted-therapy pharmacokinetics,” they concluded.
The authors reported that they received no government or private funding for this research, and that they had no conflicts of interest.
SOURCE: Gavillet M et al. Leuk. Res. 2020. doi.org/10.1016/j.leukres.2020.106353.
The SARS-CoV-2 pandemic poses significant risks to leukemia patients and their providers, impacting every aspect of care from diagnosis through therapy, according to an editorial letter published online in Leukemia Research.
One key concern to be considered is the risk of missed or delayed diagnosis due to the pandemic conditions. An estimated 50%-75% of patients with acute leukemia are febrile at diagnosis and this puts them at high risk of a misdiagnosis of COVID-19 upon initial evaluation. As with other oncological conditions (primary mediastinal lymphoma or lung cancer, for example), which often present with a cough with or without fever, their symptoms “are likely to be considered trivial after a negative SARS-CoV-2 test,” with patients then being sent home without further assessment. In a rapidly progressing disease such as acute leukemia, this could lead to critical delays in therapeutic intervention.
The authors, from the Service and Central Laboratory of Hematology, Lausanne (Switzerland) University Hospital, also discussed the problems that might occur with regard to most standard forms of therapy. In particular, they addressed potential impacts of the pandemic on chemotherapy, bone marrow transplantation, maintenance treatments, supportive measures, and targeted therapies.
Of particular concern, “most patients may suffer from postponed chemotherapy, due to a shortage of isolation beds and blood products or the wish to avoid immunosuppressive treatments,” the authors noted, warning that “delay in chemotherapy initiation may negatively affect prognosis, [particularly in patients under age 60] with favorable- or intermediate-risk disease.”
With regard to stem cell transplantation, the authors detail the many potential difficulties with regard to procedures involving both donors and recipients, and warn that in some cases, delay in transplant could result in the reappearance of a significant minimal residual disease, which has a well-established negative impact on survival.
The authors also noted that blood product shortages have already begun in most affected countries, and how, in response, transfusion societies have called for conservative transfusion policies in strict adherence to evidence-based guidelines for patient’s blood management.
“COVID-19 will result in numerous casualties. Acute leukemia patients are at a higher risk of severe complications,” the authors stated. In particular, physicians should especially be aware of how treatment for acute leukemia may have “interactions with other drugs used to treat SARS-CoV-2–related infections/complications such as antibiotics, antiviral drugs, and various other drugs that prolong QTc or impact targeted-therapy pharmacokinetics,” they concluded.
The authors reported that they received no government or private funding for this research, and that they had no conflicts of interest.
SOURCE: Gavillet M et al. Leuk. Res. 2020. doi.org/10.1016/j.leukres.2020.106353.
FROM LEUKEMIA RESEARCH
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
Accelerated fetal growth in boys associated with development of AML
Accelerated fetal growth was associated with acute myeloid leukemia (AML), especially in infant boys and those with minimally differentiated leukemia, according to researchers from the Childhood Leukemia International Consortium (CLIC).
They assessed data from 22 studies involving a total of 3,564 cases to determine if there was an association between fetal growth and AML. The researchers also examined whether this association might vary by age, sex and disease subtype, according to their report published in the European Journal of Cancer.
The researchers calculated pooled estimates by age, sex and overall for harmonized fetal growth markers in association with AML. They used data from 17 International Fetal and Newborn Growth Consortium for the 21st Century Project studies and performed meta-analyses on 5 more studies. They also did subanalyses based on AML subtype.
They found a nearly 50% increased risk of AML among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03-2.14), reduced to 34% in boys aged less than 2 years (OR: 1.34, 95% CI: 1.05-1.71) and 25% in boys aged 0-14 years (OR: 1.25, 95% CI: 1.06-1.46). The association of large for gestational age was stronger in boys with the M0/M1 subtype (OR: 1.80, 95% CI: 1.15-2.83). In addition, large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00-1.92) in boys. By contrast, there, none of these factors were associated with AML in girls, nor were there associates for girls with respect to decelerated fetal growth markers.
“Although the absolute risk seems to be low at a population level, given the rarity of childhood AML, it would be worth exploring whether modifiable factors leading to macrosomia may also affect AML risk to stimulate future monitoring and preventive interventions before and during pregnancy,” the researchers suggested.
The authors reported that they had no conflicts of interest.
SOURCE: Karalexi MA et al. Eur J Canc. 2020;130:1-11.
Accelerated fetal growth was associated with acute myeloid leukemia (AML), especially in infant boys and those with minimally differentiated leukemia, according to researchers from the Childhood Leukemia International Consortium (CLIC).
They assessed data from 22 studies involving a total of 3,564 cases to determine if there was an association between fetal growth and AML. The researchers also examined whether this association might vary by age, sex and disease subtype, according to their report published in the European Journal of Cancer.
The researchers calculated pooled estimates by age, sex and overall for harmonized fetal growth markers in association with AML. They used data from 17 International Fetal and Newborn Growth Consortium for the 21st Century Project studies and performed meta-analyses on 5 more studies. They also did subanalyses based on AML subtype.
They found a nearly 50% increased risk of AML among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03-2.14), reduced to 34% in boys aged less than 2 years (OR: 1.34, 95% CI: 1.05-1.71) and 25% in boys aged 0-14 years (OR: 1.25, 95% CI: 1.06-1.46). The association of large for gestational age was stronger in boys with the M0/M1 subtype (OR: 1.80, 95% CI: 1.15-2.83). In addition, large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00-1.92) in boys. By contrast, there, none of these factors were associated with AML in girls, nor were there associates for girls with respect to decelerated fetal growth markers.
“Although the absolute risk seems to be low at a population level, given the rarity of childhood AML, it would be worth exploring whether modifiable factors leading to macrosomia may also affect AML risk to stimulate future monitoring and preventive interventions before and during pregnancy,” the researchers suggested.
The authors reported that they had no conflicts of interest.
SOURCE: Karalexi MA et al. Eur J Canc. 2020;130:1-11.
Accelerated fetal growth was associated with acute myeloid leukemia (AML), especially in infant boys and those with minimally differentiated leukemia, according to researchers from the Childhood Leukemia International Consortium (CLIC).
They assessed data from 22 studies involving a total of 3,564 cases to determine if there was an association between fetal growth and AML. The researchers also examined whether this association might vary by age, sex and disease subtype, according to their report published in the European Journal of Cancer.
The researchers calculated pooled estimates by age, sex and overall for harmonized fetal growth markers in association with AML. They used data from 17 International Fetal and Newborn Growth Consortium for the 21st Century Project studies and performed meta-analyses on 5 more studies. They also did subanalyses based on AML subtype.
They found a nearly 50% increased risk of AML among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03-2.14), reduced to 34% in boys aged less than 2 years (OR: 1.34, 95% CI: 1.05-1.71) and 25% in boys aged 0-14 years (OR: 1.25, 95% CI: 1.06-1.46). The association of large for gestational age was stronger in boys with the M0/M1 subtype (OR: 1.80, 95% CI: 1.15-2.83). In addition, large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00-1.92) in boys. By contrast, there, none of these factors were associated with AML in girls, nor were there associates for girls with respect to decelerated fetal growth markers.
“Although the absolute risk seems to be low at a population level, given the rarity of childhood AML, it would be worth exploring whether modifiable factors leading to macrosomia may also affect AML risk to stimulate future monitoring and preventive interventions before and during pregnancy,” the researchers suggested.
The authors reported that they had no conflicts of interest.
SOURCE: Karalexi MA et al. Eur J Canc. 2020;130:1-11.
FROM THE EUROPEAN JOURNAL OF CANCER
Initial FLAG-Ida outperforms 7+3 for high-risk AML
A treatment commonly used as a salvage regimen for relapsed/refractory acute myelogenous leukemia (AML) showed better results than did standard treatment when used as initial induction therapy.
Researchers found that the use of fludarabine, high-dose cytarabine, with granulocyte-colony stimulating factor (FLAG) – with or without idarubicin (Ida) – resulted in higher remission rates for nonfavorable risk AML patients after one course of induction, compared with standard 7+3 (anthracycline plus cytarabine) treatment.
The use of FLAG+/-Ida also resulted in a shorter time to complete remission (CR) and a shorter time to transplant, compared with 7+3. Additionally, postremission overall survival (OS) and disease-free survival (DFS) were better after achieving CR from FLAG-Ida, compared with 7+3, Melhem Solh, MD, of the Blood & Marrow Transplant Program at Northside Hospital, Atlanta, and colleagues reported in Leukemia Research.
The researchers retrospectively analyzed 304 consecutive AML patients, with nonfavorable National Comprehensive Cancer Network (NCCN) risk who received initial treatment at their center with either 7+3 (86 patients) or FLAG+/-Ida (218 patients). They found that patients in the FLAG+/-Ida group were more likely to achieve remission after one course of induction (74% vs. 62%; P less than .001) and had a faster time to achieve CR (30 days vs. 37.5 days; P less than .001), compared with patients receiving 7+3.
The time from diagnosis to allogeneic hematopoietic cell transplantation was shorter among CR patients after FLAG+/-Ida, compared with 7+3 (115 days vs. 151 days; P less than .003).
Additionally, the 3-year postremission OS and DFS were significantly better for patients receiving FLAG-Ida at 54% and 49%, compared with 39% and 32% for 7+3, respectively (P = .01).
Dr. Solh and colleagues found that the factors associated with postremission survival included age at first CR, NCCN risk, induction regimen (FLAG+/-Ida vs. 7+3; hazard ratio, 0.62; P = .01), and receipt of allogeneic hematopoietic cell transplantation.
“FLAG-Ida is a more efficacious regimen when used for initial induction compared to 3+7. It appears to produce better survival and improved postremission survival for AML patients with intermediate and poor risk AML without increasing toxicity,” Dr. Solh and colleagues wrote. “Further validation of these results in a well-designed randomized prospective trial will help define the best induction approaches for AML.”
There was no outside funding for this research and the authors reported that they had no relevant financial conflicts.
SOURCE: Solh MM et al. Leuk Res. 2020 Feb 14. doi: 10.1016/j.leukres.2020.106318.
A treatment commonly used as a salvage regimen for relapsed/refractory acute myelogenous leukemia (AML) showed better results than did standard treatment when used as initial induction therapy.
Researchers found that the use of fludarabine, high-dose cytarabine, with granulocyte-colony stimulating factor (FLAG) – with or without idarubicin (Ida) – resulted in higher remission rates for nonfavorable risk AML patients after one course of induction, compared with standard 7+3 (anthracycline plus cytarabine) treatment.
The use of FLAG+/-Ida also resulted in a shorter time to complete remission (CR) and a shorter time to transplant, compared with 7+3. Additionally, postremission overall survival (OS) and disease-free survival (DFS) were better after achieving CR from FLAG-Ida, compared with 7+3, Melhem Solh, MD, of the Blood & Marrow Transplant Program at Northside Hospital, Atlanta, and colleagues reported in Leukemia Research.
The researchers retrospectively analyzed 304 consecutive AML patients, with nonfavorable National Comprehensive Cancer Network (NCCN) risk who received initial treatment at their center with either 7+3 (86 patients) or FLAG+/-Ida (218 patients). They found that patients in the FLAG+/-Ida group were more likely to achieve remission after one course of induction (74% vs. 62%; P less than .001) and had a faster time to achieve CR (30 days vs. 37.5 days; P less than .001), compared with patients receiving 7+3.
The time from diagnosis to allogeneic hematopoietic cell transplantation was shorter among CR patients after FLAG+/-Ida, compared with 7+3 (115 days vs. 151 days; P less than .003).
Additionally, the 3-year postremission OS and DFS were significantly better for patients receiving FLAG-Ida at 54% and 49%, compared with 39% and 32% for 7+3, respectively (P = .01).
Dr. Solh and colleagues found that the factors associated with postremission survival included age at first CR, NCCN risk, induction regimen (FLAG+/-Ida vs. 7+3; hazard ratio, 0.62; P = .01), and receipt of allogeneic hematopoietic cell transplantation.
“FLAG-Ida is a more efficacious regimen when used for initial induction compared to 3+7. It appears to produce better survival and improved postremission survival for AML patients with intermediate and poor risk AML without increasing toxicity,” Dr. Solh and colleagues wrote. “Further validation of these results in a well-designed randomized prospective trial will help define the best induction approaches for AML.”
There was no outside funding for this research and the authors reported that they had no relevant financial conflicts.
SOURCE: Solh MM et al. Leuk Res. 2020 Feb 14. doi: 10.1016/j.leukres.2020.106318.
A treatment commonly used as a salvage regimen for relapsed/refractory acute myelogenous leukemia (AML) showed better results than did standard treatment when used as initial induction therapy.
Researchers found that the use of fludarabine, high-dose cytarabine, with granulocyte-colony stimulating factor (FLAG) – with or without idarubicin (Ida) – resulted in higher remission rates for nonfavorable risk AML patients after one course of induction, compared with standard 7+3 (anthracycline plus cytarabine) treatment.
The use of FLAG+/-Ida also resulted in a shorter time to complete remission (CR) and a shorter time to transplant, compared with 7+3. Additionally, postremission overall survival (OS) and disease-free survival (DFS) were better after achieving CR from FLAG-Ida, compared with 7+3, Melhem Solh, MD, of the Blood & Marrow Transplant Program at Northside Hospital, Atlanta, and colleagues reported in Leukemia Research.
The researchers retrospectively analyzed 304 consecutive AML patients, with nonfavorable National Comprehensive Cancer Network (NCCN) risk who received initial treatment at their center with either 7+3 (86 patients) or FLAG+/-Ida (218 patients). They found that patients in the FLAG+/-Ida group were more likely to achieve remission after one course of induction (74% vs. 62%; P less than .001) and had a faster time to achieve CR (30 days vs. 37.5 days; P less than .001), compared with patients receiving 7+3.
The time from diagnosis to allogeneic hematopoietic cell transplantation was shorter among CR patients after FLAG+/-Ida, compared with 7+3 (115 days vs. 151 days; P less than .003).
Additionally, the 3-year postremission OS and DFS were significantly better for patients receiving FLAG-Ida at 54% and 49%, compared with 39% and 32% for 7+3, respectively (P = .01).
Dr. Solh and colleagues found that the factors associated with postremission survival included age at first CR, NCCN risk, induction regimen (FLAG+/-Ida vs. 7+3; hazard ratio, 0.62; P = .01), and receipt of allogeneic hematopoietic cell transplantation.
“FLAG-Ida is a more efficacious regimen when used for initial induction compared to 3+7. It appears to produce better survival and improved postremission survival for AML patients with intermediate and poor risk AML without increasing toxicity,” Dr. Solh and colleagues wrote. “Further validation of these results in a well-designed randomized prospective trial will help define the best induction approaches for AML.”
There was no outside funding for this research and the authors reported that they had no relevant financial conflicts.
SOURCE: Solh MM et al. Leuk Res. 2020 Feb 14. doi: 10.1016/j.leukres.2020.106318.
FROM LEUKEMIA RESEARCH
Survival for older AML patients better with HSCT from unrelated donors
For adults aged 50 and older in first or second remission after induction therapy for acute myeloid leukemia, hematopoietic stem cell transplants (HSCT) from young matched unrelated donors was associated with better overall survival and lower risk for relapse than transplants from haploidentical donors, a retrospective study suggests,
Among 823 patients from the aged 50 to 75 with acute myeloid leukemia (AML) in a transplant registry, hazard ratios for both mortality and relapse were significantly higher for patients who received transplants from haploidentical siblings or offspring, compared with patients who received transplants from HLA-matched unrelated donors aged 40 or younger, reported Miguel-Angel Perales, MD, who is affiliated with Memorial Sloan Kettering Cancer Center in New York City, and colleagues.
“Our findings lend support to our hypothesis that a young [matched unrelated donor] should be the donor of choice when available. Furthermore, the data presented here suggest comparable times to transplantation in both treatment groups, confirming timely access to unrelated donors is no longer a barrier,” they wrote in Haematologica.Allogeneic transplants from matched unrelated donors have been performed for more than 30 years for treatment of patients with advanced myeloid and lymphoid malignancies. More recently, T-cell-replete bone marrow or peripheral blood transplants from haploidentical relatives, with post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil to lower risk for graft-versus-host disease (GvHD) have become commonplace worldwide, and are established treatment options for patients with myeloid and lymphoid malignancies. There are conflicting studies suggesting that outcomes with haploidentical transplants are equivalent or superior to those seen with matched unrelated donors, the authors noted, but pointed to a 2018 study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplant and the Center for International Blood and Marrow Transplant Research (CIBMTR). Those study results found that, among transplant recipients aged 55 through 76, graft failure, nonrelapse mortality, and overall mortality were higher when the donors were haploidentical offspring rather than HLA-matched siblings.
To see whether patients aged 50 and older with AML might benefit more with transplants from hapolidentical relatives or matched unrelated donors, the investigators used CIBMTR data to review outcomes for 823 adults with AML who received a transplant in first or second remission at one of 90 U.S. centers from 2008 through 2015.
Of this cohort, 192 patients received grafts from haploidentical donors (25% from siblings and 75% from offspring), and 631 received grafts from matched unrelated donors ranging from 18 to 40 years of age.
Although the two groups were generally similar in demographic and disease characteristics, patients in the matched unrelated donor group had significantly higher frequency of poor-risk cytogenetics (P = .03) and were significantly more likely to have received a myeloablative condition regimen than a reduced-intensity regimen (P less than .001).
In the haploidentical group, 76% of patients were in first complete remission, and the remaining 24% were in second complete remission. In the HLA-matched group the respective proportions were 83% and 17%.
The median follow-up was 42 months in the haploidentical group and 47 months in the HLA-matched group. Five-year overall survival rates were 32% and 42%, respectively.
In multivariable models controlling for donor and recipient age, sex, performance score, hematopoietic cell transplant comorbidity score, cytomegalovirus serostatus, disease status, cytogenetic risk, transplant conditioning regimen intensity and transplant period, the hazard ratio (HR) for the primary endpoint of overall mortality was 1.27 for haploidentical vs. HLA-matched grafts (P = .04). The HR for relapse risk with haploidentical transplants was 1.32 (P =.04). No significant differences in risk of nonrelapse mortality were found between the two study arms.
Bone marrow grafts from matched unrelated donors were associated with significantly higher risk for chronic GvHD than haploidentical grafts (HR, 3.12; P less than .001), but there was no difference in chronic graft-versus-host disease (GvHD) incidence between peripheral blood grafts from matched unrelated donors and haploidentical grafts.
“These data support the view that matched unrelated donor transplant with donors younger than 40 years is to be preferred,” the investigators wrote.
But in an interview, coauthor
“Even though there appears to be that clinical benefit for this older AML patient population, that benefit is not huge, and when you’re also accounting for the process of finding a donor and just getting someone into transplant, a lot of us weren’t sure if this was really going to be practice changing as the field does move into haploidentical transplants being more common,” he said.
He noted that the better outcomes among patients who received transplants from matched unrelated donors may be at least in part explained by the higher proportion of patients with unrelated donors who received myeloablative conditioning regimens. In this study, 65% of patients with haploidentical donors underwent reduced-intensity conditioning with total body irradiation, cyclophosphamide, and fludarabine.“If we do a comparison of equal conditioning regimens, are we really going to see the same outcomes in this setting? This might actually argue that, if you’re going to do a haploidentical transplant, you might start thinking about those newer, more ablative conditioning regimens,” he said.Dr. Tomlinson added that the data are reassuring, because of the modest size of the benefit, and because “many, many of our studies are showing that haploidentical transplants do almost as well as the matched ones. The big question mark will be what are the long-term outcomes? What happens after 3 years from those transplants? And that is going to take a lot more high quality, mature data.”In an editorial accompanying the study, Richard E. Champlin, MD, of the University of Texas MD Anderson Cancer Center in Houston, noted that the more frequent use of reduced-intensity conditioning used for most patients in the haploidentical group has been associated in other studies with higher relapse rates, compared with other, more intense reduced-intensity regimens.
While he agreed that the study by Dr. Perales and colleagues “should give pause for thought, however, for those considering jumping to haploidentical transplants as a preferred approach in general,” he also noted that the study’s conclusion might not apply to cases where time-to-transplant is critical, or when other conditioning and GvHD prophylaxis regimens are used.
“The ideal study would compare optimized versions of both haploidentical and unrelated donor transplants, and use “intention-to-treat” analysis, including all patients for whom a transplant is intended from the time of initial HLA typing,” he wrote.
The study was funded by grants from the National Institutes of Health and the Office of Naval Research. Dr. Tomlinson reported no relevant disclosures. Dr. Champlin did not report disclosures.
SOURCE: Perales M-A et al. Haematologica. 2020 Jan 31;105(2):407-13.
For adults aged 50 and older in first or second remission after induction therapy for acute myeloid leukemia, hematopoietic stem cell transplants (HSCT) from young matched unrelated donors was associated with better overall survival and lower risk for relapse than transplants from haploidentical donors, a retrospective study suggests,
Among 823 patients from the aged 50 to 75 with acute myeloid leukemia (AML) in a transplant registry, hazard ratios for both mortality and relapse were significantly higher for patients who received transplants from haploidentical siblings or offspring, compared with patients who received transplants from HLA-matched unrelated donors aged 40 or younger, reported Miguel-Angel Perales, MD, who is affiliated with Memorial Sloan Kettering Cancer Center in New York City, and colleagues.
“Our findings lend support to our hypothesis that a young [matched unrelated donor] should be the donor of choice when available. Furthermore, the data presented here suggest comparable times to transplantation in both treatment groups, confirming timely access to unrelated donors is no longer a barrier,” they wrote in Haematologica.Allogeneic transplants from matched unrelated donors have been performed for more than 30 years for treatment of patients with advanced myeloid and lymphoid malignancies. More recently, T-cell-replete bone marrow or peripheral blood transplants from haploidentical relatives, with post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil to lower risk for graft-versus-host disease (GvHD) have become commonplace worldwide, and are established treatment options for patients with myeloid and lymphoid malignancies. There are conflicting studies suggesting that outcomes with haploidentical transplants are equivalent or superior to those seen with matched unrelated donors, the authors noted, but pointed to a 2018 study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplant and the Center for International Blood and Marrow Transplant Research (CIBMTR). Those study results found that, among transplant recipients aged 55 through 76, graft failure, nonrelapse mortality, and overall mortality were higher when the donors were haploidentical offspring rather than HLA-matched siblings.
To see whether patients aged 50 and older with AML might benefit more with transplants from hapolidentical relatives or matched unrelated donors, the investigators used CIBMTR data to review outcomes for 823 adults with AML who received a transplant in first or second remission at one of 90 U.S. centers from 2008 through 2015.
Of this cohort, 192 patients received grafts from haploidentical donors (25% from siblings and 75% from offspring), and 631 received grafts from matched unrelated donors ranging from 18 to 40 years of age.
Although the two groups were generally similar in demographic and disease characteristics, patients in the matched unrelated donor group had significantly higher frequency of poor-risk cytogenetics (P = .03) and were significantly more likely to have received a myeloablative condition regimen than a reduced-intensity regimen (P less than .001).
In the haploidentical group, 76% of patients were in first complete remission, and the remaining 24% were in second complete remission. In the HLA-matched group the respective proportions were 83% and 17%.
The median follow-up was 42 months in the haploidentical group and 47 months in the HLA-matched group. Five-year overall survival rates were 32% and 42%, respectively.
In multivariable models controlling for donor and recipient age, sex, performance score, hematopoietic cell transplant comorbidity score, cytomegalovirus serostatus, disease status, cytogenetic risk, transplant conditioning regimen intensity and transplant period, the hazard ratio (HR) for the primary endpoint of overall mortality was 1.27 for haploidentical vs. HLA-matched grafts (P = .04). The HR for relapse risk with haploidentical transplants was 1.32 (P =.04). No significant differences in risk of nonrelapse mortality were found between the two study arms.
Bone marrow grafts from matched unrelated donors were associated with significantly higher risk for chronic GvHD than haploidentical grafts (HR, 3.12; P less than .001), but there was no difference in chronic graft-versus-host disease (GvHD) incidence between peripheral blood grafts from matched unrelated donors and haploidentical grafts.
“These data support the view that matched unrelated donor transplant with donors younger than 40 years is to be preferred,” the investigators wrote.
But in an interview, coauthor
“Even though there appears to be that clinical benefit for this older AML patient population, that benefit is not huge, and when you’re also accounting for the process of finding a donor and just getting someone into transplant, a lot of us weren’t sure if this was really going to be practice changing as the field does move into haploidentical transplants being more common,” he said.
He noted that the better outcomes among patients who received transplants from matched unrelated donors may be at least in part explained by the higher proportion of patients with unrelated donors who received myeloablative conditioning regimens. In this study, 65% of patients with haploidentical donors underwent reduced-intensity conditioning with total body irradiation, cyclophosphamide, and fludarabine.“If we do a comparison of equal conditioning regimens, are we really going to see the same outcomes in this setting? This might actually argue that, if you’re going to do a haploidentical transplant, you might start thinking about those newer, more ablative conditioning regimens,” he said.Dr. Tomlinson added that the data are reassuring, because of the modest size of the benefit, and because “many, many of our studies are showing that haploidentical transplants do almost as well as the matched ones. The big question mark will be what are the long-term outcomes? What happens after 3 years from those transplants? And that is going to take a lot more high quality, mature data.”In an editorial accompanying the study, Richard E. Champlin, MD, of the University of Texas MD Anderson Cancer Center in Houston, noted that the more frequent use of reduced-intensity conditioning used for most patients in the haploidentical group has been associated in other studies with higher relapse rates, compared with other, more intense reduced-intensity regimens.
While he agreed that the study by Dr. Perales and colleagues “should give pause for thought, however, for those considering jumping to haploidentical transplants as a preferred approach in general,” he also noted that the study’s conclusion might not apply to cases where time-to-transplant is critical, or when other conditioning and GvHD prophylaxis regimens are used.
“The ideal study would compare optimized versions of both haploidentical and unrelated donor transplants, and use “intention-to-treat” analysis, including all patients for whom a transplant is intended from the time of initial HLA typing,” he wrote.
The study was funded by grants from the National Institutes of Health and the Office of Naval Research. Dr. Tomlinson reported no relevant disclosures. Dr. Champlin did not report disclosures.
SOURCE: Perales M-A et al. Haematologica. 2020 Jan 31;105(2):407-13.
For adults aged 50 and older in first or second remission after induction therapy for acute myeloid leukemia, hematopoietic stem cell transplants (HSCT) from young matched unrelated donors was associated with better overall survival and lower risk for relapse than transplants from haploidentical donors, a retrospective study suggests,
Among 823 patients from the aged 50 to 75 with acute myeloid leukemia (AML) in a transplant registry, hazard ratios for both mortality and relapse were significantly higher for patients who received transplants from haploidentical siblings or offspring, compared with patients who received transplants from HLA-matched unrelated donors aged 40 or younger, reported Miguel-Angel Perales, MD, who is affiliated with Memorial Sloan Kettering Cancer Center in New York City, and colleagues.
“Our findings lend support to our hypothesis that a young [matched unrelated donor] should be the donor of choice when available. Furthermore, the data presented here suggest comparable times to transplantation in both treatment groups, confirming timely access to unrelated donors is no longer a barrier,” they wrote in Haematologica.Allogeneic transplants from matched unrelated donors have been performed for more than 30 years for treatment of patients with advanced myeloid and lymphoid malignancies. More recently, T-cell-replete bone marrow or peripheral blood transplants from haploidentical relatives, with post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil to lower risk for graft-versus-host disease (GvHD) have become commonplace worldwide, and are established treatment options for patients with myeloid and lymphoid malignancies. There are conflicting studies suggesting that outcomes with haploidentical transplants are equivalent or superior to those seen with matched unrelated donors, the authors noted, but pointed to a 2018 study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplant and the Center for International Blood and Marrow Transplant Research (CIBMTR). Those study results found that, among transplant recipients aged 55 through 76, graft failure, nonrelapse mortality, and overall mortality were higher when the donors were haploidentical offspring rather than HLA-matched siblings.
To see whether patients aged 50 and older with AML might benefit more with transplants from hapolidentical relatives or matched unrelated donors, the investigators used CIBMTR data to review outcomes for 823 adults with AML who received a transplant in first or second remission at one of 90 U.S. centers from 2008 through 2015.
Of this cohort, 192 patients received grafts from haploidentical donors (25% from siblings and 75% from offspring), and 631 received grafts from matched unrelated donors ranging from 18 to 40 years of age.
Although the two groups were generally similar in demographic and disease characteristics, patients in the matched unrelated donor group had significantly higher frequency of poor-risk cytogenetics (P = .03) and were significantly more likely to have received a myeloablative condition regimen than a reduced-intensity regimen (P less than .001).
In the haploidentical group, 76% of patients were in first complete remission, and the remaining 24% were in second complete remission. In the HLA-matched group the respective proportions were 83% and 17%.
The median follow-up was 42 months in the haploidentical group and 47 months in the HLA-matched group. Five-year overall survival rates were 32% and 42%, respectively.
In multivariable models controlling for donor and recipient age, sex, performance score, hematopoietic cell transplant comorbidity score, cytomegalovirus serostatus, disease status, cytogenetic risk, transplant conditioning regimen intensity and transplant period, the hazard ratio (HR) for the primary endpoint of overall mortality was 1.27 for haploidentical vs. HLA-matched grafts (P = .04). The HR for relapse risk with haploidentical transplants was 1.32 (P =.04). No significant differences in risk of nonrelapse mortality were found between the two study arms.
Bone marrow grafts from matched unrelated donors were associated with significantly higher risk for chronic GvHD than haploidentical grafts (HR, 3.12; P less than .001), but there was no difference in chronic graft-versus-host disease (GvHD) incidence between peripheral blood grafts from matched unrelated donors and haploidentical grafts.
“These data support the view that matched unrelated donor transplant with donors younger than 40 years is to be preferred,” the investigators wrote.
But in an interview, coauthor
“Even though there appears to be that clinical benefit for this older AML patient population, that benefit is not huge, and when you’re also accounting for the process of finding a donor and just getting someone into transplant, a lot of us weren’t sure if this was really going to be practice changing as the field does move into haploidentical transplants being more common,” he said.
He noted that the better outcomes among patients who received transplants from matched unrelated donors may be at least in part explained by the higher proportion of patients with unrelated donors who received myeloablative conditioning regimens. In this study, 65% of patients with haploidentical donors underwent reduced-intensity conditioning with total body irradiation, cyclophosphamide, and fludarabine.“If we do a comparison of equal conditioning regimens, are we really going to see the same outcomes in this setting? This might actually argue that, if you’re going to do a haploidentical transplant, you might start thinking about those newer, more ablative conditioning regimens,” he said.Dr. Tomlinson added that the data are reassuring, because of the modest size of the benefit, and because “many, many of our studies are showing that haploidentical transplants do almost as well as the matched ones. The big question mark will be what are the long-term outcomes? What happens after 3 years from those transplants? And that is going to take a lot more high quality, mature data.”In an editorial accompanying the study, Richard E. Champlin, MD, of the University of Texas MD Anderson Cancer Center in Houston, noted that the more frequent use of reduced-intensity conditioning used for most patients in the haploidentical group has been associated in other studies with higher relapse rates, compared with other, more intense reduced-intensity regimens.
While he agreed that the study by Dr. Perales and colleagues “should give pause for thought, however, for those considering jumping to haploidentical transplants as a preferred approach in general,” he also noted that the study’s conclusion might not apply to cases where time-to-transplant is critical, or when other conditioning and GvHD prophylaxis regimens are used.
“The ideal study would compare optimized versions of both haploidentical and unrelated donor transplants, and use “intention-to-treat” analysis, including all patients for whom a transplant is intended from the time of initial HLA typing,” he wrote.
The study was funded by grants from the National Institutes of Health and the Office of Naval Research. Dr. Tomlinson reported no relevant disclosures. Dr. Champlin did not report disclosures.
SOURCE: Perales M-A et al. Haematologica. 2020 Jan 31;105(2):407-13.
FROM HAEMATOLOGICA
9/11 responders show increased risk of leukemia, other cancers
New data suggest an increased risk of leukemia among responders who worked at the World Trade Center site after the attacks on Sept. 11, 2001.
Previous studies have shown that 9/11 responders have a higher incidence of cancers than does the general population. The current study is the first to show a higher incidence of leukemia among responders. It also shows a higher incidence of thyroid and prostate cancers as well as all cancer types combined.
These findings were published in JNCI Cancer Spectrum.
“This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods,” study author Susan L, Teitelbaum, PhD, of the Icahn School of Medicine at Mount Sinai, New York, said in a press release.
“Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study.”
Dr. Teitelbaum and colleagues evaluated responders enrolled in the World Trade Center Health Program General Responder Cohort from when it was established in July 2002 through the end of follow-up, which was Dec. 31, 2013, for New York residents and Dec. 31, 2012, for residents of other states.
To be eligible for the cohort, responders must have worked on the World Trade Center rescue and recovery effort a minimum of 4 hours in the first 4 days from Sept. 11, 2001, 24 hours in September 2001, or 80 hours from September through December 2001. Responders also had to complete at least one monitoring visit.
Responders’ data were linked to data from cancer registries in New York, New Jersey, Pennsylvania, and Connecticut (where most responders lived at the time of the attacks), as well as Florida and North Carolina (where responders were known to retire). The responders were linked to the registries using probabilistic matching algorithms, which made use of information such as patient name, address, social security number, sex, race, and birth date.
The researchers noted that patients who enrolled in the General Responder Cohort had their cancer certified for federally funded treatment, and this factor might result in “sicker members disproportionately self-selecting into the program.” To reduce this potential bias, the researchers conducted a restricted analysis in which counts of cancer cases and person-years of observation began 6 months after responder enrollment.
The researchers analyzed data on 28,729 responders who primarily worked in protective services (49.0%) and construction (20.8%). Responders spent a median of 52 days on the rescue and recovery effort, and 44.4% of them had some exposure to the dust cloud caused by the collapse of the towers.
In the restricted analysis, there were 1,072 cancers observed in 999 responders. Compared with the general population, responders had a significantly higher incidence of all cancers combined, with a standardized incidence ratio (SIR) of 1.09.
Responders had a significantly higher incidence of prostate cancer (SIR,1.25), thyroid cancer (SIR, 2.19), and leukemia (SIR, 1.41). The leukemia category included acute myeloid leukemia (SIR,1.58) and chronic lymphocytic leukemia (SIR, 1.08).
“Although other studies have revealed elevated SIRs for other hematologic malignancies, this is the first reported, statistically significant, elevated SIR for leukemia,” the researchers wrote. “Leukemia is known to occur after exposure to occupational carcinogens, including benzene (burning jet fuel and other sources at the [World Trade Center] site), possibly at low levels of exposure and with a latency of several years from exposure.”
A multivariate analysis showed no association between cancer incidence and the length of time responders spent on the rescue and recovery effort or the intensity of their exposure to the dust cloud or debris pile.
The analysis did show an elevated risk of all cancers combined with each 1-year increase in responder age (hazard ratio, 1.09), among male responders (HR, 1.21), and among responders who smoked at baseline (HR, 1.29).
This research was supported by the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The researchers disclosed no conflicts of interest.
SOURCE: Shapiro MZ et al. JNCI Cancer Spectr. 2020 Jan 14. doi: 10.1093/jncics/pkz090.
New data suggest an increased risk of leukemia among responders who worked at the World Trade Center site after the attacks on Sept. 11, 2001.
Previous studies have shown that 9/11 responders have a higher incidence of cancers than does the general population. The current study is the first to show a higher incidence of leukemia among responders. It also shows a higher incidence of thyroid and prostate cancers as well as all cancer types combined.
These findings were published in JNCI Cancer Spectrum.
“This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods,” study author Susan L, Teitelbaum, PhD, of the Icahn School of Medicine at Mount Sinai, New York, said in a press release.
“Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study.”
Dr. Teitelbaum and colleagues evaluated responders enrolled in the World Trade Center Health Program General Responder Cohort from when it was established in July 2002 through the end of follow-up, which was Dec. 31, 2013, for New York residents and Dec. 31, 2012, for residents of other states.
To be eligible for the cohort, responders must have worked on the World Trade Center rescue and recovery effort a minimum of 4 hours in the first 4 days from Sept. 11, 2001, 24 hours in September 2001, or 80 hours from September through December 2001. Responders also had to complete at least one monitoring visit.
Responders’ data were linked to data from cancer registries in New York, New Jersey, Pennsylvania, and Connecticut (where most responders lived at the time of the attacks), as well as Florida and North Carolina (where responders were known to retire). The responders were linked to the registries using probabilistic matching algorithms, which made use of information such as patient name, address, social security number, sex, race, and birth date.
The researchers noted that patients who enrolled in the General Responder Cohort had their cancer certified for federally funded treatment, and this factor might result in “sicker members disproportionately self-selecting into the program.” To reduce this potential bias, the researchers conducted a restricted analysis in which counts of cancer cases and person-years of observation began 6 months after responder enrollment.
The researchers analyzed data on 28,729 responders who primarily worked in protective services (49.0%) and construction (20.8%). Responders spent a median of 52 days on the rescue and recovery effort, and 44.4% of them had some exposure to the dust cloud caused by the collapse of the towers.
In the restricted analysis, there were 1,072 cancers observed in 999 responders. Compared with the general population, responders had a significantly higher incidence of all cancers combined, with a standardized incidence ratio (SIR) of 1.09.
Responders had a significantly higher incidence of prostate cancer (SIR,1.25), thyroid cancer (SIR, 2.19), and leukemia (SIR, 1.41). The leukemia category included acute myeloid leukemia (SIR,1.58) and chronic lymphocytic leukemia (SIR, 1.08).
“Although other studies have revealed elevated SIRs for other hematologic malignancies, this is the first reported, statistically significant, elevated SIR for leukemia,” the researchers wrote. “Leukemia is known to occur after exposure to occupational carcinogens, including benzene (burning jet fuel and other sources at the [World Trade Center] site), possibly at low levels of exposure and with a latency of several years from exposure.”
A multivariate analysis showed no association between cancer incidence and the length of time responders spent on the rescue and recovery effort or the intensity of their exposure to the dust cloud or debris pile.
The analysis did show an elevated risk of all cancers combined with each 1-year increase in responder age (hazard ratio, 1.09), among male responders (HR, 1.21), and among responders who smoked at baseline (HR, 1.29).
This research was supported by the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The researchers disclosed no conflicts of interest.
SOURCE: Shapiro MZ et al. JNCI Cancer Spectr. 2020 Jan 14. doi: 10.1093/jncics/pkz090.
New data suggest an increased risk of leukemia among responders who worked at the World Trade Center site after the attacks on Sept. 11, 2001.
Previous studies have shown that 9/11 responders have a higher incidence of cancers than does the general population. The current study is the first to show a higher incidence of leukemia among responders. It also shows a higher incidence of thyroid and prostate cancers as well as all cancer types combined.
These findings were published in JNCI Cancer Spectrum.
“This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods,” study author Susan L, Teitelbaum, PhD, of the Icahn School of Medicine at Mount Sinai, New York, said in a press release.
“Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study.”
Dr. Teitelbaum and colleagues evaluated responders enrolled in the World Trade Center Health Program General Responder Cohort from when it was established in July 2002 through the end of follow-up, which was Dec. 31, 2013, for New York residents and Dec. 31, 2012, for residents of other states.
To be eligible for the cohort, responders must have worked on the World Trade Center rescue and recovery effort a minimum of 4 hours in the first 4 days from Sept. 11, 2001, 24 hours in September 2001, or 80 hours from September through December 2001. Responders also had to complete at least one monitoring visit.
Responders’ data were linked to data from cancer registries in New York, New Jersey, Pennsylvania, and Connecticut (where most responders lived at the time of the attacks), as well as Florida and North Carolina (where responders were known to retire). The responders were linked to the registries using probabilistic matching algorithms, which made use of information such as patient name, address, social security number, sex, race, and birth date.
The researchers noted that patients who enrolled in the General Responder Cohort had their cancer certified for federally funded treatment, and this factor might result in “sicker members disproportionately self-selecting into the program.” To reduce this potential bias, the researchers conducted a restricted analysis in which counts of cancer cases and person-years of observation began 6 months after responder enrollment.
The researchers analyzed data on 28,729 responders who primarily worked in protective services (49.0%) and construction (20.8%). Responders spent a median of 52 days on the rescue and recovery effort, and 44.4% of them had some exposure to the dust cloud caused by the collapse of the towers.
In the restricted analysis, there were 1,072 cancers observed in 999 responders. Compared with the general population, responders had a significantly higher incidence of all cancers combined, with a standardized incidence ratio (SIR) of 1.09.
Responders had a significantly higher incidence of prostate cancer (SIR,1.25), thyroid cancer (SIR, 2.19), and leukemia (SIR, 1.41). The leukemia category included acute myeloid leukemia (SIR,1.58) and chronic lymphocytic leukemia (SIR, 1.08).
“Although other studies have revealed elevated SIRs for other hematologic malignancies, this is the first reported, statistically significant, elevated SIR for leukemia,” the researchers wrote. “Leukemia is known to occur after exposure to occupational carcinogens, including benzene (burning jet fuel and other sources at the [World Trade Center] site), possibly at low levels of exposure and with a latency of several years from exposure.”
A multivariate analysis showed no association between cancer incidence and the length of time responders spent on the rescue and recovery effort or the intensity of their exposure to the dust cloud or debris pile.
The analysis did show an elevated risk of all cancers combined with each 1-year increase in responder age (hazard ratio, 1.09), among male responders (HR, 1.21), and among responders who smoked at baseline (HR, 1.29).
This research was supported by the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The researchers disclosed no conflicts of interest.
SOURCE: Shapiro MZ et al. JNCI Cancer Spectr. 2020 Jan 14. doi: 10.1093/jncics/pkz090.
FROM JNCI CANCER SPECTRUM
Genomic profiling of AML and MDS yields prognostic clues
ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.
“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).
The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.
The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.
The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.
Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.
The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.
For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.
In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.
They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.
At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.
“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.
In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.
“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.
The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.
SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.
ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.
“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).
The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.
The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.
The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.
Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.
The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.
For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.
In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.
They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.
At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.
“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.
In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.
“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.
The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.
SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.
ORLANDO – A genome-wide study of blood and bone marrow samples from more than 1,300 adults with myeloid disorders has both confirmed the role of known or suspected driver mutations and uncovered new associations that could inform clinical care for patients with acute myeloid leukemia and myelodysplastic syndrome.
“Integration of mutational and expression data is important to refine subytpes and constellations of mutations with prognostic significance,” Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis said during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
Her team conducted an analysis combining full genomic sequencing and gene-expression profiles in blood and bone marrow samples from 598 adults with acute myeloid leukemia (AML) and 706 with myelodysplastic syndrome (MDS).
The goals of the study were to provide “unbiased analysis of AML and MDS by integrated genomic and transcriptome data and clinico-pathologic features and clinical outcome” and to identify and define myeloid leukemia subtypes with diagnostic, prognostic, and therapeutic significance, she said.
The median age of the MDS cohort was 73.2 years (range 23.3-93.1). According to 2016 World Health Organization criteria, 37% had a diagnosis of MDS with excess blasts, 26.3% had MDS with ring sideroblasts, 20.9% had MDS with multilineage dysplasia, 14.6% had MDS with deletion 5q, and 1.1% had unclassifiable MDS.
The median age of the AML cohort was 68 years. Of this group, 31.7% had a diagnosis of AML not otherwise specified, 29.9% had known cytogenetic alterations, 27.3% had NPM1-mutated AML, and 9.7% had RUNX1-mutated disease.
Samples from all patients underwent tumor whole-genome sequencing and whole-transcriptome sequencing.
The combined sequencing confirmed a diagnosis of AML with recurrent genetic abnormalities in 11% of cases. These patients had disease with distinct gene-expression profiles and favorable prognosis. The sequencing identified combinations of mutations in genes linked with specific AML subtypes.
For example, combinations of mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 were associated with RUNX1-RUNXT1 leukemia, whereas mutations in FLT3, DDX54, WT1, and CALR in promyelocytic leukemia/retinoic acid receptor alpha were associated with promyelocytic leukemia, and KIT and BCORL1 mutations were associated with CBFB-rearranged leukemia.
In addition to rounding up the usual genomic suspects, the investigators also identified combinations that are associated with prognosis. Notably, NPM1 mutations were found in 27.4% of AML and 1% of MDS cases, and these mutations were characterized by four gene-expression signatures that were associated with different combinations of cooperating mutations in cohesin and signaling genes, and with outcome.
They found that patients with co-occurring NPM1 and FLT3 mutations had worse prognosis than those with mutations only in NPM1, whereas patients with NPM1 mutations co-occurring with cohesin gene mutations had better outcomes.
At a briefing prior to her presentation of the data, Dr. Iacobucci explained how her group’s findings might inform treatment, including the possibility of preventing development of AML in patients with MDS.
“What we are doing, in addition to the genomic part, is also establishing a repository of patient-derived xenografts, so in this way we can have the genome information, and we can have the biological material in vivo to test different therapies,” she said.
In an interview, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, who was not involved in the genomic study, commented on the role of sequencing in treatment of patients with myeloid malignancies.
“I think the future is that as the leukemia evolves, our therapy will evolve along with it. Furthermore, we now have the potential to measure many of these mutations with much higher sensitivity than just whole-genome sequencing, so we can imagine a future whereby we can track and measure these mutations as they rise in the patient’s bone marrow or blood before the patients becomes sick with florid leukemia, and it gives us the potential to predictably alter our management before they become sick,” he said.
The study was supported by St. Jude Children’s Research Hospital and the Leukemia and Lymphoma Society. Dr. Iacobucci and Dr. Wei reported having no relevant disclosures.
SOURCE: Iacobucci I et al. ASH 2019, Abstract LBA-4.
REPORTING FROM ASH 2019
Oral azacitidine: First maintenance therapy for AML
ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).
“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.
“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”
Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.
However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.
Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.
The new results suggest that oral azacitidine could be an effective maintenance therapy.
Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.
The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).
The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
Experts predict new standard of care
Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.
“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.
He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.
“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.
HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.
“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.
Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.
Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.
“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.
“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.
“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
Study details
The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.
Patients had predominantly de novo AML (89%). Other baseline characteristics of note:
- 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
- 79% achieved CR and 21% achieved CRi after induction therapy
- 78% received at least one cycle of consolidation therapy
- 43% of patients had minimal residual disease (MRD)–positive disease
Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.
At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).
Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).
Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).
Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.
But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
Awaiting longer follow-up
Both experts said that longer-term follow-up is needed.
“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.
“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.
At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”
The study was funded by Celgene.
Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.
A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
A version of this story originally appeared on Medscape.com.
ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).
“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.
“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”
Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.
However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.
Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.
The new results suggest that oral azacitidine could be an effective maintenance therapy.
Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.
The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).
The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
Experts predict new standard of care
Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.
“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.
He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.
“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.
HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.
“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.
Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.
Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.
“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.
“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.
“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
Study details
The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.
Patients had predominantly de novo AML (89%). Other baseline characteristics of note:
- 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
- 79% achieved CR and 21% achieved CRi after induction therapy
- 78% received at least one cycle of consolidation therapy
- 43% of patients had minimal residual disease (MRD)–positive disease
Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.
At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).
Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).
Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).
Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.
But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
Awaiting longer follow-up
Both experts said that longer-term follow-up is needed.
“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.
“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.
At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”
The study was funded by Celgene.
Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.
A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
A version of this story originally appeared on Medscape.com.
ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).
“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.
“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”
Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.
However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.
Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.
The new results suggest that oral azacitidine could be an effective maintenance therapy.
Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.
The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).
The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
Experts predict new standard of care
Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.
“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.
He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.
“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.
HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.
“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.
Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.
Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.
“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.
“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.
“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
Study details
The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.
Patients had predominantly de novo AML (89%). Other baseline characteristics of note:
- 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
- 79% achieved CR and 21% achieved CRi after induction therapy
- 78% received at least one cycle of consolidation therapy
- 43% of patients had minimal residual disease (MRD)–positive disease
Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.
At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).
Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).
Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).
Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.
But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
Awaiting longer follow-up
Both experts said that longer-term follow-up is needed.
“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.
“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.
At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”
The study was funded by Celgene.
Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.
A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
A version of this story originally appeared on Medscape.com.
Kidney function in African American AML patients not linked to reduced survival compared with whites
ORLANDO – While African Americans with acute myeloid leukemia were more likely to have evidence of abnormal kidney function, the excess of this comorbidity didn’t affect overall survival, compared with whites, according to a study of more than 1,000 patients.
A total of 63% of African Americans with acute myeloid leukemia (AML) presented with a renal function abnormality that could have excluded them from a clinical trial, compared with 56% in the overall cohort; however, analysis of outcomes data suggested that renal function abnormalities were not associated with decreased survival in African Americans versus whites, said Abby Statler, PhD, MPH, of the Cleveland Clinic.
The findings may have implications for the design of clinical trials that might exclude patients on the basis of comorbidities that don’t actually affect survival, according to Dr. Statler.
“If we’re able to liberalize renal function eligibility criteria ... this may reduce racial disparities in clinical trial enrollment, which might be a major step in improving the diversity of cancer patient populations,” Dr. Statler said in a press conference at the annual meeting of the American Society of Hematology.
Overly restrictive criteria could be a significant barrier to clinical trial enrollment among minority patient populations, according to Dr. Statler.
Eligibility criteria are generally biased toward “fit” patient populations, which means they may discriminate against less-fit groups, such as African Americans who, compared with whites, have higher rates of comorbidities and report poorer overall health, according to Dr. Statler.
Laura Michaelis, MD, who chaired the press conference, said these findings suggest current clinical trial designs may be “too restrictive.”
“Once it’s published and validated, [these] data should definitely make us think twice about when you limit a patient’s enrollment in a trial,” Dr. Michaelis said in an interview.
Restrictive eligibility criteria may not only limit access to minority populations, but also may slow clinical trial accrual and completion, and make it harder to generalize clinical trial findings to the overall population, said Dr. Michaelis, associate professor of medicine in the division of hematology and oncology, Medical College of Wisconsin, Milwaukee.
The study by Dr. Statler and colleagues included 1,040 AML patients who received chemotherapy at Cleveland Clinic between 2003 and 2019. About 10% of the patients in the analysis were African American and 90% were white.
Median overall survival was not significantly different by race, at 13.7 months for African Americans and 14.9 months for whites (P = 0.89), according to results published in the study abstract.
Mild creatinine elevation did not appear to affect survival in this study, according to the investigator. Survival was not significantly different between patients with normal creatinine and those with creatinine up to 1.5 times the upper limit of normal. However, higher levels of creatinine were significantly associated with worse survival, Dr. Statler said.
Further analyses showed that these survival findings by creatinine level held up specifically in the African American subgroup as well, Dr. Statler said in the press conference.
Dr. Statler provided no disclosures related to the presentation. Study coauthors described disclosures related to Amgen, SimulStat, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, Celgene Corporation, Abbvie, and Incyte, among others.
SOURCE: Statler A et al. ASH 2019, Abstract 381.
ORLANDO – While African Americans with acute myeloid leukemia were more likely to have evidence of abnormal kidney function, the excess of this comorbidity didn’t affect overall survival, compared with whites, according to a study of more than 1,000 patients.
A total of 63% of African Americans with acute myeloid leukemia (AML) presented with a renal function abnormality that could have excluded them from a clinical trial, compared with 56% in the overall cohort; however, analysis of outcomes data suggested that renal function abnormalities were not associated with decreased survival in African Americans versus whites, said Abby Statler, PhD, MPH, of the Cleveland Clinic.
The findings may have implications for the design of clinical trials that might exclude patients on the basis of comorbidities that don’t actually affect survival, according to Dr. Statler.
“If we’re able to liberalize renal function eligibility criteria ... this may reduce racial disparities in clinical trial enrollment, which might be a major step in improving the diversity of cancer patient populations,” Dr. Statler said in a press conference at the annual meeting of the American Society of Hematology.
Overly restrictive criteria could be a significant barrier to clinical trial enrollment among minority patient populations, according to Dr. Statler.
Eligibility criteria are generally biased toward “fit” patient populations, which means they may discriminate against less-fit groups, such as African Americans who, compared with whites, have higher rates of comorbidities and report poorer overall health, according to Dr. Statler.
Laura Michaelis, MD, who chaired the press conference, said these findings suggest current clinical trial designs may be “too restrictive.”
“Once it’s published and validated, [these] data should definitely make us think twice about when you limit a patient’s enrollment in a trial,” Dr. Michaelis said in an interview.
Restrictive eligibility criteria may not only limit access to minority populations, but also may slow clinical trial accrual and completion, and make it harder to generalize clinical trial findings to the overall population, said Dr. Michaelis, associate professor of medicine in the division of hematology and oncology, Medical College of Wisconsin, Milwaukee.
The study by Dr. Statler and colleagues included 1,040 AML patients who received chemotherapy at Cleveland Clinic between 2003 and 2019. About 10% of the patients in the analysis were African American and 90% were white.
Median overall survival was not significantly different by race, at 13.7 months for African Americans and 14.9 months for whites (P = 0.89), according to results published in the study abstract.
Mild creatinine elevation did not appear to affect survival in this study, according to the investigator. Survival was not significantly different between patients with normal creatinine and those with creatinine up to 1.5 times the upper limit of normal. However, higher levels of creatinine were significantly associated with worse survival, Dr. Statler said.
Further analyses showed that these survival findings by creatinine level held up specifically in the African American subgroup as well, Dr. Statler said in the press conference.
Dr. Statler provided no disclosures related to the presentation. Study coauthors described disclosures related to Amgen, SimulStat, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, Celgene Corporation, Abbvie, and Incyte, among others.
SOURCE: Statler A et al. ASH 2019, Abstract 381.
ORLANDO – While African Americans with acute myeloid leukemia were more likely to have evidence of abnormal kidney function, the excess of this comorbidity didn’t affect overall survival, compared with whites, according to a study of more than 1,000 patients.
A total of 63% of African Americans with acute myeloid leukemia (AML) presented with a renal function abnormality that could have excluded them from a clinical trial, compared with 56% in the overall cohort; however, analysis of outcomes data suggested that renal function abnormalities were not associated with decreased survival in African Americans versus whites, said Abby Statler, PhD, MPH, of the Cleveland Clinic.
The findings may have implications for the design of clinical trials that might exclude patients on the basis of comorbidities that don’t actually affect survival, according to Dr. Statler.
“If we’re able to liberalize renal function eligibility criteria ... this may reduce racial disparities in clinical trial enrollment, which might be a major step in improving the diversity of cancer patient populations,” Dr. Statler said in a press conference at the annual meeting of the American Society of Hematology.
Overly restrictive criteria could be a significant barrier to clinical trial enrollment among minority patient populations, according to Dr. Statler.
Eligibility criteria are generally biased toward “fit” patient populations, which means they may discriminate against less-fit groups, such as African Americans who, compared with whites, have higher rates of comorbidities and report poorer overall health, according to Dr. Statler.
Laura Michaelis, MD, who chaired the press conference, said these findings suggest current clinical trial designs may be “too restrictive.”
“Once it’s published and validated, [these] data should definitely make us think twice about when you limit a patient’s enrollment in a trial,” Dr. Michaelis said in an interview.
Restrictive eligibility criteria may not only limit access to minority populations, but also may slow clinical trial accrual and completion, and make it harder to generalize clinical trial findings to the overall population, said Dr. Michaelis, associate professor of medicine in the division of hematology and oncology, Medical College of Wisconsin, Milwaukee.
The study by Dr. Statler and colleagues included 1,040 AML patients who received chemotherapy at Cleveland Clinic between 2003 and 2019. About 10% of the patients in the analysis were African American and 90% were white.
Median overall survival was not significantly different by race, at 13.7 months for African Americans and 14.9 months for whites (P = 0.89), according to results published in the study abstract.
Mild creatinine elevation did not appear to affect survival in this study, according to the investigator. Survival was not significantly different between patients with normal creatinine and those with creatinine up to 1.5 times the upper limit of normal. However, higher levels of creatinine were significantly associated with worse survival, Dr. Statler said.
Further analyses showed that these survival findings by creatinine level held up specifically in the African American subgroup as well, Dr. Statler said in the press conference.
Dr. Statler provided no disclosures related to the presentation. Study coauthors described disclosures related to Amgen, SimulStat, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, Celgene Corporation, Abbvie, and Incyte, among others.
SOURCE: Statler A et al. ASH 2019, Abstract 381.
REPORTING FROM ASH 2019