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Curative allogeneic hematopoietic stem cell transplantation following reduced toxicity conditioning in adults with primary immunodeficiency
Marçais, A., Mahlaoui, N., Neven, B., Lanternier, F., Catherinot, É, Salvator, H., Cheminant, M., Jeljeli, M., Asnafi, V., van Endert, P., et al
Bone marrow transplantation. 2022;:1-11
Abstract
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 post-transplant. 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.
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Improved transplant outcomes with myeloablative conditioning for hemophagocytic lymphohistiocytosis in HLA-matched and mismatched donors: a national multicenter retrospective study
Greental Ness, Y., Kuperman, A. A., Stein, J., Yacobovich, J., Even-Or, E., Zaidman, I., Gefen, A., Nevo, N., Oberman, B., Toren, A., et al
Bone marrow transplantation. 2021
Abstract
We report the results of national retrospective study of 45 children with hemophagocytic lymphohistiocytosis (HLH) who underwent allogeneic hematopoietic stem-cell transplantation (HSCT) in Israel between the years 2000-2018. Donors were either HLA-matched (n?=?26), partially mismatched (n?=?7), haploidentical (n?=?8), or cord-blood (n?=?4). Myeloablative conditioning (MAC) was used in 20 procedures, and reduced-intensity conditioning (RIC) in 25. Forty-two patients engrafted, two had primary graft failure (one successfully retransplanted), one died prior to engraftment, and two developed secondary graft failure. Of the eight patients who had mixed donor chimerism at day 30 (5-95%), five achieved stable mixed or full donor chimerism. The 5-year probabilities of overall survival and event-free survival (EFS) were 86% and 82%, respectively. Five-year EFS was lower for patients receiving RIC compared to MAC (72% vs. 100%, p?=?0.018) and following alternative-donor transplant (68% vs. 92% for HLA-matched donors, p?=?0.034), mostly due to increased transplant-related mortality (TRM). Thus, both HLA-matched and alternative donor transplant procedures may benefit form a myeloablative conditioning regimen.
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Reduced-Intensity/Reduced-Toxicity Conditioning Approaches Are Tolerated in XIAP Deficiency but Patients Fare Poorly with Acute GVHD
Arnold, D. E., Nofal, R., Wakefield, C., Lehmberg, K., Wustrau, K., Albert, M. H., Morris, E. C., Heimall, J. R., Bunin, N. J., Kumar, A., et al
Journal of clinical immunology. 2021;:1-10
Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n?=?30, 75%) and HLA-mismatched (n?=?10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II-IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55-86%) and 64% (CI 46-77%), respectively. Recipient and donor HLA mismatch and grade II-IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5-23.3, p?=?0.01) and 8.2 (CI 2.1-32.7, p?0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT.
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Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases
Nishimura, A., Aoki, Y., Ishiwata, Y., Ichimura, T., Ueyama, J., Kawahara, Y., Tomoda, T., Inoue, M., Matsumoto, K., Inoue, K., et al
Journal of clinical immunology. 2021
Abstract
PURPOSE The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). METHODS We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. RESULTS The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. CONCLUSIONS RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.
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5.
A Comparison of Hematopoietic Cell Transplant Conditioning Regimens for Hemophagocytic Lymphohistiocytosis Disorders
Marsh, R. A., Hebert, K., Kim, S., Dvorak, C. C., Aquino, V., Baker, K. S., Chellapandian, D., Saldana, B. D., Duncan, C., Eckrich, M. J., et al
The Journal of allergy and clinical immunology. 2021
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Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality. OBJECTIVE The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen(s) for HLH disorders. METHODS Included are 261 patients with HLH disorders transplanted between 2005-2018. Risk factors for transplant outcomes by conditioning regimen groups were studied using Cox regression models. RESULTS Four regimen groups were studied: 1) fludarabine (Flu), melphalan (Mel), n=123; 2) Flu, Mel, thiotepa (TT) n=28, 3) Flu, busulfan (Bu), n=14; and 4) Bu, cyclophosphamide (Cy), n=96. The day-100 incidence of veno-occlusive disease (VOD) was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%), p<0.001. The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%), p<0.001. Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%), compared to Flu/Mel/TT (70%), Flu/Bu (79%) and Bu/Cy (61%), p=0.002. The corresponding 5-year overall survival was 68%, 75%, 86% and 64% and did not differ by conditioning regimens (p=0.19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%) and Bu/Cy (18%), p<0.001. CONCLUSION Given the high rate of graft failure with Flu/Mel, and the high rate of VOD with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.
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Experience with a Reduced Toxicity Allogeneic Transplant Regimen for Non-CGD Primary Immune Deficiencies Requiring Myeloablation
Chandra, S., Chandrakasan, S., Dávila Saldaña, B. J., Bleesing, J. J., Jordan, M. B., Kumar, A. R., Grimley, M. S., Krupski, C., Davies, S. M., Khandelwal, P., et al
Journal of clinical immunology. 2020
Abstract
PURPOSE A need exists for reduced toxicity conditioning regimens that offer less toxicity while maintaining myeloablation, especially for primary immune deficiencies where myeloablation or high donor myeloid chimerism is required to achieve cure. We adapted a busulfan and fludarabine regimen by Gungor et al. for children and young adults undergoing allogeneic HCT for non-CGD primary immune deficiencies requiring myeloablation or high donor myeloid chimerism, and herein report our experience. METHODS We retrospectively reviewed records of 41 consecutive patients who underwent allogeneic HCT for Wiskott-Aldrich syndrome (n = 12), primary HLH/XLP (n = 10), CD40L deficiency (n = 7), or other (n = 12) primary immune deficiencies with a conditioning regimen containing pharmacokinetic-guided busulfan dosing which achieved a cumulative AUC between 57 and 74 mg/L × h (65-80% of conventional myeloablative exposure), along with fludarabine and alemtuzumab or anti-thymocyte globulin at 3 transplant centers between 2014 and 2019. RESULTS Forty-one patients underwent a first (n = 33) or second (n = 8) allogeneic HCT. Median age was 2.3 years (range, 0.3 years-19.8 years). All but one patient (97.5%) achieved neutrophil recovery at a median of 14 days (range, 11-34 days). One patient developed sinusoidal obstruction syndrome and two patients developed diffuse alveolar hemorrhage. Four patients developed grades II-IV acute GVHD. Three patients developed chronic GVHD. One-year overall survival was 90% (95% confidence interval [CI] 81-99%) and event-free survival was 83% (95% CI 71-94%). CONCLUSIONS Our experience suggests that a reduced toxicity busulfan-fludarabine regimen offers low toxicity, low incidence of grades 2-4 GVHD, durable myeloid engraftment, and excellent survival, and may be considered for a variety of primary immune deficiencies where myeloablative HCT is desired.
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Effect of different conditioning regimens on survival and engraftment for children with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoeitic stem cell transplantation: A single institution experience
Ali, S., Wall, D. A., Ali, M., Chiang, K. Y., Naqvi, A., Weitzman, S., Gassas, A., Gibson, P., Brager, R., Fernandez, C. V., et al
Pediatric blood & cancer. 2020;67(9):e28477
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH), a rare hyperinflammatory immuneregulatory disorder, is a challenge in hematopoietic stem cell transplantation (HSCT) because of the high rate of mixed chimerism, relapse, and graft failure (GF) unless intensive myeloablative regimens are used. However, historically conventional myeloablative regimens (conv MA) are associated with high toxicity and mortality. PROCEDURE We retrospectively compared transplant outcomes between three preparative regimens of varying intensities: Conv MA (n = 15), reduced-intensity conditioning (RIC, n = 12), and a treosulfan-based reduced-toxicity conditioning (RTC, n = 9). RESULTS Patients in the RIC cohort had a higher incidence of mixed donor chimerism and five patients (42%) developed secondary GF (P = .002) compared to the other two regimens. There was a higher incidence of veno-occlusive disease and intensive care unit (ICU) admissions in the Conv MA cohort. With the RTC regimen, there was a similar 2-year overall survival (89, 73, and 83%; P = .87), but improved compound EFS (lack of relapse, GF, second transplant or additional donor cell infusions, or death; 89, 73, and 42%, P = .041) in RTC, Conv MA, and RIC regimen, respectively. CONCLUSIONS The intensity of the preparative regimen has a significant impact on outcome of HSCT for HLH. The newly described treosulfan-based RTC provides for a stable graft with a reasonable toxicity profile.
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8.
Prospective study of a novel, radiation-free, reduced-intensity bone marrow transplantation platform for primary immunodeficiency diseases
Dimitrova, D., Gea-Banacloche, J., Steinberg, S. M., Sadler, J. L., Hicks, S. N., Carroll, E., Wilder, J. S., Parta, M., Skeffington, L., Hughes, T. E., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, utilize alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with median hematopoietic cell transplantation-comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III-IV acute GVHD-free, graft failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells which gradually increased by day +60. The cumulative incidences of grade II-IV and grade III-IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid-responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n=2) or with unknown underlying genetic defect (n=3). All six patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.
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9.
Reduced intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies: BMT CTN 1204
Allen, C., Marsh, R., Dawson, P., Bollard, C. M., Shenoy, S., Roehrs, P., Hanna, R., Burroughs, L., Kean, L., Talano, J. A., et al
Blood. 2018
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Editor's Choice
Abstract
Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced intensity conditioning with melphalan, fludarabine and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA-locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary endpoint was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow up of 20 months, the one-year OS for transplanted patients was 80.4% (90% CI: 68.6 - 88.2). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI: 52.9 - 77.3). Two patients experienced primary graft failure and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion (DLI)). At one year the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI: 25.2 - 54.6) and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI: 45.4 - 74.9). The day-100 incidence of grade II-IV acute GVHD was 17.4% (95% CI: 8.1 - 29.7) and one-year incidence of chronic GVHD was 26.7% (95% CI: 14.6 - 40.4). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633).
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Treosulfan, Fludarabine Conditioning for HSCT in Children with Primary Immunodeficiency: UK Experience
Slatter, M. A., Rao, K., Abd Hamid, I. J., Nademi, Z., Chiesa, R., Elfeky, R., Pearce, M. S., Amrolia, P., Worth, A., Flood, T., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
We previously published results of 70 children who received treosulfan with cyclophosphamide (30) or fludarabine (40) before haematopoietic stem cell transplantation (HSCT) for Primary Immunodeficiency (PID). Toxicity was lower and T cell chimerism better in those receiving fludarabine, but numbers were relatively small and follow-up short. We now report outcome of 160 children who received homogeneous conditioning with treosulfan, fludarabine mostly with alemtuzumab (n=124). Median age at transplant was 1.36 years (0.09-18.25). Donors were: matched unrelated, 73; 1-3 antigen mismatched unrelated, 54; matched sibling, 12; other matched family, 17; haploidentical, 4. Stem cell source was: peripheral blood stem cells (PBSCs), 70; Bone marrow, 49; Cord Blood, 41. Median follow up was 4.3 years (0.8-9.4). Overall survival was 83%. There was no veno- occlusive disease. Seventy-four (46%) had acute GVHD, but only 14(9%) greater than grade II. Four patients were successfully retransplanted for graft loss or poor immune reconstitution. One further patient who rejected the graft, died. There was no association between T cell chimerism > 95% and stem cell source, but a significant association with myeloid chimerism > 95% and use of PBSC without an increased risk of significant GVHD compared to other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth are alive with up to 8.7 years follow up. Long-term studies are required to determine late gonadotoxic effects and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine and alemtuzumab gives excellent results in HSCT for PID. Copyright © 2017. Published by Elsevier Inc.