COMBINATION OF MINOR PAROXYSMAL NOCTURNAL HEMOGLOBINURIA CLONES AND LYMPHOCYTE TELOMERE LENGTH PREDICT RESPONSIVENESS TO IMMUNOSUPPRESSIVE THERAPY IN PEDIATRIC APLASTIC ANEMIA
(Abstract release date: 05/21/15)
EHA Library. Narita A. 06/14/15; 103409; S827
Dr. Atsushi Narita
Contributions
Contributions
Abstract
Abstract: S827
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room Stolz 1
Background
Acquired aplastic anemia (AA) is characterised by a hypo-cellular marrow and peripheral blood cytopenias. Unfortunately, allogeneic bone marrow transplantation is limited by the availability of human leukocyte antigen (HLA)-matched donors. Most AA patients receive immunosuppressive therapy (IST) combining anti-thymocyte globulin (ATG) and cyclosporine A (CyA). The presence of minor paroxysmal nocturnal hemoglobinuria (PNH) clones and a short telomere length (TL) were identified as predictive biomarkers of IST responsiveness.
Aims
To assess whether combining minor PNH clones and TL could predict IST response with greater accuracy.
Methods
We enrolled 118 children (67 boys and 51 girls) diagnosed with acquired AA in Japan between July 2001 and November 2013. Fifty-three patients received horse ATG (Lymphoglobulin, 15mg/kg/day for 5 days) and 65 received rabbit ATG (Thymoglobulin, 2.5−3.75 mg/kg/day for 5 days). All patients received CyA (6 mg/kg/day) starting on day 1 for at least 180 days. The dose of CyA was adjusted to maintain trough levels of 100–200 ng/ml. Written informed consent was obtained from the parents of all patients. This study was approved by the ethics committee of Nagoya University Graduate School of Medicine. A flow cytometry assay was used to detect PNH-type granulocytes and red blood cells (RBCs). The presence of >0.005% CD13+CD55−CD59− granulocytes and/or >0.010% glycophorin A+CD55−CD59− RBCs was defined as PNH clones positive (PNH+). Cut-off values were determined using receiver operator characteristic (ROC) analysis. The telomere length of peripheral lymphocytes was measured by flow-fluorescence in situ hybridization (flow-FISH). According to ROC analysis, we defined −1.21 SD of age-adjusted controls as the cut-off value.
Results
Patients’ median age when IST was administered was 9.7 years (range, 0.9–16.0 years), disease was moderate-to-very severe, and all three categories of disease severity were well represented. The causes of AA were idiopathic in 103 patients and hepatitis-associated in 15 patients. Forty-eight patients (41%) carried PNH+ clones. The median TL of AA patients was −1.08 standard deviation (SD) (range, −4.01–+3.01 SD). Overall, 63 patients (53%) responded to IST after 6 months. Multivariate logistic regression analysis identified WBC ≥ 2.0 × 106/L (OR, 2.82; 95% CI, 1.13–7.03; p = 0.026), absence of PNH+ clones (OR, 4.66; 95% CI, 1.81–12.00; p = 0.001), and a shorter TL (OR, 4.10; 95% CI, 1.66–10.10; p = 0.002) as independent unfavorable predictors of response to IST at 6 months. Accordingly, the cohort was stratified into unfavorable group (PNH− and a shorter TL, n = 41) and favorable group (PNH+ and/or a longer TL, n = 77). The response rate at 6 months of the unfavorable group was significantly lower (22%) compared with that of the favorable group (70%) (p < 0.001). Five-year transplantation free survival (TFS) and failure free survival (FFS) were significantly lower in the unfavorable group compared with those in the favorable group [TFS, 53% (95% CI, 34%–68%) vs. 73% (95% CI, 60%–82%); p = 0.010; FFS, 24% (95% CI, 11%–39%) vs. 53% (95% CI, 40%–65%); p < 0.001]. However, no difference was observed in 5-year overall survival (OS) between groups [unfavorable group, 98% (95% CI, 84%–100%) vs. favorable group, 96% (96% CI, 88%–99%); p = 0.743], possibly because of effective salvage hematopoietic stem cell transplantation (HSCT).
Summary
The current study reveals that PNH− patients with shorter TL are less likely to respond to IST. Our findings suggest that combining these two markers may help to provide the appropriate treatment option to the patients and prevent adverse events due to unnecessary treatment. Despite the risk of complications, unrelated or mismatched related donor transplantation may be considered as a front-line therapy for patients in the unfavorable group lacking HLA-matched sibling donors.
Session topic: Biology and clinics of bone marrow failure syndromes and PNH
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room Stolz 1
Background
Acquired aplastic anemia (AA) is characterised by a hypo-cellular marrow and peripheral blood cytopenias. Unfortunately, allogeneic bone marrow transplantation is limited by the availability of human leukocyte antigen (HLA)-matched donors. Most AA patients receive immunosuppressive therapy (IST) combining anti-thymocyte globulin (ATG) and cyclosporine A (CyA). The presence of minor paroxysmal nocturnal hemoglobinuria (PNH) clones and a short telomere length (TL) were identified as predictive biomarkers of IST responsiveness.
Aims
To assess whether combining minor PNH clones and TL could predict IST response with greater accuracy.
Methods
We enrolled 118 children (67 boys and 51 girls) diagnosed with acquired AA in Japan between July 2001 and November 2013. Fifty-three patients received horse ATG (Lymphoglobulin, 15mg/kg/day for 5 days) and 65 received rabbit ATG (Thymoglobulin, 2.5−3.75 mg/kg/day for 5 days). All patients received CyA (6 mg/kg/day) starting on day 1 for at least 180 days. The dose of CyA was adjusted to maintain trough levels of 100–200 ng/ml. Written informed consent was obtained from the parents of all patients. This study was approved by the ethics committee of Nagoya University Graduate School of Medicine. A flow cytometry assay was used to detect PNH-type granulocytes and red blood cells (RBCs). The presence of >0.005% CD13+CD55−CD59− granulocytes and/or >0.010% glycophorin A+CD55−CD59− RBCs was defined as PNH clones positive (PNH+). Cut-off values were determined using receiver operator characteristic (ROC) analysis. The telomere length of peripheral lymphocytes was measured by flow-fluorescence in situ hybridization (flow-FISH). According to ROC analysis, we defined −1.21 SD of age-adjusted controls as the cut-off value.
Results
Patients’ median age when IST was administered was 9.7 years (range, 0.9–16.0 years), disease was moderate-to-very severe, and all three categories of disease severity were well represented. The causes of AA were idiopathic in 103 patients and hepatitis-associated in 15 patients. Forty-eight patients (41%) carried PNH+ clones. The median TL of AA patients was −1.08 standard deviation (SD) (range, −4.01–+3.01 SD). Overall, 63 patients (53%) responded to IST after 6 months. Multivariate logistic regression analysis identified WBC ≥ 2.0 × 106/L (OR, 2.82; 95% CI, 1.13–7.03; p = 0.026), absence of PNH+ clones (OR, 4.66; 95% CI, 1.81–12.00; p = 0.001), and a shorter TL (OR, 4.10; 95% CI, 1.66–10.10; p = 0.002) as independent unfavorable predictors of response to IST at 6 months. Accordingly, the cohort was stratified into unfavorable group (PNH− and a shorter TL, n = 41) and favorable group (PNH+ and/or a longer TL, n = 77). The response rate at 6 months of the unfavorable group was significantly lower (22%) compared with that of the favorable group (70%) (p < 0.001). Five-year transplantation free survival (TFS) and failure free survival (FFS) were significantly lower in the unfavorable group compared with those in the favorable group [TFS, 53% (95% CI, 34%–68%) vs. 73% (95% CI, 60%–82%); p = 0.010; FFS, 24% (95% CI, 11%–39%) vs. 53% (95% CI, 40%–65%); p < 0.001]. However, no difference was observed in 5-year overall survival (OS) between groups [unfavorable group, 98% (95% CI, 84%–100%) vs. favorable group, 96% (96% CI, 88%–99%); p = 0.743], possibly because of effective salvage hematopoietic stem cell transplantation (HSCT).
Summary
The current study reveals that PNH− patients with shorter TL are less likely to respond to IST. Our findings suggest that combining these two markers may help to provide the appropriate treatment option to the patients and prevent adverse events due to unnecessary treatment. Despite the risk of complications, unrelated or mismatched related donor transplantation may be considered as a front-line therapy for patients in the unfavorable group lacking HLA-matched sibling donors.
Session topic: Biology and clinics of bone marrow failure syndromes and PNH
Abstract: S827
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room Stolz 1
Background
Acquired aplastic anemia (AA) is characterised by a hypo-cellular marrow and peripheral blood cytopenias. Unfortunately, allogeneic bone marrow transplantation is limited by the availability of human leukocyte antigen (HLA)-matched donors. Most AA patients receive immunosuppressive therapy (IST) combining anti-thymocyte globulin (ATG) and cyclosporine A (CyA). The presence of minor paroxysmal nocturnal hemoglobinuria (PNH) clones and a short telomere length (TL) were identified as predictive biomarkers of IST responsiveness.
Aims
To assess whether combining minor PNH clones and TL could predict IST response with greater accuracy.
Methods
We enrolled 118 children (67 boys and 51 girls) diagnosed with acquired AA in Japan between July 2001 and November 2013. Fifty-three patients received horse ATG (Lymphoglobulin, 15mg/kg/day for 5 days) and 65 received rabbit ATG (Thymoglobulin, 2.5−3.75 mg/kg/day for 5 days). All patients received CyA (6 mg/kg/day) starting on day 1 for at least 180 days. The dose of CyA was adjusted to maintain trough levels of 100–200 ng/ml. Written informed consent was obtained from the parents of all patients. This study was approved by the ethics committee of Nagoya University Graduate School of Medicine. A flow cytometry assay was used to detect PNH-type granulocytes and red blood cells (RBCs). The presence of >0.005% CD13+CD55−CD59− granulocytes and/or >0.010% glycophorin A+CD55−CD59− RBCs was defined as PNH clones positive (PNH+). Cut-off values were determined using receiver operator characteristic (ROC) analysis. The telomere length of peripheral lymphocytes was measured by flow-fluorescence in situ hybridization (flow-FISH). According to ROC analysis, we defined −1.21 SD of age-adjusted controls as the cut-off value.
Results
Patients’ median age when IST was administered was 9.7 years (range, 0.9–16.0 years), disease was moderate-to-very severe, and all three categories of disease severity were well represented. The causes of AA were idiopathic in 103 patients and hepatitis-associated in 15 patients. Forty-eight patients (41%) carried PNH+ clones. The median TL of AA patients was −1.08 standard deviation (SD) (range, −4.01–+3.01 SD). Overall, 63 patients (53%) responded to IST after 6 months. Multivariate logistic regression analysis identified WBC ≥ 2.0 × 106/L (OR, 2.82; 95% CI, 1.13–7.03; p = 0.026), absence of PNH+ clones (OR, 4.66; 95% CI, 1.81–12.00; p = 0.001), and a shorter TL (OR, 4.10; 95% CI, 1.66–10.10; p = 0.002) as independent unfavorable predictors of response to IST at 6 months. Accordingly, the cohort was stratified into unfavorable group (PNH− and a shorter TL, n = 41) and favorable group (PNH+ and/or a longer TL, n = 77). The response rate at 6 months of the unfavorable group was significantly lower (22%) compared with that of the favorable group (70%) (p < 0.001). Five-year transplantation free survival (TFS) and failure free survival (FFS) were significantly lower in the unfavorable group compared with those in the favorable group [TFS, 53% (95% CI, 34%–68%) vs. 73% (95% CI, 60%–82%); p = 0.010; FFS, 24% (95% CI, 11%–39%) vs. 53% (95% CI, 40%–65%); p < 0.001]. However, no difference was observed in 5-year overall survival (OS) between groups [unfavorable group, 98% (95% CI, 84%–100%) vs. favorable group, 96% (96% CI, 88%–99%); p = 0.743], possibly because of effective salvage hematopoietic stem cell transplantation (HSCT).
Summary
The current study reveals that PNH− patients with shorter TL are less likely to respond to IST. Our findings suggest that combining these two markers may help to provide the appropriate treatment option to the patients and prevent adverse events due to unnecessary treatment. Despite the risk of complications, unrelated or mismatched related donor transplantation may be considered as a front-line therapy for patients in the unfavorable group lacking HLA-matched sibling donors.
Session topic: Biology and clinics of bone marrow failure syndromes and PNH
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 08:30 to 14.06.2015 08:45
Location: Room Stolz 1
Background
Acquired aplastic anemia (AA) is characterised by a hypo-cellular marrow and peripheral blood cytopenias. Unfortunately, allogeneic bone marrow transplantation is limited by the availability of human leukocyte antigen (HLA)-matched donors. Most AA patients receive immunosuppressive therapy (IST) combining anti-thymocyte globulin (ATG) and cyclosporine A (CyA). The presence of minor paroxysmal nocturnal hemoglobinuria (PNH) clones and a short telomere length (TL) were identified as predictive biomarkers of IST responsiveness.
Aims
To assess whether combining minor PNH clones and TL could predict IST response with greater accuracy.
Methods
We enrolled 118 children (67 boys and 51 girls) diagnosed with acquired AA in Japan between July 2001 and November 2013. Fifty-three patients received horse ATG (Lymphoglobulin, 15mg/kg/day for 5 days) and 65 received rabbit ATG (Thymoglobulin, 2.5−3.75 mg/kg/day for 5 days). All patients received CyA (6 mg/kg/day) starting on day 1 for at least 180 days. The dose of CyA was adjusted to maintain trough levels of 100–200 ng/ml. Written informed consent was obtained from the parents of all patients. This study was approved by the ethics committee of Nagoya University Graduate School of Medicine. A flow cytometry assay was used to detect PNH-type granulocytes and red blood cells (RBCs). The presence of >0.005% CD13+CD55−CD59− granulocytes and/or >0.010% glycophorin A+CD55−CD59− RBCs was defined as PNH clones positive (PNH+). Cut-off values were determined using receiver operator characteristic (ROC) analysis. The telomere length of peripheral lymphocytes was measured by flow-fluorescence in situ hybridization (flow-FISH). According to ROC analysis, we defined −1.21 SD of age-adjusted controls as the cut-off value.
Results
Patients’ median age when IST was administered was 9.7 years (range, 0.9–16.0 years), disease was moderate-to-very severe, and all three categories of disease severity were well represented. The causes of AA were idiopathic in 103 patients and hepatitis-associated in 15 patients. Forty-eight patients (41%) carried PNH+ clones. The median TL of AA patients was −1.08 standard deviation (SD) (range, −4.01–+3.01 SD). Overall, 63 patients (53%) responded to IST after 6 months. Multivariate logistic regression analysis identified WBC ≥ 2.0 × 106/L (OR, 2.82; 95% CI, 1.13–7.03; p = 0.026), absence of PNH+ clones (OR, 4.66; 95% CI, 1.81–12.00; p = 0.001), and a shorter TL (OR, 4.10; 95% CI, 1.66–10.10; p = 0.002) as independent unfavorable predictors of response to IST at 6 months. Accordingly, the cohort was stratified into unfavorable group (PNH− and a shorter TL, n = 41) and favorable group (PNH+ and/or a longer TL, n = 77). The response rate at 6 months of the unfavorable group was significantly lower (22%) compared with that of the favorable group (70%) (p < 0.001). Five-year transplantation free survival (TFS) and failure free survival (FFS) were significantly lower in the unfavorable group compared with those in the favorable group [TFS, 53% (95% CI, 34%–68%) vs. 73% (95% CI, 60%–82%); p = 0.010; FFS, 24% (95% CI, 11%–39%) vs. 53% (95% CI, 40%–65%); p < 0.001]. However, no difference was observed in 5-year overall survival (OS) between groups [unfavorable group, 98% (95% CI, 84%–100%) vs. favorable group, 96% (96% CI, 88%–99%); p = 0.743], possibly because of effective salvage hematopoietic stem cell transplantation (HSCT).
Summary
The current study reveals that PNH− patients with shorter TL are less likely to respond to IST. Our findings suggest that combining these two markers may help to provide the appropriate treatment option to the patients and prevent adverse events due to unnecessary treatment. Despite the risk of complications, unrelated or mismatched related donor transplantation may be considered as a front-line therapy for patients in the unfavorable group lacking HLA-matched sibling donors.
Session topic: Biology and clinics of bone marrow failure syndromes and PNH
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