Conditioning regimens for inborn errors of immunity: current perspectives and future strategies.

Inborn errors of immunity (IEI) are caused by germline genetic mutations, resulting in defects of innate or acquired immunity. Hematopoietic cell transplantation (HCT) is indicated for curative therapy especially in patients with IEI who develop fatal opportunistic infections or severe manifestations of immune dysregulation. The first successful HCT for severe combined immunodeficiency (SCID) was reported in 1968. Since then, the indications for HCT have expanded from SCID to various non-SCID IEI. In general, HCT for IEI differs from that for other hematological malignancies in that the goal is not to eradicate certain immune cells but to achieve immune reconstitution. European Society for Blood and Marrow Transplantation/European Society for Immunodeficiencies guidelines recommend reduced-intensity conditioning to avoid treatment-related toxicity, and the optimal conditioning regimen should be considered for each IEI. We review conditioning regimens for some representative IEI disorders in Japanese and worldwide cohort studies, and future strategies for treating IEI.

Nishimura A ，Miyamoto S ，Imai K ，Morio T ... -  《-》

Lifelong Immune Modulation Versus Hematopoietic Cell Therapy for Inborn Errors of Immunity.

Advances in diagnosis of inborn errors of immunity (IEI) and an understanding of the molecular and immunologic mechanisms of these disorders have led to both the development of new therapies and improved approaches to hematopoietic cell transplantation (HCT). For example, monoclonal antibodies (mAbs) and small molecules, such as Janus tyrosine kinase inhibitors, that can modulate immunologic pathways have been designed for or repurposed for management of IEI. A better understanding of molecular mechanisms of IEI has led to use of drugs typically considered "immunosuppressive" to modulate the immune response, such as mammalian target of rapamycin inhibitors in disorders of phosphoinositide 3-kinase gain of function. Since the first HCT in a patient with severe combined immunodeficiency (SCID) in 1968, transplantation strategies have improved, with more than 90% probability of survival after allogeneic HCT in SCID and hence HCT is now the therapeutic standard for SCID and many other IEI. When tailoring treatment for IEI, multiple disease-specific and individual factors should be considered. In diseases such as SCID or agammaglobulinemia, the choice between HCT or medical management is straightforward. However, in many IEI, the choice between the options is challenging. This review focuses on the factors that should be taken into account in the quest for the optimal treatment for patients with IEI.

Cooper MA ，Zimmerman O ，Nataraj R ，Wynn RF ... -  《-》

Allogeneic Hematopoietic Stem Cell Transplantation Activity in Inborn Errors of Immunity in Russian Federation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established therapy for many inborn errors of immunity (IEI). The indications for HSCT have expanded over the last decade. The study aimed to collect and analyze the data on HSCT activity in IEI in Russia. The data were collected from the Russian Primary Immunodeficiency Registry and complemented with information from five Russian pediatric transplant centers. Patients diagnosed with IEI by the age of 18 years and who received allogeneic HSCT by the end of 2020 were included. From 1997 to 2020, 454 patients with IEI received 514 allogeneic HSCT. The median number of HSCTs per year has risen from 3 in 1997-2009 to 60 in 2015-2020. The most common groups of IEI were immunodeficiency affecting cellular and humoral immunity (26%), combined immunodeficiency with associated/syndromic features (28%), phagocyte defects (21%), and diseases of immune dysregulation (17%). The distribution of IEI diagnosis has changed: before 2012, the majority (65%) had severe combined immunodeficiency (SCID) and hemophagocytic lymphohistiocytosis (HLH), and after 2012, only 24% had SCID and HLH. Of 513 HSCTs, 48.5% were performed from matched-unrelated, 36.5% from mismatched-related (MMRD), and 15% from matched-related donors. In 349 transplants T-cell depletion was used: 325 TCRαβ/CD19+ depletion, 39 post-transplant cyclophosphamide, and 27 other. The proportion of MMRD has risen over the recent years. The practice of HSCT in IEI has been changing in Russia. Expanding indications to HSCT and SCID newborn screening implementation may necessitate additional transplant beds for IEI in Russia.

Laberko A ，Mukhinа A ，Machneva E ，Pashchenko O ，Bykova T ，Vahonina L ，Bronin G ，Skvortsova Y ，Skorobogatova E ，Kondratenko I ，Fechina L ，Shcherbina A ，Zubarovskaya L ，Balashov D ，Rumiantsev A ... -  《-》

Hematopoietic Cell Transplantation for Inborn Errors of Immunity Other than Severe Combined Immunodeficiency in Japan: Retrospective Analysis for 1985-2016.

Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.

Miyamoto S ，Umeda K ，Kurata M ，Yanagimachi M ，Iguchi A ，Sasahara Y ，Okada K ，Koike T ，Tanoshima R ，Ishimura M ，Yamada M ，Sato M ，Takahashi Y ，Kajiwara M ，Kawaguchi H ，Inoue M ，Hashii Y ，Yabe H ，Kato K ，Atsuta Y ，Imai K ，Morio T ... -  《-》

Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium

Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency. Historically, SCID was diagnosed in infants who presented with opportunistic infections within the first year of life. With newborn screening (NBS) for SCID in most of the United States, the majority of infants with SCID are now diagnosed and treated in the first 3.5 months of life; however, in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for SCID patients who have undergone transplantation currently is >70% at 3 years after transplantation, although this can vary significantly based on multiple factors, including age and infection status at the time of transplantation, type of donor source utilized, manipulation of graft before transplantation, graft-versus-host disease prophylaxis, type of conditioning (if any) utilized, and underlying genotype of SCID. In at least 1 study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) after transplantation. Although a majority of patients with SCID will engraft T cells without any conditioning therapy, depending on genotype, donor source, HLA match, and presence of circulating maternal cells, a sizable percentage of these will fail to achieve full immune reconstitution. Without conditioning, T cell reconstitution typically occurs, although not always fully, whereas B cell engraftment does not, leaving some molecular types of SCID patients with intrinsically defective B cells, in most cases, dependent on regular infusions of immunoglobulin. Because of this, many centers have used conditioning with alkylating agents including busulfan or melphalan known to open marrow niches in attempts to achieve B cell reconstitution. Thus, it is imperative that we understand the potential late effects of these agents in this patient population. There are also nonimmunologic risks associated with HCT for SCID that appear to be dependent upon the genotype of the patient. In this report, we have evaluated the published data on late effects and attempted to summarize the known risks associated with conditioning and alternative donor sources. These data, while informative, are also a clear demonstration that there is still much to be learned from the SCID population in terms of their post-HCT outcomes. This paper will summarize current findings and recommend further research in areas considered high priority. Specific guidelines regarding a recommended approach to long-term follow-up, including laboratory and clinical monitoring, will be forthcoming in a subsequent paper.

Heimall J ，Puck J ，Buckley R ，Fleisher TA ，Gennery AR ，Neven B ，Slatter M ，Haddad E ，Notarangelo LD ，Baker KS ，Dietz AC ，Duncan C ，Pulsipher MA ，Cowan MJ ... -  《-》