Treosulfan and Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Children with Primary Immunodeficiency: UK Experience (original) (raw)
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Journal of Allergy and Clinical Immunology, 2013
In this review we discuss recent outcomes of hematopoietic cell transplantation (HCT) for patients with severe combined immunodeficiency (SCID), including survival, T-and B-cell reconstitution, and late effects, particularly those related to genotype, use of conditioning regimen, and use of alternative donors. We identify the following issues that require additional data, which can be obtained through cooperative studies: outcomes of patients with SCID who did not receive conditioning before alternative donor HCT; outcomes of patients with SCID who did not receive graft-versus-host disease prophylaxis after T cell-replete HCT; late effects of HCT for patients with SCID, including neurocognitive outcomes, growth, and development; and their relationship to genotype and use of alkylating agents for conditioning. Careful follow-up of outcomes of all newborns receiving diagnoses based on newborn screening programs for SCID is essential because data are scarce on the effects of conditioning regimens in very young patients. A consensus on the definition of T-and B-cell recovery, criteria for additional "boosts," pharmacokinetic data of chemotherapy agents used in young children, and uniformity of the use of various chemotherapy agents are needed to compare results among institutions. Finally, development of new nontoxic conditioning regimens for HCT that can be safely used in very young children is required.
Bone Marrow Transplantation
Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m2/day (7.7%), 12 g/m2/day (35.4%), or 14 g/m2/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence ...
Biology of Blood and Marrow Transplantation, 2010
Reduced intensity (RI) allogeneic stem cell transplantation (AlloSCT) was initially demonstrated in adults following HLA-matched family and unrelated adult donor AlloSCT. There is little information about RI AlloSCT in children. We report results of a pilot study of RI AlloSCT in 21 recipients (p21 years). Age: median 13 (0.5-21) years, 8F:13M, 14 unrelated cord blood units (UCB) (10 4/6, 4 5/6), two related BM (6/6, 5/6), four related PBSC (2 6/6, 2 5/6), and one related BM þ PBSC (6/6). RI: fludarabine, busulfan (n ¼ 14); fludarabine, cyclophosphamide (n ¼ 4); fludarabine, melphalan (n ¼ 1); total body irradiation, fludarabine, cyclophosphamide (n ¼ 1); or fludarabine, cyclophosphamide, and etoposide (n ¼ 1). Graft-versus-host disease prophylaxis: FK506 0.03 mg/ kg/day and mycophenolate mofetil 15 mg/kg/q 12 h. UCB median nuc/kg and CD34/kg was 4.3 Â 10 7 /kg (0.9-10.8) and 1.9 Â 10 5 /kg (0.3-6.9), and related BM/PBSC median nuc/kg and CD34/kg was 8.3 Â 10 8 (4.7-18.9) and 5.0 Â 10 6 /kg (4.6-6.4). Maximal chimerism following unrelated cord blood transplantation, 100% Â 7, 98% Â 1, 95% Â 2, 55% Â 1, and 0% Â 3; related PBSC/BM, 100% Â 5, 65% Â 1, and 55% Â 1. Graft failure occurred in 5/21 (24%). In summary, RI AlloSCT in children is feasible and tolerable (p25% GF) and results in X85% of recipients initially achieving X50% donor chimerism.
The Journal of allergy and clinical immunology, 2016
Reduced-intensity conditioning (RIC) regimens are increasingly being used in the transplantation of patients with primary immunodeficiency disorders (PIDs), but there are no large studies looking at long-term lineage-specific chimerism. We sought to analyze long-term chimerism and event-free survival in children undergoing transplantation for PIDs using RIC with fludarabine and melphalan (Flu/Melph) and to study the effect of donor type and stem cell source. One hundred forty-two children underwent transplantation with RIC by using Flu/Melph and for PIDs by using bone marrow (n = 93) or peripheral blood stem cells (PBSCs; n = 49). Donors were matched unrelated donors (n = 72), mismatched unrelated donors (n = 37), matched sibling donors (n = 14), matched family donors (n = 12), and mismatched family donors (n = 7). Overall survival at a median follow-up of 7.5 years was 78%, irrespective of stem cell source or donor type. When bone marrow was used as the stem cell source, 26% of pat...
Clinical Pharmacology & Therapeutics
Treosulfan is given off-label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients (n = 87) receiving treosulfan-fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two-compartment model. During follow-up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC (0-∞)) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23-1.74), and the hazard ratio for low engraftment was 0.61 (0.36-1.04). A cumulative AUC (0-∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC (0-∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used in children for relapsed malignancies and nonmalignant conditions, such as primary immune deficiency. 1 To deplete host immune cells and facilitate donor engraftment, children usually receive conditioning consisting of combination cytotoxic chemotherapy. Conditioning regimen intensity varies depending on the
Journal of Allergy and Clinical Immunology, 2014
Background: Patients with severe combined immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. Objective: We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs. Methods: We performed a multicenter survey of severe combined immunodeficiency transplantation centers in North America, Europe, and Australia to compile retrospective data on patients who have undergone unconditioned HCT from either URDs (n 5 37) or MSDs (n 5 66). Results: Most patients undergoing URD HCT (92%) achieved donor T-cell engraftment compared with 97% for those with MSDs; however, estimated 5-year overall and event-free survival were worse for URD recipients (71% and 60%, respectively) compared with MSD recipients (92% and 89%, respectively; P < .01 for both). URD recipients who received pre-HCT serotherapy had similar 5-year overall survival (100%) to MSD recipients. The incidences of grade II to IV acute and chronic graft-versushost disease were higher in URD (50% and 39%, respectively) compared with MSD (22% and 5%, respectively) recipients (P < .01 for both). In the surviving patients there was no difference in T-cell reconstitution at the last follow-up between the URD and MSD recipients; however, MSD recipients were more likely to achieve B-cell reconstitution (72% vs 17%, P < .001). Conclusion: Unconditioned URD HCT achieves excellent rates of donor T-cell engraftment similar to that seen in MSD recipients, and reconstitution rates are adequate. However, only From a
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2018
This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m/day (BSA ≤ .5 m), 12 g/m/day (BSA > .5 to 1.0 m), or 14 g/m/day (BSA > 1.0 m) on days -6 to -4; fludarabine 30 mg/m/day on days -6 to -2; and a single fraction of 200 cGy total body irradiation on day -1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, ...
Anales de pediatría (Barcelona, Spain : 2003), 2015
Children with primary immunodeficiency have severe life-threatening infections and a higher prevalence of autoimmune problems, allergy and lymphoproliferative disorders. Allogenic hematopoietic stem cell transplantation has been the only potentially curative option. Patients with primary immunodeficiency underwent allogenic stem cell transplantation in the period 1985-2011, and registered in the Spanish Working Party for Bone Marrow Transplantation in Children. One hundred and fifty nine patients underwent 173 allogenic stem cell transplantations, of whom 97 had severe combined immunodeficiency, 30 with immune dysregulation disorders, 25 Wiskott-Aldrich syndrome, and 21 phagocyte disorders. The median patient age at diagnosis was 6 months (range: 17 days - 168 months) and the median patient age at transplant was 12 months (range: 1 month - 189 months). The donors were 30 (19%) identical siblings, 40 (25%) alternative family donors, and 89 (56%) unrelated donors. The source of stem c...
Archivum Immunologiae et Therapiae Experimentalis
Severe combined immunodeficiency (SCID) is fatal in early childhood if unrecognized and if not treated. The aim was to determine the efficacy of T cell depleted bone marrow transplantation (TCD BMT) in the treatment of children with SCID. Eleven children diagnosed with SCID received histocompatible related donor bone marrow transplantation--HRD BMT (group I). Thirty seven children diagnosed with SCID who did not have histocompatible donors were treated with TCD haploidentical parental bone marrow transplantation (BMT) (group II). TCD was performed by in vitro soybean lectin agglutination followed by E-rosette depletion. Patients were longitudinally assessed for the presence and function of T and B lymphocytes. In group I all children survived. The mean age of children in this group at the time of HRD BMT was 15.4 months. All surviving patients normalized their specific T cell function. Two out of 11 require treatment with intravenous immunoglobulin i.v. Ig. In group II 17 out of 37 ...
Bone Marrow Transplantation, 2022
Primary immunodeficiencies (PID) are heterogeneous inborn errors of the immune system. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative and safe at the pediatric age but remains underperformed in adults. We report our experience on 32 consecutive adult patients with various PID including 17 (53%) with a combined immune deficiency, six (19%) with a disease of immune dysregulation and nine (28%) with a chronic granulomatous disease (CGD) who underwent an allo-HSCT between 2011 and 2020. The median age at transplant was 27 years (17-41). All assessable patients engrafted. The majority of patients received a fludarabine-Busulfan (FB) based regimen (FB2-3 in 16, FB4 in 12). Overall survival (OS) was 80.4% (100% for CGD and 74% for other PID patients) at 9 months and beyond (median follow-up 51.6 months). Six patients died, all in the first-year posttransplant. Cumulative incidences of grade II-IV acute GVHD/chronic GVHD were 18%/22%. Stem cell source, GVHD prophylaxis and conditioning intensity had no impact on OS. All surviving patients had over 90% donor chimerism, immune reconstitution, no sign of active PID related complications and were clinically improved. Allo-HSCT is effective in young adults PID patients with an acceptable toxicity and should be discussed in case of life-threatening PID.