User login
Will TP53-mutated AML respond to immunotherapy?
NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).
Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.
These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.
Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.
He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*
With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.
Discovery cohort
The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.
The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.
The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).
The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).
Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).
Validation cohort and bone marrow samples
The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.
Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).
Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.
Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.
The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.
Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.
“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.
“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”
Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.
SOURCE: Rutella S et al. SITC 2019. Abstract O3.
*This article was updated on 11/19/2019.
NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).
Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.
These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.
Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.
He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*
With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.
Discovery cohort
The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.
The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.
The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).
The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).
Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).
Validation cohort and bone marrow samples
The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.
Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).
Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.
Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.
The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.
Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.
“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.
“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”
Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.
SOURCE: Rutella S et al. SITC 2019. Abstract O3.
*This article was updated on 11/19/2019.
NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).
Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.
These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.
Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.
He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*
With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.
Discovery cohort
The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.
The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.
The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).
The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).
Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).
Validation cohort and bone marrow samples
The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.
Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).
Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.
Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.
The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.
Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.
“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.
“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”
Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.
SOURCE: Rutella S et al. SITC 2019. Abstract O3.
*This article was updated on 11/19/2019.
REPORTING FROM SITC 2019
Caspofungin bests fluconazole for antifungal prophylaxis in young AML patients
Antifungal prophylaxis with caspofungin led to a lower incidence of invasive fungal disease, compared with fluconazole, in children and young adults with acute myeloid leukemia (AML), according to new study findings.
The results suggest caspofungin may be an appropriate prophylactic strategy to prevent invasive fungal disease in younger patients with newly diagnosed AML, reported Brian T. Fisher, DO, of the University of Pennsylvania, Philadelphia, and colleagues. The study was published in JAMA.
The randomized, open-label study included 517 children, adolescents, and young adults with de novo, relapsed, or secondary AML. Study patients received treatment in 115 centers throughout United States and Canada. The median age of patients in the study was 9 years (range, 0-26 years); 56% were male and approximately 69% were white.
Study subjects were randomly assigned to receive antifungal prophylaxis with 70 mg/m2 (maximum dose 70 mg/day) of intravenous caspofungin on day 1, followed by 50 mg/m2 per day (maximum dose 50 mg/day) thereafter, or age-dosed intravenous or oral fluconazole.
Prophylactic therapy was initiated 24-72 hours after the completion of each chemotherapy cycle, and was maintained until the end of the neutropenic period following each cycle.
At 5-month follow-up, the cumulative incidence rate of probable or proven invasive fungal disease was 3.1% (95% confidence interval, 1.3%-7.0%) in the caspofungin arm, compared with 7.2% (95% CI, 4.4%-11.8%) in the fluconazole arm (overall P = .03).
In addition, the 5-month cumulative incidence rate of probable or proven invasive aspergillosis infection was 0.5% (95%CI, 0.1%-3.5%) in patients who received caspofungin, compared with 3.1% (95% CI, 1.4%-6.9%) in patients who received fluconazole (overall P = .046).
“No statistically significant differences in empirical antifungal therapy or 2-year overall survival were observed,” they reported.
With respect to safety, the most frequently reported adverse events were hypokalemia (22 events in the caspofungin arm vs. 13 in the fluconazole arm), respiratory failure (6 events in the caspofungin arm vs. 9 in the fluconazole arm), and elevated alanine transaminase (4 events in the caspofungin arm vs. 8 in the fluconazole arm).
The researchers acknowledged a key limitation of the study was the short duration of follow-up. As a result, the precision of some comparative measures may have been reduced.
The National Cancer Institute funded the study. The authors reported financial affiliations with Astellas, Celgene, Leadiant Biosciences, Merck, Nabriva Therapeutics, Novartis, Pfizer, Shire, and T2 Biosystems.
SOURCE: Fisher BT et al. JAMA. 2019;322(17):1673-81.
Antifungal prophylaxis with caspofungin led to a lower incidence of invasive fungal disease, compared with fluconazole, in children and young adults with acute myeloid leukemia (AML), according to new study findings.
The results suggest caspofungin may be an appropriate prophylactic strategy to prevent invasive fungal disease in younger patients with newly diagnosed AML, reported Brian T. Fisher, DO, of the University of Pennsylvania, Philadelphia, and colleagues. The study was published in JAMA.
The randomized, open-label study included 517 children, adolescents, and young adults with de novo, relapsed, or secondary AML. Study patients received treatment in 115 centers throughout United States and Canada. The median age of patients in the study was 9 years (range, 0-26 years); 56% were male and approximately 69% were white.
Study subjects were randomly assigned to receive antifungal prophylaxis with 70 mg/m2 (maximum dose 70 mg/day) of intravenous caspofungin on day 1, followed by 50 mg/m2 per day (maximum dose 50 mg/day) thereafter, or age-dosed intravenous or oral fluconazole.
Prophylactic therapy was initiated 24-72 hours after the completion of each chemotherapy cycle, and was maintained until the end of the neutropenic period following each cycle.
At 5-month follow-up, the cumulative incidence rate of probable or proven invasive fungal disease was 3.1% (95% confidence interval, 1.3%-7.0%) in the caspofungin arm, compared with 7.2% (95% CI, 4.4%-11.8%) in the fluconazole arm (overall P = .03).
In addition, the 5-month cumulative incidence rate of probable or proven invasive aspergillosis infection was 0.5% (95%CI, 0.1%-3.5%) in patients who received caspofungin, compared with 3.1% (95% CI, 1.4%-6.9%) in patients who received fluconazole (overall P = .046).
“No statistically significant differences in empirical antifungal therapy or 2-year overall survival were observed,” they reported.
With respect to safety, the most frequently reported adverse events were hypokalemia (22 events in the caspofungin arm vs. 13 in the fluconazole arm), respiratory failure (6 events in the caspofungin arm vs. 9 in the fluconazole arm), and elevated alanine transaminase (4 events in the caspofungin arm vs. 8 in the fluconazole arm).
The researchers acknowledged a key limitation of the study was the short duration of follow-up. As a result, the precision of some comparative measures may have been reduced.
The National Cancer Institute funded the study. The authors reported financial affiliations with Astellas, Celgene, Leadiant Biosciences, Merck, Nabriva Therapeutics, Novartis, Pfizer, Shire, and T2 Biosystems.
SOURCE: Fisher BT et al. JAMA. 2019;322(17):1673-81.
Antifungal prophylaxis with caspofungin led to a lower incidence of invasive fungal disease, compared with fluconazole, in children and young adults with acute myeloid leukemia (AML), according to new study findings.
The results suggest caspofungin may be an appropriate prophylactic strategy to prevent invasive fungal disease in younger patients with newly diagnosed AML, reported Brian T. Fisher, DO, of the University of Pennsylvania, Philadelphia, and colleagues. The study was published in JAMA.
The randomized, open-label study included 517 children, adolescents, and young adults with de novo, relapsed, or secondary AML. Study patients received treatment in 115 centers throughout United States and Canada. The median age of patients in the study was 9 years (range, 0-26 years); 56% were male and approximately 69% were white.
Study subjects were randomly assigned to receive antifungal prophylaxis with 70 mg/m2 (maximum dose 70 mg/day) of intravenous caspofungin on day 1, followed by 50 mg/m2 per day (maximum dose 50 mg/day) thereafter, or age-dosed intravenous or oral fluconazole.
Prophylactic therapy was initiated 24-72 hours after the completion of each chemotherapy cycle, and was maintained until the end of the neutropenic period following each cycle.
At 5-month follow-up, the cumulative incidence rate of probable or proven invasive fungal disease was 3.1% (95% confidence interval, 1.3%-7.0%) in the caspofungin arm, compared with 7.2% (95% CI, 4.4%-11.8%) in the fluconazole arm (overall P = .03).
In addition, the 5-month cumulative incidence rate of probable or proven invasive aspergillosis infection was 0.5% (95%CI, 0.1%-3.5%) in patients who received caspofungin, compared with 3.1% (95% CI, 1.4%-6.9%) in patients who received fluconazole (overall P = .046).
“No statistically significant differences in empirical antifungal therapy or 2-year overall survival were observed,” they reported.
With respect to safety, the most frequently reported adverse events were hypokalemia (22 events in the caspofungin arm vs. 13 in the fluconazole arm), respiratory failure (6 events in the caspofungin arm vs. 9 in the fluconazole arm), and elevated alanine transaminase (4 events in the caspofungin arm vs. 8 in the fluconazole arm).
The researchers acknowledged a key limitation of the study was the short duration of follow-up. As a result, the precision of some comparative measures may have been reduced.
The National Cancer Institute funded the study. The authors reported financial affiliations with Astellas, Celgene, Leadiant Biosciences, Merck, Nabriva Therapeutics, Novartis, Pfizer, Shire, and T2 Biosystems.
SOURCE: Fisher BT et al. JAMA. 2019;322(17):1673-81.
FROM JAMA
Hematopoietic cell transplant offers realistic cure in secondary AML
yielding significantly better survival outcomes, according to findings from an observational study.
Although secondary AML has been identified as an independent predictor of poor prognosis, it is not included in current risk classifications that provide the basis of deciding when to perform HCT.
Christer Nilsson, MD, of Karolinska Institute, Stockholm, and colleagues, used two nationwide Swedish registries – the Swedish AML Registry and the Swedish Cancer Registry – to characterize how often HCT is performed in these patients and to evaluate its impact in a real-world setting. The registries include all patients with AML diagnosed between 1997 and 2013.
Their findings are in Biology of Blood and Marrow Transplantation.
The analysis included 3,337 adult patients with AML who were intensively treated and did not have acute promyelocytic leukemia. More than three-quarters of the patients had de novo AML and the remainder had secondary AML that was either therapy related or developed after an antecedent myeloid disease. In total, 100 patients with secondary AML underwent HCT while in first complete remission.
In terms of crude survival at 5 years after diagnosis, patients with secondary AML who did not undergo HCT did very poorly. The survival rate was 0% in those with AML preceded by myeloproliferative neoplasm (MPN-AML), 2% in patients with AML preceded by myelodysplastic syndrome (MDS-AML), and 4% in patients with therapy-related AML (t-AML). In contrast, the 5-year overall survival in patients who underwent HCT at any time point or disease stage was 32% for patients with MPN-AML, 18% for patients with MDS-AML, and 25% for patients t-AML.
These crude survival figures suggest that “HCT is the sole realistic curable treatment option for [secondary] AML,” the researchers wrote.
The researchers also performed a propensity score matching analysis of HCT versus chemotherapy consolidation in patients with secondary AML who had been in first complete remission for more than 90 days. The model matched 45 patients who underwent HCT with 66 patients treated with chemotherapy consolidation. The projected 5-year overall survival was 48% in the HCT group, compared with 20% in the consolidation group (P = .01). Similarly, 5-year relapse-free survival was also higher in the HCT group, compared with the consolidation group (43% vs. 21%, P = .02).
“Ideally, the role of transplantation in [secondary] AML should be evaluated in a prospective randomized trial, minimizing the risk of any bias,” the researchers wrote. “However, such a trial is lacking and most likely will never be performed.”
The researchers concluded that HCT should be considered for all patients with secondary AML who are eligible and fit for transplantation.
The study was supported by the Swedish Cancer Foundation, Swedish Research Council, Stockholm County Council, Gothenberg Medical Society, and Assar Gabrielsson Foundation. The researchers reported having no conflicts of interest.
SOURCE: Nilson C et al. Biol Blood Marrow Tranplant. 2019;25:1770-8.
yielding significantly better survival outcomes, according to findings from an observational study.
Although secondary AML has been identified as an independent predictor of poor prognosis, it is not included in current risk classifications that provide the basis of deciding when to perform HCT.
Christer Nilsson, MD, of Karolinska Institute, Stockholm, and colleagues, used two nationwide Swedish registries – the Swedish AML Registry and the Swedish Cancer Registry – to characterize how often HCT is performed in these patients and to evaluate its impact in a real-world setting. The registries include all patients with AML diagnosed between 1997 and 2013.
Their findings are in Biology of Blood and Marrow Transplantation.
The analysis included 3,337 adult patients with AML who were intensively treated and did not have acute promyelocytic leukemia. More than three-quarters of the patients had de novo AML and the remainder had secondary AML that was either therapy related or developed after an antecedent myeloid disease. In total, 100 patients with secondary AML underwent HCT while in first complete remission.
In terms of crude survival at 5 years after diagnosis, patients with secondary AML who did not undergo HCT did very poorly. The survival rate was 0% in those with AML preceded by myeloproliferative neoplasm (MPN-AML), 2% in patients with AML preceded by myelodysplastic syndrome (MDS-AML), and 4% in patients with therapy-related AML (t-AML). In contrast, the 5-year overall survival in patients who underwent HCT at any time point or disease stage was 32% for patients with MPN-AML, 18% for patients with MDS-AML, and 25% for patients t-AML.
These crude survival figures suggest that “HCT is the sole realistic curable treatment option for [secondary] AML,” the researchers wrote.
The researchers also performed a propensity score matching analysis of HCT versus chemotherapy consolidation in patients with secondary AML who had been in first complete remission for more than 90 days. The model matched 45 patients who underwent HCT with 66 patients treated with chemotherapy consolidation. The projected 5-year overall survival was 48% in the HCT group, compared with 20% in the consolidation group (P = .01). Similarly, 5-year relapse-free survival was also higher in the HCT group, compared with the consolidation group (43% vs. 21%, P = .02).
“Ideally, the role of transplantation in [secondary] AML should be evaluated in a prospective randomized trial, minimizing the risk of any bias,” the researchers wrote. “However, such a trial is lacking and most likely will never be performed.”
The researchers concluded that HCT should be considered for all patients with secondary AML who are eligible and fit for transplantation.
The study was supported by the Swedish Cancer Foundation, Swedish Research Council, Stockholm County Council, Gothenberg Medical Society, and Assar Gabrielsson Foundation. The researchers reported having no conflicts of interest.
SOURCE: Nilson C et al. Biol Blood Marrow Tranplant. 2019;25:1770-8.
yielding significantly better survival outcomes, according to findings from an observational study.
Although secondary AML has been identified as an independent predictor of poor prognosis, it is not included in current risk classifications that provide the basis of deciding when to perform HCT.
Christer Nilsson, MD, of Karolinska Institute, Stockholm, and colleagues, used two nationwide Swedish registries – the Swedish AML Registry and the Swedish Cancer Registry – to characterize how often HCT is performed in these patients and to evaluate its impact in a real-world setting. The registries include all patients with AML diagnosed between 1997 and 2013.
Their findings are in Biology of Blood and Marrow Transplantation.
The analysis included 3,337 adult patients with AML who were intensively treated and did not have acute promyelocytic leukemia. More than three-quarters of the patients had de novo AML and the remainder had secondary AML that was either therapy related or developed after an antecedent myeloid disease. In total, 100 patients with secondary AML underwent HCT while in first complete remission.
In terms of crude survival at 5 years after diagnosis, patients with secondary AML who did not undergo HCT did very poorly. The survival rate was 0% in those with AML preceded by myeloproliferative neoplasm (MPN-AML), 2% in patients with AML preceded by myelodysplastic syndrome (MDS-AML), and 4% in patients with therapy-related AML (t-AML). In contrast, the 5-year overall survival in patients who underwent HCT at any time point or disease stage was 32% for patients with MPN-AML, 18% for patients with MDS-AML, and 25% for patients t-AML.
These crude survival figures suggest that “HCT is the sole realistic curable treatment option for [secondary] AML,” the researchers wrote.
The researchers also performed a propensity score matching analysis of HCT versus chemotherapy consolidation in patients with secondary AML who had been in first complete remission for more than 90 days. The model matched 45 patients who underwent HCT with 66 patients treated with chemotherapy consolidation. The projected 5-year overall survival was 48% in the HCT group, compared with 20% in the consolidation group (P = .01). Similarly, 5-year relapse-free survival was also higher in the HCT group, compared with the consolidation group (43% vs. 21%, P = .02).
“Ideally, the role of transplantation in [secondary] AML should be evaluated in a prospective randomized trial, minimizing the risk of any bias,” the researchers wrote. “However, such a trial is lacking and most likely will never be performed.”
The researchers concluded that HCT should be considered for all patients with secondary AML who are eligible and fit for transplantation.
The study was supported by the Swedish Cancer Foundation, Swedish Research Council, Stockholm County Council, Gothenberg Medical Society, and Assar Gabrielsson Foundation. The researchers reported having no conflicts of interest.
SOURCE: Nilson C et al. Biol Blood Marrow Tranplant. 2019;25:1770-8.
FROM BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
Adverse cytogenetics trump molecular risk in NPM1-mutated AML
A pooled analysis suggests adverse cytogenetics are a key factor negatively impacting outcomes in patients with NPM1mut/FLT3-ITDneg/low acute myeloid leukemia (AML).
In patients with adverse chromosomal abnormalities, NPM1 mutational status was found not to confer a favorable outcome. The findings suggest cytogenetic risk outweighs molecular risk in patients with NPM1 mutations and the FLT3-ITDneg/low genotype.
“Patients carrying adverse-risk cytogenetics shared a virtually identical unfavorable outcome, regardless of whether the otherwise beneficial NPM1mut/FLT3-ITDneg/low status was present. The type of the adverse chromosomal abnormality did not seem to influence this effect, although low numbers might obscure detection of heterogeneity among individual aberrations,” Linus Angenendt, MD, of University Hospital Munster (Germany) and colleagues, wrote in the Journal of Clinical Oncology.
The researchers retrospectively analyzed 2,426 patients with NPM1mut/FLT3-ITDneg/low AML. Of these, 17.6% had an abnormal karyotype, and 3.4% had adverse-risk chromosomal aberrations.
Prior to analysis, individual patient data were pooled from nine international AML study group registries or treatment centers.
After analysis, the researchers found that adverse cytogenetics were associated with inferior complete remission rates (66.3%), compared with in patients with normal karyotype or intermediate-risk cytogenetic abnormalities (87.7% and 86.0%, respectively; P less than .001). The complete remission rates for the NPM1mut/FLT3-ITDneg/low AML adverse cytogenetics group was similar to patients with NPM1wt/FLT3-ITDneg/low and adverse cytogenetic abnormalities (66.3% vs. 57.5%).
Five-year event-free survival rates and overall survival rates were also lower in patients with NPM1mut/FLT3-ITDneg/low AML and adverse cytogenetics, compared with patients with normal karyotype or intermediate-risk cytogenetic abnormalities (P less than .001).
“Even though the combination of an NPM1 mutation with these abnormalities is rare, the prognostic effect of adverse cytogenetics in NPM1mut AML has important implications for postremission treatment decisions, in particular, the current recommendation that patients who are NPM1mut/FLT3-ITDneg/low not receive allogeneic hematopoietic stem cell transplantation (HSCT), given their presumed low risk of relapse might be altered if the adverse karyotype increased the risk,” they wrote.
The type of chromosomal aberration did not appear to impact this effect, but the small sample size may have hindered the ability to detect a difference between different abnormalities, the researchers noted.
One key limitation of the study was the retrospective design. As a result, in patients with an abnormal karyotype, some genetic analyses could have been underutilized.
“These results demand additional validation within prospective trials,” the researchers concluded.
The study was funded by the University of Munster Medical School, the German Research Foundation, the French government, the Ministry of Health of the Czech Republic, and others. The authors reported financial affiliations with numerous pharmaceutical companies.
SOURCE: Angenendt L et al. J Clin Oncol. 2019 Oct 10;37(29):2632-42.
A pooled analysis suggests adverse cytogenetics are a key factor negatively impacting outcomes in patients with NPM1mut/FLT3-ITDneg/low acute myeloid leukemia (AML).
In patients with adverse chromosomal abnormalities, NPM1 mutational status was found not to confer a favorable outcome. The findings suggest cytogenetic risk outweighs molecular risk in patients with NPM1 mutations and the FLT3-ITDneg/low genotype.
“Patients carrying adverse-risk cytogenetics shared a virtually identical unfavorable outcome, regardless of whether the otherwise beneficial NPM1mut/FLT3-ITDneg/low status was present. The type of the adverse chromosomal abnormality did not seem to influence this effect, although low numbers might obscure detection of heterogeneity among individual aberrations,” Linus Angenendt, MD, of University Hospital Munster (Germany) and colleagues, wrote in the Journal of Clinical Oncology.
The researchers retrospectively analyzed 2,426 patients with NPM1mut/FLT3-ITDneg/low AML. Of these, 17.6% had an abnormal karyotype, and 3.4% had adverse-risk chromosomal aberrations.
Prior to analysis, individual patient data were pooled from nine international AML study group registries or treatment centers.
After analysis, the researchers found that adverse cytogenetics were associated with inferior complete remission rates (66.3%), compared with in patients with normal karyotype or intermediate-risk cytogenetic abnormalities (87.7% and 86.0%, respectively; P less than .001). The complete remission rates for the NPM1mut/FLT3-ITDneg/low AML adverse cytogenetics group was similar to patients with NPM1wt/FLT3-ITDneg/low and adverse cytogenetic abnormalities (66.3% vs. 57.5%).
Five-year event-free survival rates and overall survival rates were also lower in patients with NPM1mut/FLT3-ITDneg/low AML and adverse cytogenetics, compared with patients with normal karyotype or intermediate-risk cytogenetic abnormalities (P less than .001).
“Even though the combination of an NPM1 mutation with these abnormalities is rare, the prognostic effect of adverse cytogenetics in NPM1mut AML has important implications for postremission treatment decisions, in particular, the current recommendation that patients who are NPM1mut/FLT3-ITDneg/low not receive allogeneic hematopoietic stem cell transplantation (HSCT), given their presumed low risk of relapse might be altered if the adverse karyotype increased the risk,” they wrote.
The type of chromosomal aberration did not appear to impact this effect, but the small sample size may have hindered the ability to detect a difference between different abnormalities, the researchers noted.
One key limitation of the study was the retrospective design. As a result, in patients with an abnormal karyotype, some genetic analyses could have been underutilized.
“These results demand additional validation within prospective trials,” the researchers concluded.
The study was funded by the University of Munster Medical School, the German Research Foundation, the French government, the Ministry of Health of the Czech Republic, and others. The authors reported financial affiliations with numerous pharmaceutical companies.
SOURCE: Angenendt L et al. J Clin Oncol. 2019 Oct 10;37(29):2632-42.
A pooled analysis suggests adverse cytogenetics are a key factor negatively impacting outcomes in patients with NPM1mut/FLT3-ITDneg/low acute myeloid leukemia (AML).
In patients with adverse chromosomal abnormalities, NPM1 mutational status was found not to confer a favorable outcome. The findings suggest cytogenetic risk outweighs molecular risk in patients with NPM1 mutations and the FLT3-ITDneg/low genotype.
“Patients carrying adverse-risk cytogenetics shared a virtually identical unfavorable outcome, regardless of whether the otherwise beneficial NPM1mut/FLT3-ITDneg/low status was present. The type of the adverse chromosomal abnormality did not seem to influence this effect, although low numbers might obscure detection of heterogeneity among individual aberrations,” Linus Angenendt, MD, of University Hospital Munster (Germany) and colleagues, wrote in the Journal of Clinical Oncology.
The researchers retrospectively analyzed 2,426 patients with NPM1mut/FLT3-ITDneg/low AML. Of these, 17.6% had an abnormal karyotype, and 3.4% had adverse-risk chromosomal aberrations.
Prior to analysis, individual patient data were pooled from nine international AML study group registries or treatment centers.
After analysis, the researchers found that adverse cytogenetics were associated with inferior complete remission rates (66.3%), compared with in patients with normal karyotype or intermediate-risk cytogenetic abnormalities (87.7% and 86.0%, respectively; P less than .001). The complete remission rates for the NPM1mut/FLT3-ITDneg/low AML adverse cytogenetics group was similar to patients with NPM1wt/FLT3-ITDneg/low and adverse cytogenetic abnormalities (66.3% vs. 57.5%).
Five-year event-free survival rates and overall survival rates were also lower in patients with NPM1mut/FLT3-ITDneg/low AML and adverse cytogenetics, compared with patients with normal karyotype or intermediate-risk cytogenetic abnormalities (P less than .001).
“Even though the combination of an NPM1 mutation with these abnormalities is rare, the prognostic effect of adverse cytogenetics in NPM1mut AML has important implications for postremission treatment decisions, in particular, the current recommendation that patients who are NPM1mut/FLT3-ITDneg/low not receive allogeneic hematopoietic stem cell transplantation (HSCT), given their presumed low risk of relapse might be altered if the adverse karyotype increased the risk,” they wrote.
The type of chromosomal aberration did not appear to impact this effect, but the small sample size may have hindered the ability to detect a difference between different abnormalities, the researchers noted.
One key limitation of the study was the retrospective design. As a result, in patients with an abnormal karyotype, some genetic analyses could have been underutilized.
“These results demand additional validation within prospective trials,” the researchers concluded.
The study was funded by the University of Munster Medical School, the German Research Foundation, the French government, the Ministry of Health of the Czech Republic, and others. The authors reported financial affiliations with numerous pharmaceutical companies.
SOURCE: Angenendt L et al. J Clin Oncol. 2019 Oct 10;37(29):2632-42.
REPORTING FROM THE JOURNAL OF CLINICAL ONCOLOGY
Genetic analysis highlights value of germline variants in MDS, AML
Germline DDX41 mutations were found to be relatively prevalent and showed favorable outcomes in a cohort of patients with myelodysplastic syndromes or acute myeloid leukemia, according to a genetic analysis.
The results demonstrate that systematic genetic testing for DDX41 mutations may aid in clinical decision making for adults with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).
“We screened a large, unselected cohort of adult patients diagnosed with MDS/AML to analyze the biological and clinical features of DDX41-related myeloid malignancies,” wrote Marie Sébert, MD, PhD, of Hôpital Saint Louis in Paris and colleagues. The results were published in Blood.
The researchers used next-generation sequencing to analyze blood and bone marrow samples from 1,385 patients with MDS or AML to detect DDX41 mutations. A variant allele frequency of greater than 0.4 was regarded as indicative of a germline origin, and only specific variants (minor allele frequency of less than 0.01) were included.
The team analyzed various parameters relevant to DDX41-related myeloid disorders, including patient demographics, karyotyping, and treatment response rates, in addition to the prevalence of DDX41-related malignancies.
A total of 28 distinct germline DDX41 variants were detected among 43 unrelated patients. The researchers classified 21 of the variants as causal, with the rest being of unknown significance.
“We focused on the 33 patients having causal variants, representing 2.4% of our cohort,” they wrote.
The majority of patients with DDX41-related MDS/AML were male, with a median age of 69 years. Few patients (27%) had a family history of blood malignancies, while the majority of patients (85%) had a normal karyotype.
With respect to treatment, most high-risk patients received either azacitidine or intensive chemotherapy, with overall response rates of 73% and 100%, respectively. The median overall survival was 5.2 years.
There are currently no consensus recommendations on genetic counseling and follow-up of asymptomatic carriers and more studies are needed to refine clinical management and genetic counseling, the researchers wrote. “However, in our experience, DDX41-mutated patients frequently presented mild cytopenias years before overt hematological myeloid malignancy, suggesting that watchful surveillance would allow the detection of disease evolution.”
No funding sources were reported, and the authors reported having no conflicts of interest.
SOURCE: Sébert M et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000909.
Germline DDX41 mutations were found to be relatively prevalent and showed favorable outcomes in a cohort of patients with myelodysplastic syndromes or acute myeloid leukemia, according to a genetic analysis.
The results demonstrate that systematic genetic testing for DDX41 mutations may aid in clinical decision making for adults with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).
“We screened a large, unselected cohort of adult patients diagnosed with MDS/AML to analyze the biological and clinical features of DDX41-related myeloid malignancies,” wrote Marie Sébert, MD, PhD, of Hôpital Saint Louis in Paris and colleagues. The results were published in Blood.
The researchers used next-generation sequencing to analyze blood and bone marrow samples from 1,385 patients with MDS or AML to detect DDX41 mutations. A variant allele frequency of greater than 0.4 was regarded as indicative of a germline origin, and only specific variants (minor allele frequency of less than 0.01) were included.
The team analyzed various parameters relevant to DDX41-related myeloid disorders, including patient demographics, karyotyping, and treatment response rates, in addition to the prevalence of DDX41-related malignancies.
A total of 28 distinct germline DDX41 variants were detected among 43 unrelated patients. The researchers classified 21 of the variants as causal, with the rest being of unknown significance.
“We focused on the 33 patients having causal variants, representing 2.4% of our cohort,” they wrote.
The majority of patients with DDX41-related MDS/AML were male, with a median age of 69 years. Few patients (27%) had a family history of blood malignancies, while the majority of patients (85%) had a normal karyotype.
With respect to treatment, most high-risk patients received either azacitidine or intensive chemotherapy, with overall response rates of 73% and 100%, respectively. The median overall survival was 5.2 years.
There are currently no consensus recommendations on genetic counseling and follow-up of asymptomatic carriers and more studies are needed to refine clinical management and genetic counseling, the researchers wrote. “However, in our experience, DDX41-mutated patients frequently presented mild cytopenias years before overt hematological myeloid malignancy, suggesting that watchful surveillance would allow the detection of disease evolution.”
No funding sources were reported, and the authors reported having no conflicts of interest.
SOURCE: Sébert M et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000909.
Germline DDX41 mutations were found to be relatively prevalent and showed favorable outcomes in a cohort of patients with myelodysplastic syndromes or acute myeloid leukemia, according to a genetic analysis.
The results demonstrate that systematic genetic testing for DDX41 mutations may aid in clinical decision making for adults with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).
“We screened a large, unselected cohort of adult patients diagnosed with MDS/AML to analyze the biological and clinical features of DDX41-related myeloid malignancies,” wrote Marie Sébert, MD, PhD, of Hôpital Saint Louis in Paris and colleagues. The results were published in Blood.
The researchers used next-generation sequencing to analyze blood and bone marrow samples from 1,385 patients with MDS or AML to detect DDX41 mutations. A variant allele frequency of greater than 0.4 was regarded as indicative of a germline origin, and only specific variants (minor allele frequency of less than 0.01) were included.
The team analyzed various parameters relevant to DDX41-related myeloid disorders, including patient demographics, karyotyping, and treatment response rates, in addition to the prevalence of DDX41-related malignancies.
A total of 28 distinct germline DDX41 variants were detected among 43 unrelated patients. The researchers classified 21 of the variants as causal, with the rest being of unknown significance.
“We focused on the 33 patients having causal variants, representing 2.4% of our cohort,” they wrote.
The majority of patients with DDX41-related MDS/AML were male, with a median age of 69 years. Few patients (27%) had a family history of blood malignancies, while the majority of patients (85%) had a normal karyotype.
With respect to treatment, most high-risk patients received either azacitidine or intensive chemotherapy, with overall response rates of 73% and 100%, respectively. The median overall survival was 5.2 years.
There are currently no consensus recommendations on genetic counseling and follow-up of asymptomatic carriers and more studies are needed to refine clinical management and genetic counseling, the researchers wrote. “However, in our experience, DDX41-mutated patients frequently presented mild cytopenias years before overt hematological myeloid malignancy, suggesting that watchful surveillance would allow the detection of disease evolution.”
No funding sources were reported, and the authors reported having no conflicts of interest.
SOURCE: Sébert M et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000909.
FROM BLOOD
Nonmyeloablative conditioning carries lowers infection risk in patients with AML
For patients with acute myeloid leukemia (AML) in need of allogeneic hematopoietic cell transplantation (alloHCT), reduced-intensity/nonmyeloablative conditioning (RIC/NMA) offers a lower risk of infection than myeloablative conditioning (MAC), based on a retrospective study involving more than 1,700 patients.
Within 100 days of treatment, patients who underwent MAC were significantly more likely to develop a bacterial infection, and develop it at an earlier date, than patients who had undergone RIC/NMA, reported lead author Celalettin Ustun, MD, of Rush University in Chicago, and colleagues.
“The incidence of infections, a common and often severe complication of alloHCT, is expected to be lower after RIC/NMA compared with MAC and thus contribute to the decreased [nonrelapse mortality],” the investigators wrote in Blood Advances, noting that this hypothesis has previously lacked supporting data, prompting the present study.
The retrospective analysis involved 1,755 patients with AML who were in first complete remission. Data were drawn from the Center for International Blood and Marrow Transplant Research (CIBMTR). The primary end point was incidence of infection within 100 days after T-cell replete alloHCT in patients receiving MAC (n = 978) versus those who underwent RIC/NMA (n = 777). Secondary end points included comparisons of infection types and infection density.
Patients who received RIC/NMA were generally older and more likely to have myelodysplastic syndrome than patients in the MAC group; the groups were otherwise similar, based on comorbidities, cytogenetic risks, and Karnofsky performance scores.
The proportion of patients who developed at least one infection was comparable between groups: 61% of MAC patients versus 58% of RIC/NMA patients (P = .21), but further analysis showed that MAC was in fact associated with some relatively increased risks. For instance, patients in the MAC group tended to develop infections sooner than patients treated with RIC/NMA (21 vs. 15 days), and more patients treated with MAC had at least one bacterial infection by day 100 (46% vs. 37%).
Although the proportion of patients developing at least one viral infection was slightly lower in the MAC group than the RIC/NMA group (34% vs. 39%), overall infection density was higher, which takes into account multiple infections.
The increased bacterial infections after MAC were caused by gram-positive bacteria, while the increased viral infections with RIC/NMA were caused by cytomegalovirus, the investigators reported.
“RIC/NMA alloHCT is associated with a decreased risk of any infection and particularly early bacterial infections,” the investigators wrote. “The risk of viral and fungal infections per days at risk is similar.”
The Center for International Blood and Marrow Transplant Research is supported by grants from the U.S. government and several pharmaceutical companies. The investigators reported having no conflicts of interest.
SOURCE: Ustun C et al. Blood Adv. 2019 Sep 10;3(17):2525-36.
For patients with acute myeloid leukemia (AML) in need of allogeneic hematopoietic cell transplantation (alloHCT), reduced-intensity/nonmyeloablative conditioning (RIC/NMA) offers a lower risk of infection than myeloablative conditioning (MAC), based on a retrospective study involving more than 1,700 patients.
Within 100 days of treatment, patients who underwent MAC were significantly more likely to develop a bacterial infection, and develop it at an earlier date, than patients who had undergone RIC/NMA, reported lead author Celalettin Ustun, MD, of Rush University in Chicago, and colleagues.
“The incidence of infections, a common and often severe complication of alloHCT, is expected to be lower after RIC/NMA compared with MAC and thus contribute to the decreased [nonrelapse mortality],” the investigators wrote in Blood Advances, noting that this hypothesis has previously lacked supporting data, prompting the present study.
The retrospective analysis involved 1,755 patients with AML who were in first complete remission. Data were drawn from the Center for International Blood and Marrow Transplant Research (CIBMTR). The primary end point was incidence of infection within 100 days after T-cell replete alloHCT in patients receiving MAC (n = 978) versus those who underwent RIC/NMA (n = 777). Secondary end points included comparisons of infection types and infection density.
Patients who received RIC/NMA were generally older and more likely to have myelodysplastic syndrome than patients in the MAC group; the groups were otherwise similar, based on comorbidities, cytogenetic risks, and Karnofsky performance scores.
The proportion of patients who developed at least one infection was comparable between groups: 61% of MAC patients versus 58% of RIC/NMA patients (P = .21), but further analysis showed that MAC was in fact associated with some relatively increased risks. For instance, patients in the MAC group tended to develop infections sooner than patients treated with RIC/NMA (21 vs. 15 days), and more patients treated with MAC had at least one bacterial infection by day 100 (46% vs. 37%).
Although the proportion of patients developing at least one viral infection was slightly lower in the MAC group than the RIC/NMA group (34% vs. 39%), overall infection density was higher, which takes into account multiple infections.
The increased bacterial infections after MAC were caused by gram-positive bacteria, while the increased viral infections with RIC/NMA were caused by cytomegalovirus, the investigators reported.
“RIC/NMA alloHCT is associated with a decreased risk of any infection and particularly early bacterial infections,” the investigators wrote. “The risk of viral and fungal infections per days at risk is similar.”
The Center for International Blood and Marrow Transplant Research is supported by grants from the U.S. government and several pharmaceutical companies. The investigators reported having no conflicts of interest.
SOURCE: Ustun C et al. Blood Adv. 2019 Sep 10;3(17):2525-36.
For patients with acute myeloid leukemia (AML) in need of allogeneic hematopoietic cell transplantation (alloHCT), reduced-intensity/nonmyeloablative conditioning (RIC/NMA) offers a lower risk of infection than myeloablative conditioning (MAC), based on a retrospective study involving more than 1,700 patients.
Within 100 days of treatment, patients who underwent MAC were significantly more likely to develop a bacterial infection, and develop it at an earlier date, than patients who had undergone RIC/NMA, reported lead author Celalettin Ustun, MD, of Rush University in Chicago, and colleagues.
“The incidence of infections, a common and often severe complication of alloHCT, is expected to be lower after RIC/NMA compared with MAC and thus contribute to the decreased [nonrelapse mortality],” the investigators wrote in Blood Advances, noting that this hypothesis has previously lacked supporting data, prompting the present study.
The retrospective analysis involved 1,755 patients with AML who were in first complete remission. Data were drawn from the Center for International Blood and Marrow Transplant Research (CIBMTR). The primary end point was incidence of infection within 100 days after T-cell replete alloHCT in patients receiving MAC (n = 978) versus those who underwent RIC/NMA (n = 777). Secondary end points included comparisons of infection types and infection density.
Patients who received RIC/NMA were generally older and more likely to have myelodysplastic syndrome than patients in the MAC group; the groups were otherwise similar, based on comorbidities, cytogenetic risks, and Karnofsky performance scores.
The proportion of patients who developed at least one infection was comparable between groups: 61% of MAC patients versus 58% of RIC/NMA patients (P = .21), but further analysis showed that MAC was in fact associated with some relatively increased risks. For instance, patients in the MAC group tended to develop infections sooner than patients treated with RIC/NMA (21 vs. 15 days), and more patients treated with MAC had at least one bacterial infection by day 100 (46% vs. 37%).
Although the proportion of patients developing at least one viral infection was slightly lower in the MAC group than the RIC/NMA group (34% vs. 39%), overall infection density was higher, which takes into account multiple infections.
The increased bacterial infections after MAC were caused by gram-positive bacteria, while the increased viral infections with RIC/NMA were caused by cytomegalovirus, the investigators reported.
“RIC/NMA alloHCT is associated with a decreased risk of any infection and particularly early bacterial infections,” the investigators wrote. “The risk of viral and fungal infections per days at risk is similar.”
The Center for International Blood and Marrow Transplant Research is supported by grants from the U.S. government and several pharmaceutical companies. The investigators reported having no conflicts of interest.
SOURCE: Ustun C et al. Blood Adv. 2019 Sep 10;3(17):2525-36.
FROM BLOOD ADVANCES
Key clinical point: For patients with acute myeloid leukemia (AML) in need of allogeneic hematopoietic cell transplantation (alloHCT), reduced-intensity/nonmyeloablative conditioning (RIC/NMA) offers a lower risk of infection than myeloablative conditioning (MAC).
Major finding: By day 100, 37% of patients who received RIC/NMA had at least one bacterial infection, compared with 46% of patients who underwent MAC (P = .0004).
Study details: A retrospective study involving 1,755 patients with AML in first complete remission.
Disclosures: The Center for International Blood and Marrow Transplant Research is supported by grants from the U.S. government and several pharmaceutical companies. The investigators reported having no conflicts of interest.
Source: Ustun C et al. Blood Adv. 2019 Sep 3(17):2525-36.
How to recognize pediatric leukemia cutis
Researchers have characterized the clinical presentation, progression, and prognosis of leukemia cutis in a pediatric population, according to findings from a retrospective case series.
“To our knowledge, this is the largest reported case series of pediatric leukemia cutis,” wrote Elena Corina Andriescu of the University of Texas, Houston, and colleagues. The results were published in Pediatric Dermatology.
The study included 31 children with histologically confirmed leukemia cutis at one of two pediatric institutions. The researchers reviewed medical records to distinguish common features among patients.
Various clinical data, including disease subtype, related symptoms, management, and prognosis, were collected from January 1993 to March 2014. The children in the case series ranged in age up to 19 years with a median age at diagnosis of 26.8 months.
After analysis, the researchers reported that the magnitude and morphology of disease lesions differed among pediatric patients, with the most common sites being the lower extremities and head. The most common morphologies were nodules and papules. Additionally, the researchers found that lesions were often erythematous, violaceous, or both colors.
The majority of patients (65%) presented with concomitant systemic leukemia and leukemia cutis. The most common types of leukemia associated with the skin condition were acute myeloid leukemia (in 74% of cases) and acute lymphoblastic leukemia (in 16% of cases). The researchers saw no significant differences in leukemia cutis morphology or distribution based on the leukemia diagnosis.
“Most cases of leukemia cutis arose during initial leukemia episodes, rather than with relapsed leukemia,” they added.
Because of an insufficiency of specific genetic data, investigators were unable to make prognostic inferences in the majority of participants.
Two key limitations of the study were the small sample size and retrospective design. As a result, the investigators were unable to prospectively classify skin findings in a systematic manner. Despite these limitations, the authors noted that these findings add to the present knowledge of leukemia cutis in pediatric patients.
“Importantly, the presence of [leukemia cutis] changed the management of systemic leukemia in one‐third of patients,” the researchers wrote. “The potential for major changes in treatment plans such as adding radiation therapy and deferring hematopoietic stem cell transplantation underscores the importance of diagnosing [leukemia cutis].”
No funding sources were reported. The authors did not report conflicts of interest.
SOURCE: Andriescu EC et al. Pediatr Dermatol. 2019 Jul 5. doi: 10.1111/pde.13864.
Researchers have characterized the clinical presentation, progression, and prognosis of leukemia cutis in a pediatric population, according to findings from a retrospective case series.
“To our knowledge, this is the largest reported case series of pediatric leukemia cutis,” wrote Elena Corina Andriescu of the University of Texas, Houston, and colleagues. The results were published in Pediatric Dermatology.
The study included 31 children with histologically confirmed leukemia cutis at one of two pediatric institutions. The researchers reviewed medical records to distinguish common features among patients.
Various clinical data, including disease subtype, related symptoms, management, and prognosis, were collected from January 1993 to March 2014. The children in the case series ranged in age up to 19 years with a median age at diagnosis of 26.8 months.
After analysis, the researchers reported that the magnitude and morphology of disease lesions differed among pediatric patients, with the most common sites being the lower extremities and head. The most common morphologies were nodules and papules. Additionally, the researchers found that lesions were often erythematous, violaceous, or both colors.
The majority of patients (65%) presented with concomitant systemic leukemia and leukemia cutis. The most common types of leukemia associated with the skin condition were acute myeloid leukemia (in 74% of cases) and acute lymphoblastic leukemia (in 16% of cases). The researchers saw no significant differences in leukemia cutis morphology or distribution based on the leukemia diagnosis.
“Most cases of leukemia cutis arose during initial leukemia episodes, rather than with relapsed leukemia,” they added.
Because of an insufficiency of specific genetic data, investigators were unable to make prognostic inferences in the majority of participants.
Two key limitations of the study were the small sample size and retrospective design. As a result, the investigators were unable to prospectively classify skin findings in a systematic manner. Despite these limitations, the authors noted that these findings add to the present knowledge of leukemia cutis in pediatric patients.
“Importantly, the presence of [leukemia cutis] changed the management of systemic leukemia in one‐third of patients,” the researchers wrote. “The potential for major changes in treatment plans such as adding radiation therapy and deferring hematopoietic stem cell transplantation underscores the importance of diagnosing [leukemia cutis].”
No funding sources were reported. The authors did not report conflicts of interest.
SOURCE: Andriescu EC et al. Pediatr Dermatol. 2019 Jul 5. doi: 10.1111/pde.13864.
Researchers have characterized the clinical presentation, progression, and prognosis of leukemia cutis in a pediatric population, according to findings from a retrospective case series.
“To our knowledge, this is the largest reported case series of pediatric leukemia cutis,” wrote Elena Corina Andriescu of the University of Texas, Houston, and colleagues. The results were published in Pediatric Dermatology.
The study included 31 children with histologically confirmed leukemia cutis at one of two pediatric institutions. The researchers reviewed medical records to distinguish common features among patients.
Various clinical data, including disease subtype, related symptoms, management, and prognosis, were collected from January 1993 to March 2014. The children in the case series ranged in age up to 19 years with a median age at diagnosis of 26.8 months.
After analysis, the researchers reported that the magnitude and morphology of disease lesions differed among pediatric patients, with the most common sites being the lower extremities and head. The most common morphologies were nodules and papules. Additionally, the researchers found that lesions were often erythematous, violaceous, or both colors.
The majority of patients (65%) presented with concomitant systemic leukemia and leukemia cutis. The most common types of leukemia associated with the skin condition were acute myeloid leukemia (in 74% of cases) and acute lymphoblastic leukemia (in 16% of cases). The researchers saw no significant differences in leukemia cutis morphology or distribution based on the leukemia diagnosis.
“Most cases of leukemia cutis arose during initial leukemia episodes, rather than with relapsed leukemia,” they added.
Because of an insufficiency of specific genetic data, investigators were unable to make prognostic inferences in the majority of participants.
Two key limitations of the study were the small sample size and retrospective design. As a result, the investigators were unable to prospectively classify skin findings in a systematic manner. Despite these limitations, the authors noted that these findings add to the present knowledge of leukemia cutis in pediatric patients.
“Importantly, the presence of [leukemia cutis] changed the management of systemic leukemia in one‐third of patients,” the researchers wrote. “The potential for major changes in treatment plans such as adding radiation therapy and deferring hematopoietic stem cell transplantation underscores the importance of diagnosing [leukemia cutis].”
No funding sources were reported. The authors did not report conflicts of interest.
SOURCE: Andriescu EC et al. Pediatr Dermatol. 2019 Jul 5. doi: 10.1111/pde.13864.
FROM PEDIATRIC DERMATOLOGY
ADMIRAL results solidify gilteritinib as new standard for FLT3-mutated AML
AMSTERDAM – For patients with FLT3-mutated, relapsed or refractory acute myeloid leukemia (AML), gilteritinib (Xospata) offers better median overall survival than salvage chemotherapy, according to results from the phase 3 ADMIRAL trial.
Patients treated with gilteritinib also more often responded to therapy and entered remission, reported lead author Alexander Perl, MD, of the University of Pennsylvania, Philadelphia.
To overcome resistance mechanisms to existing FLT3 inhibitors, drug developers have been seeking agents with activity against both FLT3-ITD and FLT3-TKD mutations, Dr. Perl explained during his presentation at the annual congress of the European Hematology Association. “Gilteritinib is one of these agents,” he said, noting a unique mechanism of action that also may limit toxicity concerns associated with existing FLT3 inhibitors.
The international ADMIRAL trial involved 371 patients with FLT3-mutated AML who had not responded to induction therapy or were untreated after first relapse.
The population was randomized in a 2:1 ratio to receive either gilteritinib 120 mg/day or one of four salvage chemotherapy regimens: azacitidine (AZA), low-dose cytarabine (LoDAC), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA).
Coprimary endpoints were overall survival and the combined rate of complete remission and complete remission with partial hematologic recovery (CR/CRh). Secondary endpoints were complete remission rate and event-free survival.
Demographic data showed that the median patient age was 62 years with a broad range (19-85 years). Most patients were positive for FLT3-ITD (88.4%), while fewer tested positive for FLT3-TKD (8.4%) or both mutations (1.9%). Relapsed AML was more common than refractory disease (60.6% vs. 39.4%).
The efficacy analysis revealed that patients treated with gilteritinib had a median overall survival of 9.3 months, significantly longer than the 5.6 months among those treated with salvage chemotherapy (hazard ratio for death = 0.637; P = .0007). The 1-year survival rate was 37.1% for the gilteritinib group, compared with 16.7% among those who received chemotherapy.
The superiority of gilteritinib was further supported by twofold higher rates of CR/CRh (34.0% vs. 15.3%) and complete remission (21.1% vs. 10.5%). Similarly, median event-free survival was significantly longer in the gilteritinib group (2.8 vs. 0.7 months). Most subgroups, such as age and sex, showed consistent benefit.
Overall, gilteritinib demonstrated a favorable safety profile. After adjusting for exposure duration, serious treatment related adverse events were more common in the chemotherapy group than the gilteritinib group (9.2% vs. 7.1%). Common grade 3 or higher adverse events related to gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%).
“We were able to give [gilteritinib] in an outpatient setting,” Dr. Perl said.
Although comparisons between responses based on mutation type were not possible, owing to small sample sizes, Dr. Perl highlighted that gilteritinib showed activity against both FLT3 mutation subtypes.
“This drug has been approved on the results of this study,” Dr. Perl said. “Because of this, we have a new standard of care for this population.”
The study was funded by Astellas. The investigators reported financial relationships with AbbVie, Bayer, Takeda, and other companies.
SOURCE: Perl A et al. EHA Congress, Abstract S876.
AMSTERDAM – For patients with FLT3-mutated, relapsed or refractory acute myeloid leukemia (AML), gilteritinib (Xospata) offers better median overall survival than salvage chemotherapy, according to results from the phase 3 ADMIRAL trial.
Patients treated with gilteritinib also more often responded to therapy and entered remission, reported lead author Alexander Perl, MD, of the University of Pennsylvania, Philadelphia.
To overcome resistance mechanisms to existing FLT3 inhibitors, drug developers have been seeking agents with activity against both FLT3-ITD and FLT3-TKD mutations, Dr. Perl explained during his presentation at the annual congress of the European Hematology Association. “Gilteritinib is one of these agents,” he said, noting a unique mechanism of action that also may limit toxicity concerns associated with existing FLT3 inhibitors.
The international ADMIRAL trial involved 371 patients with FLT3-mutated AML who had not responded to induction therapy or were untreated after first relapse.
The population was randomized in a 2:1 ratio to receive either gilteritinib 120 mg/day or one of four salvage chemotherapy regimens: azacitidine (AZA), low-dose cytarabine (LoDAC), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA).
Coprimary endpoints were overall survival and the combined rate of complete remission and complete remission with partial hematologic recovery (CR/CRh). Secondary endpoints were complete remission rate and event-free survival.
Demographic data showed that the median patient age was 62 years with a broad range (19-85 years). Most patients were positive for FLT3-ITD (88.4%), while fewer tested positive for FLT3-TKD (8.4%) or both mutations (1.9%). Relapsed AML was more common than refractory disease (60.6% vs. 39.4%).
The efficacy analysis revealed that patients treated with gilteritinib had a median overall survival of 9.3 months, significantly longer than the 5.6 months among those treated with salvage chemotherapy (hazard ratio for death = 0.637; P = .0007). The 1-year survival rate was 37.1% for the gilteritinib group, compared with 16.7% among those who received chemotherapy.
The superiority of gilteritinib was further supported by twofold higher rates of CR/CRh (34.0% vs. 15.3%) and complete remission (21.1% vs. 10.5%). Similarly, median event-free survival was significantly longer in the gilteritinib group (2.8 vs. 0.7 months). Most subgroups, such as age and sex, showed consistent benefit.
Overall, gilteritinib demonstrated a favorable safety profile. After adjusting for exposure duration, serious treatment related adverse events were more common in the chemotherapy group than the gilteritinib group (9.2% vs. 7.1%). Common grade 3 or higher adverse events related to gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%).
“We were able to give [gilteritinib] in an outpatient setting,” Dr. Perl said.
Although comparisons between responses based on mutation type were not possible, owing to small sample sizes, Dr. Perl highlighted that gilteritinib showed activity against both FLT3 mutation subtypes.
“This drug has been approved on the results of this study,” Dr. Perl said. “Because of this, we have a new standard of care for this population.”
The study was funded by Astellas. The investigators reported financial relationships with AbbVie, Bayer, Takeda, and other companies.
SOURCE: Perl A et al. EHA Congress, Abstract S876.
AMSTERDAM – For patients with FLT3-mutated, relapsed or refractory acute myeloid leukemia (AML), gilteritinib (Xospata) offers better median overall survival than salvage chemotherapy, according to results from the phase 3 ADMIRAL trial.
Patients treated with gilteritinib also more often responded to therapy and entered remission, reported lead author Alexander Perl, MD, of the University of Pennsylvania, Philadelphia.
To overcome resistance mechanisms to existing FLT3 inhibitors, drug developers have been seeking agents with activity against both FLT3-ITD and FLT3-TKD mutations, Dr. Perl explained during his presentation at the annual congress of the European Hematology Association. “Gilteritinib is one of these agents,” he said, noting a unique mechanism of action that also may limit toxicity concerns associated with existing FLT3 inhibitors.
The international ADMIRAL trial involved 371 patients with FLT3-mutated AML who had not responded to induction therapy or were untreated after first relapse.
The population was randomized in a 2:1 ratio to receive either gilteritinib 120 mg/day or one of four salvage chemotherapy regimens: azacitidine (AZA), low-dose cytarabine (LoDAC), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA).
Coprimary endpoints were overall survival and the combined rate of complete remission and complete remission with partial hematologic recovery (CR/CRh). Secondary endpoints were complete remission rate and event-free survival.
Demographic data showed that the median patient age was 62 years with a broad range (19-85 years). Most patients were positive for FLT3-ITD (88.4%), while fewer tested positive for FLT3-TKD (8.4%) or both mutations (1.9%). Relapsed AML was more common than refractory disease (60.6% vs. 39.4%).
The efficacy analysis revealed that patients treated with gilteritinib had a median overall survival of 9.3 months, significantly longer than the 5.6 months among those treated with salvage chemotherapy (hazard ratio for death = 0.637; P = .0007). The 1-year survival rate was 37.1% for the gilteritinib group, compared with 16.7% among those who received chemotherapy.
The superiority of gilteritinib was further supported by twofold higher rates of CR/CRh (34.0% vs. 15.3%) and complete remission (21.1% vs. 10.5%). Similarly, median event-free survival was significantly longer in the gilteritinib group (2.8 vs. 0.7 months). Most subgroups, such as age and sex, showed consistent benefit.
Overall, gilteritinib demonstrated a favorable safety profile. After adjusting for exposure duration, serious treatment related adverse events were more common in the chemotherapy group than the gilteritinib group (9.2% vs. 7.1%). Common grade 3 or higher adverse events related to gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%).
“We were able to give [gilteritinib] in an outpatient setting,” Dr. Perl said.
Although comparisons between responses based on mutation type were not possible, owing to small sample sizes, Dr. Perl highlighted that gilteritinib showed activity against both FLT3 mutation subtypes.
“This drug has been approved on the results of this study,” Dr. Perl said. “Because of this, we have a new standard of care for this population.”
The study was funded by Astellas. The investigators reported financial relationships with AbbVie, Bayer, Takeda, and other companies.
SOURCE: Perl A et al. EHA Congress, Abstract S876.
REPORTING FROM EHA CONGRESS
Guadecitabine offers limited advantage over other standards for high-risk AML
AMSTERDAM – For treatment-naive patients with acute myeloid leukemia (AML) who are ineligible for chemotherapy, guadecitabine offers similar efficacy to other standard treatment options until four cycles are administered, after which guadecitabine offers a slight survival advantage, based on results from the phase 3 ASTRAL-1 trial.
Complete responders also derived greater benefit from guadecitabine, a new hypomethylating agent, reported lead author Pierre Fenaux, MD, PhD, of the Hôpital Saint Louis, Paris.
With 815 patients, ASTRAL-1 was the largest global, randomized trial to compare low-intensity therapy options in this elderly, unfit population – specifically, patients who were at least 75 years old or had an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or more, Dr. Fenaux said at the annual congress of the European Hematology Association.
They were randomized in a 1:1 ratio to receive guadecitabine or one of three other treatment options: azacitidine, decitabine, or low-dose cytarabine. The coprimary endpoints of the trial were complete response rate and median overall survival. Safety measures were also investigated.
A demographic analysis showed that almost two-thirds of patients were at least 75 years old (62%), and about half had an ECOG status of 2 or 3, or bone marrow blasts. Approximately one-third of patients had poor-risk cytogenetics and a slightly higher proportion had secondary AML.
After a median follow-up of 25.5 months, patients had received, on average, five cycles of therapy. However, many patients (42%) received three or fewer cycles because of early death or disease progression. This therapy cessation rate was similar between the guadecitabine group (42.4%) and the other treatment group (40.8%).
The study failed to meet either coprimary endpoint across the entire patient population. Median overall survival was 7.10 months for guadecitabine versus 8.47 months for the other treatments, but this difference was not statistically significant (P = .73). Similarly, the complete response rate was slightly higher for guadecitabine (19.4% vs. 17.4%), but again, this finding carried a nonsignificant P value (P = .48).
The benefit offered by guadecitabine was realized only with extended treatment and in complete responders.
Patients who received a minimum of four cycles of guadecitabine had a median overall survival of 15.6 months, compared with 13.0 months for other treatments (P = .02). This benefit became more pronounced in those who received at least six cycles, which was associated with median overall survival of 19.5 months versus 14.9 months (P = .002). Complete responders also had extended survival when treated with guadecitabine, although this benefit was of a lesser magnitude (22.6 vs. 20.6 months; P = .07).
Most subgroup analyses, accounting for various clinical and genetic factors, showed no significant differences in primary outcomes between treatment arms, with one exception: TP53 mutations were associated with poor responses to guadecitabine, and a lack of the TP53 mutation predicted better responses to guadecitabine.
Adverse events were common, although most measures were not significantly different between treatment arms. For example, serious adverse events occurred in 81% and 75.5% of patients treated with guadecitabine and other options, respectively, while grade 3 or higher adverse events occurred in 91.5% of guadecitabine patients and 87.5% of patients treated with other options, but neither difference was statistically significant.
Adverse events leading to death occurred in 28.7% of patients treated with guadecitabine versus 29.8% of other patients, a nonsignificant difference. In contrast, Dr. Fenaux noted that patients treated with guadecitabine were significantly more likely to develop febrile neutropenia (33.9% vs. 26.5%), neutropenia (27.4% vs. 20.7%), and pneumonia (29.4% vs. 19.6%).
“In those patients [that received at least four cycles], there seemed to be some advantage of guadecitabine, which needs to be further explored,” Dr. Fenaux said. “But at least [this finding] suggests once more that for a hypomethylating agent to be efficacious, it requires a certain number of cycles, and whenever possible, at least 6 cycles to have full efficacy.”
The study was funded by Astex and Otsuka. The investigators reported additional relationships with Celgene, Janssen, and other companies.
SOURCE: Fenaux P et al. EHA Congress, Abstract S879.
AMSTERDAM – For treatment-naive patients with acute myeloid leukemia (AML) who are ineligible for chemotherapy, guadecitabine offers similar efficacy to other standard treatment options until four cycles are administered, after which guadecitabine offers a slight survival advantage, based on results from the phase 3 ASTRAL-1 trial.
Complete responders also derived greater benefit from guadecitabine, a new hypomethylating agent, reported lead author Pierre Fenaux, MD, PhD, of the Hôpital Saint Louis, Paris.
With 815 patients, ASTRAL-1 was the largest global, randomized trial to compare low-intensity therapy options in this elderly, unfit population – specifically, patients who were at least 75 years old or had an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or more, Dr. Fenaux said at the annual congress of the European Hematology Association.
They were randomized in a 1:1 ratio to receive guadecitabine or one of three other treatment options: azacitidine, decitabine, or low-dose cytarabine. The coprimary endpoints of the trial were complete response rate and median overall survival. Safety measures were also investigated.
A demographic analysis showed that almost two-thirds of patients were at least 75 years old (62%), and about half had an ECOG status of 2 or 3, or bone marrow blasts. Approximately one-third of patients had poor-risk cytogenetics and a slightly higher proportion had secondary AML.
After a median follow-up of 25.5 months, patients had received, on average, five cycles of therapy. However, many patients (42%) received three or fewer cycles because of early death or disease progression. This therapy cessation rate was similar between the guadecitabine group (42.4%) and the other treatment group (40.8%).
The study failed to meet either coprimary endpoint across the entire patient population. Median overall survival was 7.10 months for guadecitabine versus 8.47 months for the other treatments, but this difference was not statistically significant (P = .73). Similarly, the complete response rate was slightly higher for guadecitabine (19.4% vs. 17.4%), but again, this finding carried a nonsignificant P value (P = .48).
The benefit offered by guadecitabine was realized only with extended treatment and in complete responders.
Patients who received a minimum of four cycles of guadecitabine had a median overall survival of 15.6 months, compared with 13.0 months for other treatments (P = .02). This benefit became more pronounced in those who received at least six cycles, which was associated with median overall survival of 19.5 months versus 14.9 months (P = .002). Complete responders also had extended survival when treated with guadecitabine, although this benefit was of a lesser magnitude (22.6 vs. 20.6 months; P = .07).
Most subgroup analyses, accounting for various clinical and genetic factors, showed no significant differences in primary outcomes between treatment arms, with one exception: TP53 mutations were associated with poor responses to guadecitabine, and a lack of the TP53 mutation predicted better responses to guadecitabine.
Adverse events were common, although most measures were not significantly different between treatment arms. For example, serious adverse events occurred in 81% and 75.5% of patients treated with guadecitabine and other options, respectively, while grade 3 or higher adverse events occurred in 91.5% of guadecitabine patients and 87.5% of patients treated with other options, but neither difference was statistically significant.
Adverse events leading to death occurred in 28.7% of patients treated with guadecitabine versus 29.8% of other patients, a nonsignificant difference. In contrast, Dr. Fenaux noted that patients treated with guadecitabine were significantly more likely to develop febrile neutropenia (33.9% vs. 26.5%), neutropenia (27.4% vs. 20.7%), and pneumonia (29.4% vs. 19.6%).
“In those patients [that received at least four cycles], there seemed to be some advantage of guadecitabine, which needs to be further explored,” Dr. Fenaux said. “But at least [this finding] suggests once more that for a hypomethylating agent to be efficacious, it requires a certain number of cycles, and whenever possible, at least 6 cycles to have full efficacy.”
The study was funded by Astex and Otsuka. The investigators reported additional relationships with Celgene, Janssen, and other companies.
SOURCE: Fenaux P et al. EHA Congress, Abstract S879.
AMSTERDAM – For treatment-naive patients with acute myeloid leukemia (AML) who are ineligible for chemotherapy, guadecitabine offers similar efficacy to other standard treatment options until four cycles are administered, after which guadecitabine offers a slight survival advantage, based on results from the phase 3 ASTRAL-1 trial.
Complete responders also derived greater benefit from guadecitabine, a new hypomethylating agent, reported lead author Pierre Fenaux, MD, PhD, of the Hôpital Saint Louis, Paris.
With 815 patients, ASTRAL-1 was the largest global, randomized trial to compare low-intensity therapy options in this elderly, unfit population – specifically, patients who were at least 75 years old or had an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or more, Dr. Fenaux said at the annual congress of the European Hematology Association.
They were randomized in a 1:1 ratio to receive guadecitabine or one of three other treatment options: azacitidine, decitabine, or low-dose cytarabine. The coprimary endpoints of the trial were complete response rate and median overall survival. Safety measures were also investigated.
A demographic analysis showed that almost two-thirds of patients were at least 75 years old (62%), and about half had an ECOG status of 2 or 3, or bone marrow blasts. Approximately one-third of patients had poor-risk cytogenetics and a slightly higher proportion had secondary AML.
After a median follow-up of 25.5 months, patients had received, on average, five cycles of therapy. However, many patients (42%) received three or fewer cycles because of early death or disease progression. This therapy cessation rate was similar between the guadecitabine group (42.4%) and the other treatment group (40.8%).
The study failed to meet either coprimary endpoint across the entire patient population. Median overall survival was 7.10 months for guadecitabine versus 8.47 months for the other treatments, but this difference was not statistically significant (P = .73). Similarly, the complete response rate was slightly higher for guadecitabine (19.4% vs. 17.4%), but again, this finding carried a nonsignificant P value (P = .48).
The benefit offered by guadecitabine was realized only with extended treatment and in complete responders.
Patients who received a minimum of four cycles of guadecitabine had a median overall survival of 15.6 months, compared with 13.0 months for other treatments (P = .02). This benefit became more pronounced in those who received at least six cycles, which was associated with median overall survival of 19.5 months versus 14.9 months (P = .002). Complete responders also had extended survival when treated with guadecitabine, although this benefit was of a lesser magnitude (22.6 vs. 20.6 months; P = .07).
Most subgroup analyses, accounting for various clinical and genetic factors, showed no significant differences in primary outcomes between treatment arms, with one exception: TP53 mutations were associated with poor responses to guadecitabine, and a lack of the TP53 mutation predicted better responses to guadecitabine.
Adverse events were common, although most measures were not significantly different between treatment arms. For example, serious adverse events occurred in 81% and 75.5% of patients treated with guadecitabine and other options, respectively, while grade 3 or higher adverse events occurred in 91.5% of guadecitabine patients and 87.5% of patients treated with other options, but neither difference was statistically significant.
Adverse events leading to death occurred in 28.7% of patients treated with guadecitabine versus 29.8% of other patients, a nonsignificant difference. In contrast, Dr. Fenaux noted that patients treated with guadecitabine were significantly more likely to develop febrile neutropenia (33.9% vs. 26.5%), neutropenia (27.4% vs. 20.7%), and pneumonia (29.4% vs. 19.6%).
“In those patients [that received at least four cycles], there seemed to be some advantage of guadecitabine, which needs to be further explored,” Dr. Fenaux said. “But at least [this finding] suggests once more that for a hypomethylating agent to be efficacious, it requires a certain number of cycles, and whenever possible, at least 6 cycles to have full efficacy.”
The study was funded by Astex and Otsuka. The investigators reported additional relationships with Celgene, Janssen, and other companies.
SOURCE: Fenaux P et al. EHA Congress, Abstract S879.
REPORTING FROM EHA CONGRESS
Risk model could help predict VTE in acute leukemia
AMSTERDAM – A new clinical prediction model can determine the risk of venous thromboembolism in patients with leukemia, according to investigators.
The scoring system, which incorporates historical, morphological, and cytologic factors, was internally validated at multiple time points over the course of a year, reported lead author, Alejandro Lazo-Langner, MD, of the University of Western Ontario, London.
“It is important that we can predict or anticipate which patients [with acute leukemia] will develop venous thrombosis so that we can develop preventions and aim for better surveillance strategies,” Dr. Lazo-Langner said at the annual congress of the European Hematology Association. Venous thromboembolism (VTE) risk modeling is available for patients with solid tumors, but a similar prognostic tool for leukemia patients has been missing.
To fill this practice gap, Dr. Lazo-Langner and colleagues conducted a retrospective cohort study involving 501 patients with acute leukemia who were diagnosed between 2006 and 2017. Of these patients, 427 (85.2%) had myeloid lineage and 74 (14.8%) had lymphoblastic disease. VTE outcomes of interest included proximal lower- and upper-extremity deep vein thrombosis; pulmonary embolism; and thrombosis of unusual sites, such as splanchnic and cerebral. Patients were followed until last follow-up, VTE, or death. Single variable and multiple variable logistic regression were used sequentially to evaluate and confirm potential predictive factors, with nonparametric bootstrapping for internal validation.
After last follow-up, 77 patients (15.3%) had developed VTE; specifically, 44 patients had upper-extremity deep vein thrombosis, 28 had lower-extremity deep vein thrombosis or pulmonary embolism, and 5 had cerebral vein thrombosis. The median time from leukemia diagnosis to VTE was approximately 2 months (64 days). Out of 20 possible predictive factors, 7 were included in the multivariable model, and 3 constitute the final model. These three factors are platelet count greater than 50 x 109/L at time of diagnosis (1 point), lymphoblastic leukemia (2 points), and previous history of venous thromboembolism (3 points).
Dr. Lazo-Langner explained that leukemia patients at high risk of VTE are those with a score of 3 or more points. Using this risk threshold, the investigators found that the overall cumulative incidence of VTE in the high-risk group was 44.0%, compared with 10.5% in the low-risk group. Temporal analysis showed a widening disparity between the two groups, from 3 months (28.8% vs. 6.3%), to 6 months (41.1% vs. 7.9%), and 12 months (42.5% vs. 9.3%).
When asked if treatment type was evaluated, Dr. Lazo-Langner said that treatment type was evaluated but proved unfruitful for the model, which is designed for universal use in leukemia.
“We did include a number of different chemotherapy regimens,” he said. “The problem is, because we included both AML [acute myeloid leukemia] and ALL [acute lymphoblastic leukemia] lineage, and the cornerstone of treatment is different for both lineages. It’s difficult to actually include what kind of chemotherapy [patients had]. For instance, it is known that anthracyclines increase risk of thrombosis, but in both lineages, you use anthracyclines, so you really cannot use that as a predictor.”
Looking to the future, the next step will be validation in other cohorts. If this is successful, then Dr. Lazo-Langner speculated that clinicians could use the scoring system to direct monitoring and treatment. For example, patients with high scores and low platelet counts could receive earlier transfusional support, while all high-risk patients could be placed under more intensive surveillance and given additional education about thrombosis.
“I think recognizing symptoms early is important,” Dr. Lazo-Langner said, “and that would be training not only clinicians, but also nursing personnel and the patients themselves to be aware of the symptoms, so they can actually recognize them sooner.”
The study was funded by the Canadian Institutes of Health Research. Dr. Lazo-Langner is an investigator with the Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network.
SOURCE: Lazo-Langner A et al. EHA 2019, Abstract S1642.
AMSTERDAM – A new clinical prediction model can determine the risk of venous thromboembolism in patients with leukemia, according to investigators.
The scoring system, which incorporates historical, morphological, and cytologic factors, was internally validated at multiple time points over the course of a year, reported lead author, Alejandro Lazo-Langner, MD, of the University of Western Ontario, London.
“It is important that we can predict or anticipate which patients [with acute leukemia] will develop venous thrombosis so that we can develop preventions and aim for better surveillance strategies,” Dr. Lazo-Langner said at the annual congress of the European Hematology Association. Venous thromboembolism (VTE) risk modeling is available for patients with solid tumors, but a similar prognostic tool for leukemia patients has been missing.
To fill this practice gap, Dr. Lazo-Langner and colleagues conducted a retrospective cohort study involving 501 patients with acute leukemia who were diagnosed between 2006 and 2017. Of these patients, 427 (85.2%) had myeloid lineage and 74 (14.8%) had lymphoblastic disease. VTE outcomes of interest included proximal lower- and upper-extremity deep vein thrombosis; pulmonary embolism; and thrombosis of unusual sites, such as splanchnic and cerebral. Patients were followed until last follow-up, VTE, or death. Single variable and multiple variable logistic regression were used sequentially to evaluate and confirm potential predictive factors, with nonparametric bootstrapping for internal validation.
After last follow-up, 77 patients (15.3%) had developed VTE; specifically, 44 patients had upper-extremity deep vein thrombosis, 28 had lower-extremity deep vein thrombosis or pulmonary embolism, and 5 had cerebral vein thrombosis. The median time from leukemia diagnosis to VTE was approximately 2 months (64 days). Out of 20 possible predictive factors, 7 were included in the multivariable model, and 3 constitute the final model. These three factors are platelet count greater than 50 x 109/L at time of diagnosis (1 point), lymphoblastic leukemia (2 points), and previous history of venous thromboembolism (3 points).
Dr. Lazo-Langner explained that leukemia patients at high risk of VTE are those with a score of 3 or more points. Using this risk threshold, the investigators found that the overall cumulative incidence of VTE in the high-risk group was 44.0%, compared with 10.5% in the low-risk group. Temporal analysis showed a widening disparity between the two groups, from 3 months (28.8% vs. 6.3%), to 6 months (41.1% vs. 7.9%), and 12 months (42.5% vs. 9.3%).
When asked if treatment type was evaluated, Dr. Lazo-Langner said that treatment type was evaluated but proved unfruitful for the model, which is designed for universal use in leukemia.
“We did include a number of different chemotherapy regimens,” he said. “The problem is, because we included both AML [acute myeloid leukemia] and ALL [acute lymphoblastic leukemia] lineage, and the cornerstone of treatment is different for both lineages. It’s difficult to actually include what kind of chemotherapy [patients had]. For instance, it is known that anthracyclines increase risk of thrombosis, but in both lineages, you use anthracyclines, so you really cannot use that as a predictor.”
Looking to the future, the next step will be validation in other cohorts. If this is successful, then Dr. Lazo-Langner speculated that clinicians could use the scoring system to direct monitoring and treatment. For example, patients with high scores and low platelet counts could receive earlier transfusional support, while all high-risk patients could be placed under more intensive surveillance and given additional education about thrombosis.
“I think recognizing symptoms early is important,” Dr. Lazo-Langner said, “and that would be training not only clinicians, but also nursing personnel and the patients themselves to be aware of the symptoms, so they can actually recognize them sooner.”
The study was funded by the Canadian Institutes of Health Research. Dr. Lazo-Langner is an investigator with the Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network.
SOURCE: Lazo-Langner A et al. EHA 2019, Abstract S1642.
AMSTERDAM – A new clinical prediction model can determine the risk of venous thromboembolism in patients with leukemia, according to investigators.
The scoring system, which incorporates historical, morphological, and cytologic factors, was internally validated at multiple time points over the course of a year, reported lead author, Alejandro Lazo-Langner, MD, of the University of Western Ontario, London.
“It is important that we can predict or anticipate which patients [with acute leukemia] will develop venous thrombosis so that we can develop preventions and aim for better surveillance strategies,” Dr. Lazo-Langner said at the annual congress of the European Hematology Association. Venous thromboembolism (VTE) risk modeling is available for patients with solid tumors, but a similar prognostic tool for leukemia patients has been missing.
To fill this practice gap, Dr. Lazo-Langner and colleagues conducted a retrospective cohort study involving 501 patients with acute leukemia who were diagnosed between 2006 and 2017. Of these patients, 427 (85.2%) had myeloid lineage and 74 (14.8%) had lymphoblastic disease. VTE outcomes of interest included proximal lower- and upper-extremity deep vein thrombosis; pulmonary embolism; and thrombosis of unusual sites, such as splanchnic and cerebral. Patients were followed until last follow-up, VTE, or death. Single variable and multiple variable logistic regression were used sequentially to evaluate and confirm potential predictive factors, with nonparametric bootstrapping for internal validation.
After last follow-up, 77 patients (15.3%) had developed VTE; specifically, 44 patients had upper-extremity deep vein thrombosis, 28 had lower-extremity deep vein thrombosis or pulmonary embolism, and 5 had cerebral vein thrombosis. The median time from leukemia diagnosis to VTE was approximately 2 months (64 days). Out of 20 possible predictive factors, 7 were included in the multivariable model, and 3 constitute the final model. These three factors are platelet count greater than 50 x 109/L at time of diagnosis (1 point), lymphoblastic leukemia (2 points), and previous history of venous thromboembolism (3 points).
Dr. Lazo-Langner explained that leukemia patients at high risk of VTE are those with a score of 3 or more points. Using this risk threshold, the investigators found that the overall cumulative incidence of VTE in the high-risk group was 44.0%, compared with 10.5% in the low-risk group. Temporal analysis showed a widening disparity between the two groups, from 3 months (28.8% vs. 6.3%), to 6 months (41.1% vs. 7.9%), and 12 months (42.5% vs. 9.3%).
When asked if treatment type was evaluated, Dr. Lazo-Langner said that treatment type was evaluated but proved unfruitful for the model, which is designed for universal use in leukemia.
“We did include a number of different chemotherapy regimens,” he said. “The problem is, because we included both AML [acute myeloid leukemia] and ALL [acute lymphoblastic leukemia] lineage, and the cornerstone of treatment is different for both lineages. It’s difficult to actually include what kind of chemotherapy [patients had]. For instance, it is known that anthracyclines increase risk of thrombosis, but in both lineages, you use anthracyclines, so you really cannot use that as a predictor.”
Looking to the future, the next step will be validation in other cohorts. If this is successful, then Dr. Lazo-Langner speculated that clinicians could use the scoring system to direct monitoring and treatment. For example, patients with high scores and low platelet counts could receive earlier transfusional support, while all high-risk patients could be placed under more intensive surveillance and given additional education about thrombosis.
“I think recognizing symptoms early is important,” Dr. Lazo-Langner said, “and that would be training not only clinicians, but also nursing personnel and the patients themselves to be aware of the symptoms, so they can actually recognize them sooner.”
The study was funded by the Canadian Institutes of Health Research. Dr. Lazo-Langner is an investigator with the Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network.
SOURCE: Lazo-Langner A et al. EHA 2019, Abstract S1642.
REPORTING FROM EHA CONGRESS