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Haploidentical Stem Cell Transplant with Post-Transplant Cyclophosphamide with Busulfan, Fludarabine and Thiotepa Conditioning for Children with Thalassemia Major
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Abstracts / Biol Blood Marrow Transplant 26 (2020) S96 S255
significantly differ between the HLA-donor type (Figure 1). There were 26 deaths (15.9%) and 7 (4.3%) graft rejections during the follow-up. Infections are the major cause of deaths. The day 100 survival was 89%, the overall survival was 84% and the thalassemia free survival was 74.4%. Conclusion: HSCT with various preparative regimens, GVHD preventive strategies, and varied graft sources is certainly a unique curative option for the Thalassemia major patients in the developing world. The survival after HSCT in Thalassemia patients are similar regardless of stem cell source, donor-HLA type (Figure 2) and GVHD (Figure 3). However, the incidence of GVHD is more with matched unrelated donors.
Figure 2. Overall survival functions of Thalassemia patients after Haematopoietic stem cell transplantation based on HLA-match
Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH Introduction: We wanted to study the role of abatacept on the incidence of graft versus host disease (GVHD) in patients with sickle cell disease (SCD) undergoing allogeneic hematopoietic stem cell transplant (HSCT). Methods: We conducted a retrospective chart review of patients who received an allogeneic HSCT for SCD at Cincinnati Children’s Hospital Medical Center and compared various transplant characteristics between patients with and without abatacept for acute GVHD prophylaxis. Results: Sixteen patients were transplanted for SCD at our center. Nine patients received a calcineurin inhibitor, methotrexate and abatacept at 10 mg/kg intravenously on days -1, +5, +14 and +28 while 7 patients received a calcineurin inhibitor with methotrexate and methylprednisolone for acute GVHD prophylaxis (table 1). No abatacept infusion related adverse effects were observed. Neutrophil engraftment was comparable at a median of 12.5 days (range 11-21) in patients without abatacept versus 13 days (range 12-16 days) in the abatacept cohort. Incidence of grade 2-4 GVHD was 0/9 in the abatacept cohort versus 3/7 patients in the no-abatacept cohort. Two of the 3 acute GVHD patients in the no-abatacept cohort had visceral involvement. One patient in the abatacept cohort had mild chronic GVHD compared to 3 patients in the no-abatacept cohort with mild (n=1) and moderate (n=2) chronic GVHD. Six patients in the no-abatacept cohort had viral reactivation compared to 8/9 patients in the abatacept cohort. No patient in either cohort had viral disease. One patient in the abatacept cohort had secondary graft loss and was transplanted again with the same donor and conditioning regimen successfully. There was no graft loss in patients who did not receive abatacept. The disease-free survival was 100% in both groups at last follow up of 1925 days (range 837-8164 days) in the no-abatacept group and 770 days (range 112-1634 days) after HSCT in the abatacept cohort. Conclusions: Abatacept is well tolerated and decreases the incidence of acute and chronic GVHD in children with SCD undergoing fully matched sibling transplants. Larger studies are needed to definitively determine the impact of abatacept in GVHD prophylaxis in the matched sibling donor setting.
Table 1 Patient demographics
Figure 3. Effect of GVHD on overall survival functions of Thalassemia patients after Haematopoietic stem cell transplantation
323 Abatacept Decreases the Rate of Acute and Chronic Gvhd in Children with Sickle Cell Disease Undergoing Matched Sibling Transplants Ruby Khoury1, Michael S. Grimley MD2, Stella M. Davies MBBS, PhD3, Pooja Khandelwal MD1. 1 Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 2 Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 3 Division of
324 Haploidentical Stem Cell Transplant with Post-Transplant Cyclophosphamide with Busulfan, Fludarabine and Thiotepa Conditioning for Children with Thalassemia Major Satya Prakash Yadav MBBS, DCH, DNB, Anil Sharma, Rohit Kapoor, Goutomi Chatterjee, Neha Rastogi. Pediatric Hematology Oncology & BMT, Medanta The Medicity, Gurgaon, India
Abstracts / Biol Blood Marrow Transplant 26 (2020) S96 S255
Introduction: Allogeneic stem cell transplant (SCT) is a curative option for children with thalassemia major. For non-Caucasian children lacking a matched donor success of haploidentical SCT with post-transplant cyclophosphamide (PTCy) has widened donor pool. Now the next need is to avoid total body irradiation (TBI) as it is not universally available. Another need is to avoid pre-transplant immune suppression (PTIS) with fludarabine and dexamethasone as it increases the risk of infection prior to HSCT. Starting cyclosporine as early as day-1 has shown to reduce severe cytokine release syndrome (CRS) post haploidentical SCT. Severe CRS can lead to increase morbidity & mortality. Here we describe outcomes of two children with thalassemia who underwent haploidentical SCT with PTCy with TBI free conditioning and had early introduction of cyclosporine. Methods: Two children with thalassemia major aged 4 and 5years respectively who had no matched donor underwent haploidentical SCT after taking informed consent of the parents. Donor for the first patient was her father and for the second patient was his mother. Both patients were Pesaro class II. Both children received PTIS in the form of oral hydroxyurea and MMF for 60 days before starting conditioning. The conditioning was with Rituximab 100 mg/m2 IV on day-8, Thiotepa 10 mg/kg on day-7, Busulfan 3.2 mg/kg/dose daily IV for 4 days(day-6 to -3), Fludarabine 40 mg/m2/dose daily IV for 4 days(day-6 to -3) and Rabbit ATG 1.5 mg/kg/dose daily for 3 days (day-4 to -2). Peripheral blood stem cell dose was 8 and 10 million/kg CD34+ cells respectively for them. Graft vs. host disease(GVHD) prophylaxis was with PTCy 50 mg/kg on day+3 & 4, intravenous cyclosporine from day-1 and MMF from day+5. Results: Both children engrafted(neutrophils on day+16, day +17 & platelets on day+13, day+12 respectively). None developed CRS. First patient developed acute GVHD of both eyes on day+30 along with skin involvement. She needed steroids topical and systemic and later Ruxolitinib to control GVHD and amniotic membrane covering of both corneas. Second patient developed late onset acute GVHD grade III on day+132. Managed successfully with steroids, etanercept and MMF. No chronic GVHD was seen in both the cases. Chimerism on day+30, day+100 and 1-year is fully donor for both the patients. Both children are alive and thalassemia free at follow up of 12-months. First patient is off immune suppression and second is on tapering doses of immune suppression. Immune reconstitution on day+128 in Case 1, showed CD4-167/ul, CD8-170/ul and on day+100 in Case 2 showed CD4-204/ul, CD8-592/ul. Conclusion: Thiotepa, Busulfan & Fludarabine based conditioning is a radiotherapy free option for children with thalassemia major undergoing haploidentical SCT with PTCy. PTIS with oral MMF and hydroxyurea is feasible. Early introduction of cyclosporine is feasible and can possibly reduce CRS.
325 Successful Umbilical Cord Blood Stem Cell Transplantation for Pelizaeus Marzbacher Leukodystrophy Satya Prakash Yadav MBBS, DCH, DNB, Dhwanee Thakkar, Neha Rastogi. Pediatric Hematology Oncology & BMT, Medanta The Medicity, Gurgaon, India Introduction: Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein-1 (PLP-1) gene on the Xq22 chromosome affecting myelination of neurons. Clinical phenotype varies from mild motor deficits to severe spasticity and death at very young age. There is no definitive curative treatment. We report here a successful umbilical cord blood stem cell transplantation (UCBT) for PMD in a 2-year-old boy.
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Methods: A 2-year-old Russian boy, first child of non-consanguineous parentage, presented to us with global developmental delay. Child had a history of prolonged seizures at 11/2 yrs of age and was symptomatically managed in his native country. Subsequently child had total 5 episodes of right sided focal seizures. On examination, he had hypotonia and developmental delay with no evidence of dysmorphism or neurocutaneous markers. MRI brain revealed changes of leukodystrophy. CT scan head showed agenesis of corpus callosum & cerebellar vermis along with moderate ventriculomegaly. Genetic testing showed PLP-1 gene duplication. Child development quotient was approximately 70. He then underwent an UCBT from a 10/ 10 matched unrelated cord at our centre. Parents gave written informed consent before transplant. Myeloablative conditioning was used with Busulfan day-9 to -6 (3.2mg/kg/day), Cyclophosphamide day-5 to -2 (50mg/kg/day), Rabbit ATG day-3 to -1 (2.5mg/kg/day) and Rituximab on day-8 (100mg/m2). Cord blood stem cell (CD34+) dose was 0.2 million/kg. MMF and Cyclosporine were used for graft-vs-host disease (GVHD) prophylaxis. Results: His neutrophil engrafted on day+29 and platelets on day+33. Post-transplant on day+30 he had reactivation of CMV and BK virus along with haemorrhagic cystitis which was managed successfully. On day+53, he had an episode of hematemesis and malena with sudden drop in hemoglobin. Upper and lower Gastrointestinal endoscopies were performed. Biopsies were suggestive of MMF induced enterocolitis which resolved after discontinuation of MMF. Chimerism on day+32, day+56 and day+100, 1-year and 2years was fully donor. There was no evidence of acute or chronic GVHD. His further post-transplant period was uneventful. Neurodevelopmental assessment was done at 12 months and 24 months post-transplant which showed overall good improvement in all domain of developmental. His motor skills improved, he can walk independently and run for few meters with infrequent falls. Child could speak in sentences and better social communications skills. No further seizures were recorded post transplant. At present child is more than two years post-transplant and is doing fine. Conclusion: PMD is a rare metabolic leukodystrophy with sparse treatment options. It appears that UCBT is feasible and beneficial treatment option for children with PMD.
326 Improving Post-Transplant Outcomes Following Allogeneic Hematopoietic Stem Cell Transplant for Sickle Cell Disease in a Low Resource Setting: Experience from a Dedicated Post-Transplant Clinic in Nigeria Adeseye Akinsete1, Michael DeBaun MD2, Adetola A. Kassim MD3. 1 Pediatrics, University of Lagos/Lagos University Teaching Hospital, Nigeria, Lagos, Nigeria; 2 Pediatrics, Vanderbilt University School of Medicine, Nashville, TN; 3 Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN Background: Allogeneic hematopoietic stem cell transplantation (Allo-HCT) is potentially curative in eligible patients with sickle cell disease (SCD). Improved transplant technology coupled with low transplant-related mortality has resulted in the development of a cottage industry in most of Africa, where 85% of all SCD births world-wide occurs. Families are seeking curative options primarily outside their country of residence, only to return back to a low-resource setting like Nigeria where long-term programs for the management of patient’s post-transplant are lacking.
Abstracts / Biol Blood Marrow Transplant 26 (2020) S96 S255
significantly differ between the HLA-donor type (Figure 1). There were 26 deaths (15.9%) and 7 (4.3%) graft rejections during the follow-up. Infections are the major cause of deaths. The day 100 survival was 89%, the overall survival was 84% and the thalassemia free survival was 74.4%. Conclusion: HSCT with various preparative regimens, GVHD preventive strategies, and varied graft sources is certainly a unique curative option for the Thalassemia major patients in the developing world. The survival after HSCT in Thalassemia patients are similar regardless of stem cell source, donor-HLA type (Figure 2) and GVHD (Figure 3). However, the incidence of GVHD is more with matched unrelated donors.
Figure 2. Overall survival functions of Thalassemia patients after Haematopoietic stem cell transplantation based on HLA-match
Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH Introduction: We wanted to study the role of abatacept on the incidence of graft versus host disease (GVHD) in patients with sickle cell disease (SCD) undergoing allogeneic hematopoietic stem cell transplant (HSCT). Methods: We conducted a retrospective chart review of patients who received an allogeneic HSCT for SCD at Cincinnati Children’s Hospital Medical Center and compared various transplant characteristics between patients with and without abatacept for acute GVHD prophylaxis. Results: Sixteen patients were transplanted for SCD at our center. Nine patients received a calcineurin inhibitor, methotrexate and abatacept at 10 mg/kg intravenously on days -1, +5, +14 and +28 while 7 patients received a calcineurin inhibitor with methotrexate and methylprednisolone for acute GVHD prophylaxis (table 1). No abatacept infusion related adverse effects were observed. Neutrophil engraftment was comparable at a median of 12.5 days (range 11-21) in patients without abatacept versus 13 days (range 12-16 days) in the abatacept cohort. Incidence of grade 2-4 GVHD was 0/9 in the abatacept cohort versus 3/7 patients in the no-abatacept cohort. Two of the 3 acute GVHD patients in the no-abatacept cohort had visceral involvement. One patient in the abatacept cohort had mild chronic GVHD compared to 3 patients in the no-abatacept cohort with mild (n=1) and moderate (n=2) chronic GVHD. Six patients in the no-abatacept cohort had viral reactivation compared to 8/9 patients in the abatacept cohort. No patient in either cohort had viral disease. One patient in the abatacept cohort had secondary graft loss and was transplanted again with the same donor and conditioning regimen successfully. There was no graft loss in patients who did not receive abatacept. The disease-free survival was 100% in both groups at last follow up of 1925 days (range 837-8164 days) in the no-abatacept group and 770 days (range 112-1634 days) after HSCT in the abatacept cohort. Conclusions: Abatacept is well tolerated and decreases the incidence of acute and chronic GVHD in children with SCD undergoing fully matched sibling transplants. Larger studies are needed to definitively determine the impact of abatacept in GVHD prophylaxis in the matched sibling donor setting.
Table 1 Patient demographics
Figure 3. Effect of GVHD on overall survival functions of Thalassemia patients after Haematopoietic stem cell transplantation
323 Abatacept Decreases the Rate of Acute and Chronic Gvhd in Children with Sickle Cell Disease Undergoing Matched Sibling Transplants Ruby Khoury1, Michael S. Grimley MD2, Stella M. Davies MBBS, PhD3, Pooja Khandelwal MD1. 1 Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 2 Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 3 Division of
324 Haploidentical Stem Cell Transplant with Post-Transplant Cyclophosphamide with Busulfan, Fludarabine and Thiotepa Conditioning for Children with Thalassemia Major Satya Prakash Yadav MBBS, DCH, DNB, Anil Sharma, Rohit Kapoor, Goutomi Chatterjee, Neha Rastogi. Pediatric Hematology Oncology & BMT, Medanta The Medicity, Gurgaon, India
Abstracts / Biol Blood Marrow Transplant 26 (2020) S96 S255
Introduction: Allogeneic stem cell transplant (SCT) is a curative option for children with thalassemia major. For non-Caucasian children lacking a matched donor success of haploidentical SCT with post-transplant cyclophosphamide (PTCy) has widened donor pool. Now the next need is to avoid total body irradiation (TBI) as it is not universally available. Another need is to avoid pre-transplant immune suppression (PTIS) with fludarabine and dexamethasone as it increases the risk of infection prior to HSCT. Starting cyclosporine as early as day-1 has shown to reduce severe cytokine release syndrome (CRS) post haploidentical SCT. Severe CRS can lead to increase morbidity & mortality. Here we describe outcomes of two children with thalassemia who underwent haploidentical SCT with PTCy with TBI free conditioning and had early introduction of cyclosporine. Methods: Two children with thalassemia major aged 4 and 5years respectively who had no matched donor underwent haploidentical SCT after taking informed consent of the parents. Donor for the first patient was her father and for the second patient was his mother. Both patients were Pesaro class II. Both children received PTIS in the form of oral hydroxyurea and MMF for 60 days before starting conditioning. The conditioning was with Rituximab 100 mg/m2 IV on day-8, Thiotepa 10 mg/kg on day-7, Busulfan 3.2 mg/kg/dose daily IV for 4 days(day-6 to -3), Fludarabine 40 mg/m2/dose daily IV for 4 days(day-6 to -3) and Rabbit ATG 1.5 mg/kg/dose daily for 3 days (day-4 to -2). Peripheral blood stem cell dose was 8 and 10 million/kg CD34+ cells respectively for them. Graft vs. host disease(GVHD) prophylaxis was with PTCy 50 mg/kg on day+3 & 4, intravenous cyclosporine from day-1 and MMF from day+5. Results: Both children engrafted(neutrophils on day+16, day +17 & platelets on day+13, day+12 respectively). None developed CRS. First patient developed acute GVHD of both eyes on day+30 along with skin involvement. She needed steroids topical and systemic and later Ruxolitinib to control GVHD and amniotic membrane covering of both corneas. Second patient developed late onset acute GVHD grade III on day+132. Managed successfully with steroids, etanercept and MMF. No chronic GVHD was seen in both the cases. Chimerism on day+30, day+100 and 1-year is fully donor for both the patients. Both children are alive and thalassemia free at follow up of 12-months. First patient is off immune suppression and second is on tapering doses of immune suppression. Immune reconstitution on day+128 in Case 1, showed CD4-167/ul, CD8-170/ul and on day+100 in Case 2 showed CD4-204/ul, CD8-592/ul. Conclusion: Thiotepa, Busulfan & Fludarabine based conditioning is a radiotherapy free option for children with thalassemia major undergoing haploidentical SCT with PTCy. PTIS with oral MMF and hydroxyurea is feasible. Early introduction of cyclosporine is feasible and can possibly reduce CRS.
325 Successful Umbilical Cord Blood Stem Cell Transplantation for Pelizaeus Marzbacher Leukodystrophy Satya Prakash Yadav MBBS, DCH, DNB, Dhwanee Thakkar, Neha Rastogi. Pediatric Hematology Oncology & BMT, Medanta The Medicity, Gurgaon, India Introduction: Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein-1 (PLP-1) gene on the Xq22 chromosome affecting myelination of neurons. Clinical phenotype varies from mild motor deficits to severe spasticity and death at very young age. There is no definitive curative treatment. We report here a successful umbilical cord blood stem cell transplantation (UCBT) for PMD in a 2-year-old boy.
S219
Methods: A 2-year-old Russian boy, first child of non-consanguineous parentage, presented to us with global developmental delay. Child had a history of prolonged seizures at 11/2 yrs of age and was symptomatically managed in his native country. Subsequently child had total 5 episodes of right sided focal seizures. On examination, he had hypotonia and developmental delay with no evidence of dysmorphism or neurocutaneous markers. MRI brain revealed changes of leukodystrophy. CT scan head showed agenesis of corpus callosum & cerebellar vermis along with moderate ventriculomegaly. Genetic testing showed PLP-1 gene duplication. Child development quotient was approximately 70. He then underwent an UCBT from a 10/ 10 matched unrelated cord at our centre. Parents gave written informed consent before transplant. Myeloablative conditioning was used with Busulfan day-9 to -6 (3.2mg/kg/day), Cyclophosphamide day-5 to -2 (50mg/kg/day), Rabbit ATG day-3 to -1 (2.5mg/kg/day) and Rituximab on day-8 (100mg/m2). Cord blood stem cell (CD34+) dose was 0.2 million/kg. MMF and Cyclosporine were used for graft-vs-host disease (GVHD) prophylaxis. Results: His neutrophil engrafted on day+29 and platelets on day+33. Post-transplant on day+30 he had reactivation of CMV and BK virus along with haemorrhagic cystitis which was managed successfully. On day+53, he had an episode of hematemesis and malena with sudden drop in hemoglobin. Upper and lower Gastrointestinal endoscopies were performed. Biopsies were suggestive of MMF induced enterocolitis which resolved after discontinuation of MMF. Chimerism on day+32, day+56 and day+100, 1-year and 2years was fully donor. There was no evidence of acute or chronic GVHD. His further post-transplant period was uneventful. Neurodevelopmental assessment was done at 12 months and 24 months post-transplant which showed overall good improvement in all domain of developmental. His motor skills improved, he can walk independently and run for few meters with infrequent falls. Child could speak in sentences and better social communications skills. No further seizures were recorded post transplant. At present child is more than two years post-transplant and is doing fine. Conclusion: PMD is a rare metabolic leukodystrophy with sparse treatment options. It appears that UCBT is feasible and beneficial treatment option for children with PMD.
326 Improving Post-Transplant Outcomes Following Allogeneic Hematopoietic Stem Cell Transplant for Sickle Cell Disease in a Low Resource Setting: Experience from a Dedicated Post-Transplant Clinic in Nigeria Adeseye Akinsete1, Michael DeBaun MD2, Adetola A. Kassim MD3. 1 Pediatrics, University of Lagos/Lagos University Teaching Hospital, Nigeria, Lagos, Nigeria; 2 Pediatrics, Vanderbilt University School of Medicine, Nashville, TN; 3 Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN Background: Allogeneic hematopoietic stem cell transplantation (Allo-HCT) is potentially curative in eligible patients with sickle cell disease (SCD). Improved transplant technology coupled with low transplant-related mortality has resulted in the development of a cottage industry in most of Africa, where 85% of all SCD births world-wide occurs. Families are seeking curative options primarily outside their country of residence, only to return back to a low-resource setting like Nigeria where long-term programs for the management of patient’s post-transplant are lacking.