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Hyperferritinemia is Common in Pediatric Patients with Malignant Diseases Prior to Transplant
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Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
events of TMA occurred after high dose a busulfan/ melphalan regimen. This observation implies that particular chemotherapies or chemotherapy combinations may target the endothelium of organs differently and warrants further investigation for better understanding of the pathogenesis of these diseases. We demonstrate that patients with TMA associated multi-organ injury can be salvaged with complement blocking therapy using eculizumab if this complication is identified. Patients receiving carboplatin/etoposide/ melphalan regimen should be prospectively monitored for TMA.
315 Ruxolitinib in a Pediatric Patient with Chronic Gvhd Nicole Karras 1, Jae Jung 2, Jonathan Cotliar 3. 1 Pediatrics, City of Hope, Duarte, CA; 2 City of Hope, Duarte, CA; 3 Department of Dermatology, City of Hope, Duarte, CA Ruxolitinib in a pediatric steroid refractory chronic graft vs host disease patient. Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a potentially curative treatment for many different malignant and non-malignant conditions. One of the major complications after HSCT is graft versus host disease (gvhd), which can be acute or chronic. Severe, treatment refractory gvhd causes significant transplant related morbidity and mortality. Currently, the front line treatment of gvhd (both acute and chronic) in pediatrics is corticosteroid therapy, which has a large toxicity profile. Additionally, approximately 40% of patients with gvhd will be steroid refractory. New research into alternative therapies for gvhd have illustrated the potential benefit of a janus kinase 1/2 inhibitor (JAK). Clinical experience with this target is encouraging, but limited, and currently there are no reports of use in a pediatric setting. Case Report: A 13 year old male, with a history of induction failure pre-B cell ALL, underwent a 10/10 matched unrelated donor marrow HSCT in December 2014 (at age 11). He had an infusion CD 3 count of 0.25 × 106/kg. He had multiple flares of first acute ghvd of the skin, grade 3, and then chronic skin gvhd grade 3. He was treated with steroids, photophoresis, and basiliximab, but was unable to be weaned off steroids. He developed skin thinning and poor wound healing. Ruxolitinib was started in April 2016 at 10 mg twice a day. His skin started to improve 1 month into treatment, however he continued on photophoresis and a slow steroid taper. In July 2016 his dose of ruxolitinib was decreased to 10 mg in the morning, and 5 mg in the evening, secondary to anemia requiring transfusion. In September 2016 the dose was weaned to 5 BID for improvement/resolution of his skin gvhd. Prednisone discontinued in May 2016. His photophoresis was discontinued in August. He did not have CMV reactivation. Conclusion: The addition of ruxolitinib for this 13 year old boy not only enabled him to stop prednisone therapy, but also his other supplemental gvhd treatments. With the exception of dose dependent anemia, this drug was very well tolerated. Further clinical studies in pediatric HSCT patients are warranted.
316 Hyperferritinemia is Common in Pediatric Patients with Malignant Diseases Prior to Transplant Amy K. Keating 1,2, Urvi Sanghvi 2. 1 Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO; 2 Children’s Hospital of Colorado, Aurora, CO
Background: Previous reports have shown that serum ferritin levels greater than 300-1000 ng/mL prior to hematopoietic stem cell transplant (HSCT) in adults is associated with higher rates of graft versus host disease, bacterial bloodstream infections, invasive mold infections, and venoocclusive disease. A European adult study, which included a small number of pediatric patients, found that serum ferritins greater than 1000 ng/mL prior to HSCT significantly reduced both event-free and overall survival. It is hypothesized that free serum iron, which correlates to ferritin level, causes oxidant stress and a mild systemic inflammation which leads to these complications post HSCT. Little is known about the prevalence of high serum ferritin in pediatric patients with malignancies that are preparing for HSCT or if high ferritin affects post-HSCT outcomes. Objective: To determine the prevalence of high ferritin prior to HSCT in pediatric patients with malignant conditions. Method: We evaluated all patients transplanted for a malignant condition (excluding neuro-oncological diagnoses) at the Children’s Hospital of Colorado between January 1, 2009 and July 31, 2015. Patients were categorized by primary indication for HSCT and allogeneic versus autologous transplant. Serum ferritins were reported as ng/mL on patients who were screened within 3 months prior to the start of the HSCT preparative regimen. Neuro-oncological patients are not routinely screened for ferritin levels and were therefore excluded from this analysis. Results: There were 104 patients that received an allogeneic HSCT for leukemia, non-Hodgkins lymphoma or MDS; there were 59 autologous transplants done for solid (non-CNS) tumors or Hodgkins lymphoma. In the allogeneic group 87.5% had ferritin levels screened prior to HSCT while 52.5% of patients preparing for autologous HSCT were screened, for a total of 123 patients included in the analysis. Amongst all patients transplanted for malignancy, the geometric mean preHSCT ferritin was 795.6 ng/mL (95%CI: 620.4-1020), while within the allogeneic group is was 1052 ng/mL (95%CI: 817.41355) and in the autologous group is was 347.1 ng/mL (95%CI:
Figure 1. Serum ferritin levels of pediatric patients coming to transplant at Children’s Hospital Colorado for malignant conditions between January 1, 2009 and July 15, 2015 with pre-HSCT screening. Ferritin of 0-60 ng/mL is considered normal (green), 61-299 is midly elevated (yellow), 300-999 is moderately elevated, and 1000 or greater is severely elevated. Two patients are not represented because they fall outside the range of this graph (ferritin of 5,795 and 11,300 ng/mL). Of all transplanted patients screened, 92.6% had a pre-HSCT ferritin above the normal range (>60 ng/ mL), while 78.5% were above 300 ng/mL and 54.5% were above 1000 ng/ mL, levels that in adults have been associated with poor post-HSCT outcomes.
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
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317 Augmenting GVHD Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant for Beta Thalassemia Major Reduces Acute GVHD Incidence and Severity without Impacting Engraftment Pooja Khandelwal, Stella M. Davies, Christopher E. Dandoy, Javier El-Bietar, Michael S. Grimley. Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Figure 2. Each shape (circle, square, triangle) represents the pre-HSCT ferritin level of a single screened patient, categorized by type of HSCT planned. Amongst all patients transplanted for malignancy, the geometric mean preHSCT ferritin was 795.6 ng/mL (95%CI:620.4-1020), while within the allogeneic group is was 1052 ng/mL (95%CI: 817.4-1355) and in the autologous group is was 347.1 ng/mL (95%CI:191.9.627.8). Four patient data points are not represented in this graph as they are outside the axis limits (All HSCT and Allogeneic group = 5,795 and 11,300 ng/mL).
191.9-627.8). In the allogeneic pre-HSCT patients, 60.4% had considerably elevated ferritins (GT> 1000 ng/mL) and in the autologous group 32.3% of those screened had similarly elevated ferritins. Conclusion: A large percentage of pediatric patients with malignant conditions have considerably elevated ferritin levels prior to HSCT, levels which are associated with poor postHSCT outcomes in adults. A larger multi-institutional or registry analysis will be necessary to determine whether this prevalence is true in most centers and whether high ferritin pre-HSCT puts these children at risk for the significant acute sequelae following HSCT that is seen in adults (Figures 1-3).
We observed a higher than desired rate of aGVHD in our heavily transfused beta thalassemia patients undergoing HSCT. Patients with beta thalassemia major receiving HSCT between 2010-2016 were included. Patients received busulfan daily × 4 days (targeted AUC 3900-4200 μmol*min/day), fludarabine 40 mg/m2 daily x4 days and 5 mg/kg of thiotepa daily × 2 days. Standard aGVHD prophylaxis included a calcineurin inhibitor with corticosteroids at 2 mg/kg/day. Augmented arm included an additional agent (abatacept or maraviroc). Abatacept dose was 10 mg/kg, (maximum dose of 1000 mg i.v) on days −1, +5, +14 and +28. Maravirocdose was 300 mg/ m2 orally twice daily (institutional clinical trial) from day −3 to day +30. Twenty-one patients, median age 7.2 years (3.74-13.8 years) received HSCT for beta thalassemia. Transplant characteristics are described in Table 1. Patients fell into 2 groups: standard GVHD prophylaxis (SGP) (n = 8) and augmented GVHD prophylaxis (AGP) (n = 13). Neutrophils engrafted a median of 10 days (9-15 days) in the SGP cohort and a median of 11 days (8-15 days) in the AGP cohort. Platelets engrafted a median of 16 days (12-81 days) in the SGP cohort and a median of 18 days (12-100 days) in the AGP cohort. Incidence of any aGVHD was 75% (n = 6) in the SGP cohort and 30% (n = 4) in the AGP cohort. Organs involved are shown in Figure 1. Incidence of grades III-IV aGVHD was 50% (n = 4) in the SGP cohort compared to 7% (n = 1) in the AGP cohort. Viral reactivation occurred in 50% (n = 4) of SGP cohort compared to 46% in the AGP cohort. Viral disease occurred in 37.5 % (n = 3) in SGP cohort compared to 15 % (n = 2) in AGP cohort. Mixed chimerism (lowest whole blood donor chimerism of 95%) occurred in 12.5% (n = 1) in the SGP cohort and 7% (n = 1) in AGP cohort. Secondary graft failure was 0%
Table 1 Demographics
Figure 3. Geometric mean ferritin of patients who were alive at 1 year post HSCT was 687.9 ng/ml (95%CI:506.9-933.4) while it was 1045 ng/ml (95%CI:691.2-1580) for those who died with in the first year. This was not a statistically significant difference for this small study but highlights a potentially important trend.
Age (years) Liver iron (MRI T2*) pre- transplant (mcg/g dry weight) HLA Match & relation 9/10 10/10 Related Unrelated Stem cell source Marrow Cord blood GVHD prophylaxis CSA†/ steroids CSA/steroids/ abatacept CSA/steroids/ maraviroc
Standard GVHD Prophylaxis (n = 8)
Augmented GVHD Prophylaxis (n = 13)
6 (3.7-10.9) 5975 (1780-9697)
8 (4.1-13.8) 3262 (1568-7564)
1 (12%) 7 (88%) 5 (62%) 3 (38%)
3 (23%) 10 (77%) 8 (62%) 5 (38%)
7 (88%) 1 (12%)
13 (100%) 4 (30%)*
8 (100%)
* Both bone marrow and cord blood infused. † Cyclosporine.
7 (54%) 6 (46%)
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
events of TMA occurred after high dose a busulfan/ melphalan regimen. This observation implies that particular chemotherapies or chemotherapy combinations may target the endothelium of organs differently and warrants further investigation for better understanding of the pathogenesis of these diseases. We demonstrate that patients with TMA associated multi-organ injury can be salvaged with complement blocking therapy using eculizumab if this complication is identified. Patients receiving carboplatin/etoposide/ melphalan regimen should be prospectively monitored for TMA.
315 Ruxolitinib in a Pediatric Patient with Chronic Gvhd Nicole Karras 1, Jae Jung 2, Jonathan Cotliar 3. 1 Pediatrics, City of Hope, Duarte, CA; 2 City of Hope, Duarte, CA; 3 Department of Dermatology, City of Hope, Duarte, CA Ruxolitinib in a pediatric steroid refractory chronic graft vs host disease patient. Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a potentially curative treatment for many different malignant and non-malignant conditions. One of the major complications after HSCT is graft versus host disease (gvhd), which can be acute or chronic. Severe, treatment refractory gvhd causes significant transplant related morbidity and mortality. Currently, the front line treatment of gvhd (both acute and chronic) in pediatrics is corticosteroid therapy, which has a large toxicity profile. Additionally, approximately 40% of patients with gvhd will be steroid refractory. New research into alternative therapies for gvhd have illustrated the potential benefit of a janus kinase 1/2 inhibitor (JAK). Clinical experience with this target is encouraging, but limited, and currently there are no reports of use in a pediatric setting. Case Report: A 13 year old male, with a history of induction failure pre-B cell ALL, underwent a 10/10 matched unrelated donor marrow HSCT in December 2014 (at age 11). He had an infusion CD 3 count of 0.25 × 106/kg. He had multiple flares of first acute ghvd of the skin, grade 3, and then chronic skin gvhd grade 3. He was treated with steroids, photophoresis, and basiliximab, but was unable to be weaned off steroids. He developed skin thinning and poor wound healing. Ruxolitinib was started in April 2016 at 10 mg twice a day. His skin started to improve 1 month into treatment, however he continued on photophoresis and a slow steroid taper. In July 2016 his dose of ruxolitinib was decreased to 10 mg in the morning, and 5 mg in the evening, secondary to anemia requiring transfusion. In September 2016 the dose was weaned to 5 BID for improvement/resolution of his skin gvhd. Prednisone discontinued in May 2016. His photophoresis was discontinued in August. He did not have CMV reactivation. Conclusion: The addition of ruxolitinib for this 13 year old boy not only enabled him to stop prednisone therapy, but also his other supplemental gvhd treatments. With the exception of dose dependent anemia, this drug was very well tolerated. Further clinical studies in pediatric HSCT patients are warranted.
316 Hyperferritinemia is Common in Pediatric Patients with Malignant Diseases Prior to Transplant Amy K. Keating 1,2, Urvi Sanghvi 2. 1 Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO; 2 Children’s Hospital of Colorado, Aurora, CO
Background: Previous reports have shown that serum ferritin levels greater than 300-1000 ng/mL prior to hematopoietic stem cell transplant (HSCT) in adults is associated with higher rates of graft versus host disease, bacterial bloodstream infections, invasive mold infections, and venoocclusive disease. A European adult study, which included a small number of pediatric patients, found that serum ferritins greater than 1000 ng/mL prior to HSCT significantly reduced both event-free and overall survival. It is hypothesized that free serum iron, which correlates to ferritin level, causes oxidant stress and a mild systemic inflammation which leads to these complications post HSCT. Little is known about the prevalence of high serum ferritin in pediatric patients with malignancies that are preparing for HSCT or if high ferritin affects post-HSCT outcomes. Objective: To determine the prevalence of high ferritin prior to HSCT in pediatric patients with malignant conditions. Method: We evaluated all patients transplanted for a malignant condition (excluding neuro-oncological diagnoses) at the Children’s Hospital of Colorado between January 1, 2009 and July 31, 2015. Patients were categorized by primary indication for HSCT and allogeneic versus autologous transplant. Serum ferritins were reported as ng/mL on patients who were screened within 3 months prior to the start of the HSCT preparative regimen. Neuro-oncological patients are not routinely screened for ferritin levels and were therefore excluded from this analysis. Results: There were 104 patients that received an allogeneic HSCT for leukemia, non-Hodgkins lymphoma or MDS; there were 59 autologous transplants done for solid (non-CNS) tumors or Hodgkins lymphoma. In the allogeneic group 87.5% had ferritin levels screened prior to HSCT while 52.5% of patients preparing for autologous HSCT were screened, for a total of 123 patients included in the analysis. Amongst all patients transplanted for malignancy, the geometric mean preHSCT ferritin was 795.6 ng/mL (95%CI: 620.4-1020), while within the allogeneic group is was 1052 ng/mL (95%CI: 817.41355) and in the autologous group is was 347.1 ng/mL (95%CI:
Figure 1. Serum ferritin levels of pediatric patients coming to transplant at Children’s Hospital Colorado for malignant conditions between January 1, 2009 and July 15, 2015 with pre-HSCT screening. Ferritin of 0-60 ng/mL is considered normal (green), 61-299 is midly elevated (yellow), 300-999 is moderately elevated, and 1000 or greater is severely elevated. Two patients are not represented because they fall outside the range of this graph (ferritin of 5,795 and 11,300 ng/mL). Of all transplanted patients screened, 92.6% had a pre-HSCT ferritin above the normal range (>60 ng/ mL), while 78.5% were above 300 ng/mL and 54.5% were above 1000 ng/ mL, levels that in adults have been associated with poor post-HSCT outcomes.
Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391
S237
317 Augmenting GVHD Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant for Beta Thalassemia Major Reduces Acute GVHD Incidence and Severity without Impacting Engraftment Pooja Khandelwal, Stella M. Davies, Christopher E. Dandoy, Javier El-Bietar, Michael S. Grimley. Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Figure 2. Each shape (circle, square, triangle) represents the pre-HSCT ferritin level of a single screened patient, categorized by type of HSCT planned. Amongst all patients transplanted for malignancy, the geometric mean preHSCT ferritin was 795.6 ng/mL (95%CI:620.4-1020), while within the allogeneic group is was 1052 ng/mL (95%CI: 817.4-1355) and in the autologous group is was 347.1 ng/mL (95%CI:191.9.627.8). Four patient data points are not represented in this graph as they are outside the axis limits (All HSCT and Allogeneic group = 5,795 and 11,300 ng/mL).
191.9-627.8). In the allogeneic pre-HSCT patients, 60.4% had considerably elevated ferritins (GT> 1000 ng/mL) and in the autologous group 32.3% of those screened had similarly elevated ferritins. Conclusion: A large percentage of pediatric patients with malignant conditions have considerably elevated ferritin levels prior to HSCT, levels which are associated with poor postHSCT outcomes in adults. A larger multi-institutional or registry analysis will be necessary to determine whether this prevalence is true in most centers and whether high ferritin pre-HSCT puts these children at risk for the significant acute sequelae following HSCT that is seen in adults (Figures 1-3).
We observed a higher than desired rate of aGVHD in our heavily transfused beta thalassemia patients undergoing HSCT. Patients with beta thalassemia major receiving HSCT between 2010-2016 were included. Patients received busulfan daily × 4 days (targeted AUC 3900-4200 μmol*min/day), fludarabine 40 mg/m2 daily x4 days and 5 mg/kg of thiotepa daily × 2 days. Standard aGVHD prophylaxis included a calcineurin inhibitor with corticosteroids at 2 mg/kg/day. Augmented arm included an additional agent (abatacept or maraviroc). Abatacept dose was 10 mg/kg, (maximum dose of 1000 mg i.v) on days −1, +5, +14 and +28. Maravirocdose was 300 mg/ m2 orally twice daily (institutional clinical trial) from day −3 to day +30. Twenty-one patients, median age 7.2 years (3.74-13.8 years) received HSCT for beta thalassemia. Transplant characteristics are described in Table 1. Patients fell into 2 groups: standard GVHD prophylaxis (SGP) (n = 8) and augmented GVHD prophylaxis (AGP) (n = 13). Neutrophils engrafted a median of 10 days (9-15 days) in the SGP cohort and a median of 11 days (8-15 days) in the AGP cohort. Platelets engrafted a median of 16 days (12-81 days) in the SGP cohort and a median of 18 days (12-100 days) in the AGP cohort. Incidence of any aGVHD was 75% (n = 6) in the SGP cohort and 30% (n = 4) in the AGP cohort. Organs involved are shown in Figure 1. Incidence of grades III-IV aGVHD was 50% (n = 4) in the SGP cohort compared to 7% (n = 1) in the AGP cohort. Viral reactivation occurred in 50% (n = 4) of SGP cohort compared to 46% in the AGP cohort. Viral disease occurred in 37.5 % (n = 3) in SGP cohort compared to 15 % (n = 2) in AGP cohort. Mixed chimerism (lowest whole blood donor chimerism of 95%) occurred in 12.5% (n = 1) in the SGP cohort and 7% (n = 1) in AGP cohort. Secondary graft failure was 0%
Table 1 Demographics
Figure 3. Geometric mean ferritin of patients who were alive at 1 year post HSCT was 687.9 ng/ml (95%CI:506.9-933.4) while it was 1045 ng/ml (95%CI:691.2-1580) for those who died with in the first year. This was not a statistically significant difference for this small study but highlights a potentially important trend.
Age (years) Liver iron (MRI T2*) pre- transplant (mcg/g dry weight) HLA Match & relation 9/10 10/10 Related Unrelated Stem cell source Marrow Cord blood GVHD prophylaxis CSA†/ steroids CSA/steroids/ abatacept CSA/steroids/ maraviroc
Standard GVHD Prophylaxis (n = 8)
Augmented GVHD Prophylaxis (n = 13)
6 (3.7-10.9) 5975 (1780-9697)
8 (4.1-13.8) 3262 (1568-7564)
1 (12%) 7 (88%) 5 (62%) 3 (38%)
3 (23%) 10 (77%) 8 (62%) 5 (38%)
7 (88%) 1 (12%)
13 (100%) 4 (30%)*
8 (100%)
* Both bone marrow and cord blood infused. † Cyclosporine.
7 (54%) 6 (46%)