Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Allergy and Asthma Reports
Published in: Current Allergy and Asthma Reports 11/2019

Open Access 01-11-2019 | Primary Immunodeficiency | Immune Deficiency and Dysregulation(C Kuo, Section Editor)

Conditioning Regimens for Hematopoietic Cell Transplantation in Primary Immunodeficiency

Authors: S. H. Lum, M. Hoenig, A. R. Gennery, M. A. Slatter

Published in: Current Allergy and Asthma Reports | Issue 11/2019

Login to get access

Abstract

Purpose of Review

Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments in conditioning regimens for primary immunodeficiency (PID). It focuses on data regarding transplant outcomes according to newer reduced toxicity conditioning regimens used in HCT for PID.

Recent Findings

Conventional myeloablative conditioning regimens are associated with significant acute toxicities, transplant-related mortality, and late effects such as infertility. Reduced toxicity conditioning regimens have had significant positive impacts on HCT outcome, and there are now well-established strategies in children with PID. Treosulfan has emerged as a promising preparative agent. Use of a peripheral stem cell source has been shown to be associated with better donor chimerism in patients receiving reduced toxicity conditioning. Minimal conditioning regimens using monoclonal antibodies are in clinical trials with promising results thus far.

Summary

Reduced toxicity conditioning has emerged as standard of care for PID and has resulted in improved transplant survival for patients with significant comorbidities.
Literature
1.
Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968;2(7583):1366–9.PubMed
2.
Bach FH, Albertini RJ, Joo P, Anderson JL, Bortin MM. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet. 1968;2(7583):1364–6.PubMed
3.
Slatter MA, Gennery AR. Hematopoietic cell transplantation in primary immunodeficiency - conventional and emerging indications. Expert Rev Clin Immunol. 2018;14(2):103–14.PubMed
4.
• Slatter MA, Gennery AR. Advances in hematopoietic stem cell transplantation for primary immunodeficiency. Expert Rev Clin Immunol. 2013;9(10):991–9 An expert review on new indications of HCT in children with PID. PubMed
5.
•• Shah RM, Elfeky R, Nademi Z, Qasim W, Amrolia P, Chiesa R, et al. T-cell receptor alphabeta(+) and CD19(+) cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency. J Allergy Clin Immunol. 2018;141(4):1417–26 e1. An important paper demonstrating excellent transplant outcome after haploidentical donor transplant using graft engineering for children with PID. PubMed
6.
Fischer A, Landais P, Friedrich W, Gerritsen B, Fasth A, Porta F, et al. Bone marrow transplantation (BMT) in Europe for primary immunodeficiencies other than severe combined immunodeficiency: a report from the European Group for BMT and the European Group for Immunodeficiency. Blood. 1994;83(4):1149–54.PubMed
7.
Klein C, Cavazzana-Calvo M, Le Deist F, Jabado N, Benkerrou M, Blanche S, et al. Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients. Blood. 1995;85(2):580–7.PubMed
8.
Antoine C, Muller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Lancet. 2003;361(9357):553–60.PubMed
9.
Renella R, Picard C, Neven B, Ouachee-Chardin M, Casanova JL, Le Deist F, et al. Human leucocyte antigen-identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and pre-existing viral infections. Br J Haematol. 2006;134(5):510–6.PubMed
10.
Malar R, Sjoo F, Rentsch K, Hassan M, Gungor T. Therapeutic drug monitoring is essential for intravenous busulfan therapy in pediatric hematopoietic stem cell recipients. Pediatr Transplant. 2011;15(6):580–8.PubMed
11.
•• Slatter MA, Rao K, Abd Hamid IJ, Nademi Z, Chiesa R, Elfeky R, et al. Treosulfan and fludarabine conditioning for hematopoietic stem cell transplantation in children with primary immunodeficiency: UK experience. Biol Blood Marrow Transplant. 2018;24(3):529–36 An important study in a large cohort of PID patient received treosulfan demonstrating excellent survival, chimerism and low toxicity. PubMed
12.
Morillo-Gutierrez B, Beier R, Rao K, Burroughs L, Schulz A, Ewins AM, et al. Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience. Blood. 2016;128(3):440–8.
13.
Slatter MA, Boztug H, Potschger U, Sykora KW, Lankester A, Yaniv I, et al. Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases. Bone Marrow Transplant. 2015;50(12):1536–41.PubMed
14.
• Burroughs LM, Nemecek ER, Torgerson TR, Storer BE, Talano JA, Domm J, et al. Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial. Biol Blood Marrow Transplant. 2014;20(12):1996–2003 A large multicentre study demonstrating the safety and excellent transplant survival using Treosulfan-based conditiniong for nonmaligant diseases. PubMedPubMedCentral
15.
Dinur-Schejter Y, Krauss AC, Erlich O, Gorelik N, Yahel A, Porat I, et al. Bone marrow transplantation for non-malignant diseases using treosulfan-based conditioning. Pediatr Blood Cancer. 2015;62(2):299–304.
16.
Lehmberg K, Albert MH, Beier R, Beutel K, Gruhn B, Kroger N, et al. Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis. Haematologica. 2014;99(1):180–4.PubMed
17.
Beier R, Schulz A, Honig M, Eyrich M, Schlegel PG, Holter W, et al. Long-term follow-up of children conditioned with Treosulfan: German and Austrian experience. Bone Marrow Transplant. 2013;48(4):491–501.PubMed
18.
Slatter MA, Rao K, Amrolia P, Flood T, Abinun M, Hambleton S, et al. Treosulfan-based conditioning regimens for hematopoietic stem cell transplantation in children with primary immunodeficiency: United Kingdom experience. Blood. 2011;117(16):4367–75.PubMed
19.
Dvorak CC, Long-Boyle J, Dara J, Melton A, Shimano KA, Huang JN, et al. Low exposure busulfan conditioning to achieve sufficient multilineage chimerism in patients with severe combined immunodeficiency. Biol Blood Marrow Transplant. 2019;25(7):1355–62.PubMed
20.
•• Gungor T, Teira P, Slatter M, Stussi G, Stepensky P, Moshous D, et al. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Lancet. 2014;383(9915):436–48 A landmark study which demonstrates excellent transplant outcome using Bu-Flu in children with chronic granulomatous disease. PubMed
21.
Jacobsohn DA, Duerst R, Tse W, Kletzel M. Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in children. Lancet. 2004;364(9429):156–62.PubMed
22.
Allen CE, Marsh R, Dawson P, Bollard CM, Shenoy S, Roehrs P, et al. Reduced-intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies. Blood. 2018;132(13):1438–51.PubMedPubMedCentral
23.
Fox TA, Chakraverty R, Burns S, Carpenter B, Thomson K, Lowe D, et al. Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency. Blood. 2018;131(8):917–31.PubMedPubMedCentral
24.
Straathof KC, Rao K, Eyrich M, Hale G, Bird P, Berrie E, et al. Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study. Lancet. 2009;374(9693):912–20.
25.
Ritchie DS, Morton J, Szer J, Roberts AW, Durrant S, Shuttleworth P, et al. Graft-versus-host disease, donor chimerism, and organ toxicity in stem cell transplantation after conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant. 2003;9(7):435–42.PubMed
26.
Unni MNM, Elfeky R, Rao K, Nademi Z, Chiesa R, Amrolia P, et al. Non-posttransplant lymphoproliferative disorder malignancy after hematopoietic stem cell transplantation in patients with primary immunodeficiency: UK experience. J Allergy Clin Immunol. 2018;141(6):2319–21 e1.PubMed
27.
Haskologlu S, Kostel Bal S, Islamoglu C, Altun D, Kendirli T, Dogu EF, et al. Outcome of treosulfan-based reduced-toxicity conditioning regimens for HSCT in high-risk patients with primary immune deficiencies. Pediatr Transplant. 2018;22(7):e13266.PubMed
28.
Ben-Barouch S, Cohen O, Vidal L, Avivi I, Ram R. Busulfan fludarabine vs busulfan cyclophosphamide as a preparative regimen before allogeneic hematopoietic cell transplantation: systematic review and meta-analysis. Bone Marrow Transplant. 2016;51(2):232–40.PubMed
29.
Harris AC, Boelens JJ, Ahn KW, Fei M, Abraham A, Artz A, et al. Comparison of pediatric allogeneic transplant outcomes using myeloablative busulfan with cyclophosphamide or fludarabine. Blood Adv. 2018;2(11):1198–206.PubMedPubMedCentral
30.
Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010;116(26):5824–31.PubMed
31.
Amrolia P, Gaspar HB, Hassan A, Webb D, Jones A, Sturt N, et al. Nonmyeloablative stem cell transplantation for congenital immunodeficiencies. Blood. 2000;96(4):1239–46.PubMed
32.
Ritchie DS, Seymour JF, Roberts AW, Szer J, Grigg AP. Acute left ventricular failure following melphalan and fludarabine conditioning. Bone Marrow Transplant. 2001;28(1):101–3.PubMed
33.
Marsh RA, Bleesing JJ, Chandrakasan S, Jordan MB, Davies SM, Filipovich AH. Reduced-intensity conditioning hematopoietic cell transplantation is an effective treatment for patients with SLAM-associated protein deficiency/X-linked lymphoproliferative disease type 1. Biol Blood Marrow Transplant. 2014;20(10):1641–5.PubMed
34.
Ono S, Okano T, Hoshino A, Yanagimachi M, Hamamoto K, Nakazawa Y, et al. Hematopoietic stem cell transplantation for XIAP deficiency in Japan. J Clin Immunol. 2017;37(1):85–91.PubMed
35.
Burroughs LM, Storb R, Leisenring WM, Pulsipher MA, Loken MR, Torgerson TR, et al. Intensive postgrafting immune suppression combined with nonmyeloablative conditioning for transplantation of HLA-identical hematopoietic cell grafts: results of a pilot study for treatment of primary immunodeficiency disorders. Bone Marrow Transplant. 2007;40(7):633–42.PubMed
36.
Burroughs LM, Torgerson TR, Storb R, Carpenter PA, Rawlings DJ, Sanders J, et al. Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Allergy Clin Immunol. 2010;126(5):1000–5.PubMed
37.
Schuetz C, Neven B, Dvorak CC, Leroy S, Ege MJ, Pannicke U, et al. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood. 2014;123(2):281–9.
38.
Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, et al. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders. J Allergy Clin Immunol. 2018;141(1):322–8 e10.PubMed
39.
Haddad E, Logan BR, Griffith LM, Buckley RH, Parrott RE, Prockop SE, et al. SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery. Blood. 2018;132(17):1737–49.
40.
Ali AM, Dehdashti F, DiPersio JF, Cashen AF. Radioimmunotherapy-based conditioning for hematopoietic stem cell transplantation: another step forward. Blood Rev. 2016;30(5):389–99.PubMed
41.
Pagel JM, Appelbaum FR, Eary JF, Rajendran J, Fisher DR, Gooley T, et al. 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission. Blood. 2006;107(5):2184–91.PubMedPubMedCentral
42.
Pagel JM, Gooley TA, Rajendran J, Fisher DR, Wilson WA, Sandmaier BM, et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2009;114(27):5444–53.PubMedPubMedCentral
43.
Mawad R, Gooley TA, Rajendran JG, Fisher DR, Gopal AK, Shields AT, et al. Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome. Biol Blood Marrow Transplant. 2014;20(9):1363–8.PubMedPubMedCentral
44.
Schulz AS, Glatting G, Hoenig M, Schuetz C, Gatz SA, Grewendorf S, et al. Radioimmunotherapy-based conditioning for hematopoietic cell transplantation in children with malignant and nonmalignant diseases. Blood. 2011;117(17):4642–50.PubMed
45.
Derderian SC, Jeanty C, Walters MC, Vichinsky E, MacKenzie TC. In utero hematopoietic cell transplantation for hemoglobinopathies. Front Pharmacol. 2014;5:278.PubMed
46.
Agarwal R, Dvora CC, Proshaska S, et al. Toxicity-free hematopoietic stem cell engraftment achieved with anti-CD117 monoclonal antibody conditioning. Biol Blood Marrow Transplant. 2019;25:S92.
47.
Rastogi N, Katewa S, Thakkar D, Kohli S, Nivargi S, Yadav SP. Reduced-toxicity alternate-donor stem cell transplantation with posttransplant cyclophosphamide for primary immunodeficiency disorders. Pediatric Blood Cancer. 2018;65(1).
48.
Neven B, Diana JS, Castelle M, Magnani A, Rosain J, Touzot F, et al. Haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for primary immunodeficiencies and inherited disorders in children. Biol Blood Marrow Transplant. 2019;25(7):1363–73.PubMed
49.
Rao K, Amrolia PJ, Jones A, Cale CM, Naik P, King D, et al. Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen. Blood. 2005;105(2):879–85.PubMed
50.
Chiesa R, Veys P. Reduced-intensity conditioning for allogeneic stem cell transplant in primary immune deficiencies. Expert Rev Clin Immunol. 2012;8(3):255–66 quiz 67.PubMed
51.
Balashov D, Shcherbina A, Maschan M, Trakhtman P, Skvortsova Y, Shelikhova L, et al. Single-center experience of unrelated and haploidentical stem cell transplantation with TCRalphabeta and CD19 depletion in children with primary immunodeficiency syndromes. Biol Blood Marrow Transplant. 2015;21(11):1955–62.
52.
Ivaturi V, Dvorak CC, Chan D, Liu T, Cowan MJ, Wahlstrom J, et al. Pharmacokinetics and model-based dosing to optimize fludarabine therapy in pediatric hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2017;23(10):1701–13.PubMedPubMedCentral
53.
Romanski M, Wachowiak J, Glowka FK. Treosulfan pharmacokinetics and its variability in pediatric and adult patients undergoing conditioning prior to hematopoietic stem cell transplantation: current state of the art, in-depth analysis, and perspectives. Clin Pharmacokinet. 2018;57(10):1255–65.PubMedPubMedCentral
54.
Marsh RA, Lane A, Mehta PA, Neumeier L, Jodele S, Davies SM, et al. Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT. Blood. 2016;127(4):503–12.PubMed
55.
Oostenbrink LVE, Jol-van der Zijde CM, Kielsen K, Jansen-Hoogendijk AM, Ifversen M, Muller KG, et al. Differential elimination of anti-thymocyte globulin of Fresenius and Genzyme impacts T-cell reconstitution after hematopoietic stem cell transplantation. Front Immunol. 2019;10:315.PubMedPubMedCentral
56.
Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014;312(7):729–38.
57.
Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014;371(5):434–46.PubMed
58.
Dvorak CC, Puck JM, Wahlstrom JT, Dorsey M, Melton A, Cowan MJ. Neurologic event-free survival demonstrates a benefit for SCID patients diagnosed by newborn screening. Blood Adv. 2017;1(20):1694–8.PubMedPubMedCentral
59.
Cicalese MP, Ferrua F, Castagnaro L, Pajno R, Barzaghi F, Giannelli S, et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood. 2016;128(1):45–54.
60.
Mamcarz E, Zhou S, Lockey T, Abdelsamed H, Cross SJ, Kang G, et al. Lentiviral gene therapy combined with low-dose busulfan in infants with SCID-X1. N Engl J Med. 2019;380(16):1525–34.
61.
Moratto D, Giliani S, Bonfim C, Mazzolari E, Fischer A, Ochs HD, et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood. 2011;118(6):1675–84.PubMedPubMedCentral
62.
Battersby AC, Braggins H, Pearce MS, Cale CM, Burns SO, Hackett S, et al. Inflammatory and autoimmune manifestations in X-linked carriers of chronic granulomatous disease in the United Kingdom. J Allergy Clin Immunol. 2017;140(2):628–30 e6.PubMed
63.
Seidel MG, Bohm K, Dogu F, Worth A, Thrasher A, Florkin B, et al. Treatment of severe forms of LPS-responsive beige-like anchor protein deficiency with allogeneic hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2018;141(2):770–5 e1.PubMed
64.
Leiding JW, Okada S, Hagin D, Abinun M, Shcherbina A, Balashov DN, et al. Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations. J Allergy Clin Immunol. 2018;141(2):704–17 e5.PubMed
Metadata
Title
Conditioning Regimens for Hematopoietic Cell Transplantation in Primary Immunodeficiency
Authors
S. H. Lum
M. Hoenig
A. R. Gennery
M. A. Slatter
Publication date
01-11-2019