scholarly journals Case Report: Unmanipulated Matched Sibling Donor Hematopoietic Cell Transplantation In TBX1 Congenital Athymia: A Lifesaving Therapeutic Approach When Facing a Systemic Viral Infection

2022 ◽  
Vol 12 ◽  
Author(s):  
Maria Chitty-Lopez ◽  
Carla Duff ◽  
Gretchen Vaughn ◽  
Jessica Trotter ◽  
Hector Monforte ◽  
...  

Congenital athymia can present with severe T cell lymphopenia (TCL) in the newborn period, which can be detected by decreased T cell receptor excision circles (TRECs) on newborn screening (NBS). The most common thymic stromal defect causing selective TCL is 22q11.2 deletion syndrome (22q11.2DS). T-box transcription factor 1 (TBX1), present on chromosome 22, is responsible for thymic epithelial development. Single variants in TBX1 causing haploinsufficiency cause a clinical syndrome that mimics 22q11.2DS. Definitive therapy for congenital athymia is allogeneic thymic transplantation. However, universal availability of such therapy is limited. We present a patient with early diagnosis of congenital athymia due to TBX1 haploinsufficiency. While evaluating for thymic transplantation, she developed Omenn Syndrome (OS) and life-threatening adenoviremia. Despite treatment with anti-virals and cytotoxic T lymphocytes (CTLs), life threatening adenoviremia persisted. Given the imminent need for rapid establishment of T cell immunity and viral clearance, the patient underwent an unmanipulated matched sibling donor (MSD) hematopoietic cell transplant (HCT), ultimately achieving post-thymic donor-derived engraftment, viral clearance, and immune reconstitution. This case illustrates that because of the slower immune recovery that occurs following thymus transplantation and the restricted availability of thymus transplantation globally, clinicians may consider CTL therapy and HCT to treat congenital athymia patients with severe infections.

2020 ◽  
Vol 222 (7) ◽  
pp. 1180-1187
Author(s):  
Yeon Joo Lee ◽  
Jiaqi Fang ◽  
Phaedon D Zavras ◽  
Susan E Prockop ◽  
Farid Boulad ◽  
...  

Abstract Background We report on predictors of adenovirus (ADV) viremia and correlation of ADV viral kinetics with mortality in ex vivo T-cell depleted (TCD) hematopoietic cell transplant (HCT). Methods T cell-depleted HCT recipients from January 1, 2012 through September 30, 2018 were prospectively monitored for ADV in the plasma through Day (D) +100 posttransplant or for 16 weeks after the onset of ADV viremia. Adenovirus viremia was defined as ≥2 consecutive viral loads (VLs) ≥1000 copies/mL through D +100. Time-averaged area under the curve (AAUC) or peak ADV VL through 16 weeks after onset of ADV viremia were explored as predictors of mortality in Cox models. Results Of 586 patients (adult 81.7%), 51 (8.7%) developed ADV viremia by D +100. Age <18 years, recipient cytomegalovirus seropositivity, absolute lymphocyte count <300 cells/µL at D +30, and acute graft-versus-host disease were predictors of ADV viremia in multivariate models. Fifteen (29%) patients with ADV viremia died by D +180; 8 of 15 (53%) died from ADV. Peak ADV VL (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.52–3.33) and increasing AAUC (HR, 2.95; 95% CI, 1.83–4.75) correlated with mortality at D +180. Conclusions In TCD HCT, peak ADV VL and ADV AAUC correlated with mortality at D +180. Our data support the potential utility of ADV viral kinetics as endpoints in clinical trials of ADV therapies.


Blood ◽  
2013 ◽  
Vol 121 (2) ◽  
pp. 339-350 ◽  
Author(s):  
Vikas Gupta ◽  
Sue Richards ◽  
Jacob Rowe

Abstract Hematopoietic cell transplantation (HCT) and prolonged chemotherapy are standard postremission strategies for adult acute lymphoblastic leukemia in first complete remission, but the optimal strategy remains controversial. There are no randomized trials of allogeneic HCT. In the present study, updated individual patient data were collected and analyzed from studies with information on availability of matched sibling donor (used to mimic randomization) and from randomized trials of autograft versus chemotherapy. Data from 13 studies including 2962 patients, excluding Philadelphia chromosome–positive patients, showed a survival benefit for having a matched sibling donor for patients < 35 years of age (OR = 0.79; 95% CI, 0.70-0.90, P = .0003) but not for those ≥ 35 years of age (OR = 1.01; 95% CI, 0.85-1.19, P = .9; heterogeneity P = .03) because of the higher absolute risk of nonrelapse mortality for older patients. No differences were seen by risk group. There was a trend toward inferior survival for autograft versus chemotherapy (OR = 1.18; 95% CI, 0.99-1.41; P = .06). No beneficial effect of autografting was seen compared with chemotherapy in this analysis. We conclude that matched sibling donor myeloablative HCT improves survival only for younger patients, with an absolute benefit of approximately 10% at 5 years. Improved chemotherapy outcomes and reduced nonrelapse mortality associated with allogeneic HCT may change the relative effects of these treatments in the future.


2020 ◽  
Vol 4 (17) ◽  
pp. 4232-4243
Author(s):  
Pingping Zheng ◽  
John Tamaresis ◽  
Govindarajan Thangavelu ◽  
Liwen Xu ◽  
Xiaoqing You ◽  
...  

Abstract Graft-versus-host disease (GVHD) is a complication of hematopoietic cell transplantation (HCT) caused by alloreactive T cells. Murine models of HCT are used to understand GVHD and T-cell reconstitution in GVHD target organs, most notably the gastrointestinal (GI) tract where the disease contributes most to patient mortality. T-cell receptor (TCR) repertoire sequencing was used to measure T-cell reconstitution from the same donor graft (C57BL/6 H-2b) in the GI tract of different recipients across a spectrum of matching, from syngeneic (C57BL/6), to minor histocompatibility (MHC) antigen mismatch BALB.B (H-2b), to major MHC mismatched B10.BR (H-2k) and BALB/c (H-2d). Although the donor T-cell pools had highly similar TCR, the TCR repertoire after HCT was very specific to recipients in each experiment independent of geography. A single invariant natural killer T clone was identifiable in every recipient group and was enriched in syngeneic recipients according to clonal count and confirmatory flow cytometry. Using a novel cluster analysis of the TCR repertoire, we could classify recipient groups based only on their CDR3 size distribution or TCR repertoire relatedness. Using a method for evaluating the contribution of common TCR motifs to relatedness, we found that reproducible sets of clones were associated with specific recipient groups within each experiment and that relatedness did not necessarily depend on the most common clones in allogeneic recipients. This finding suggests that TCR reconstitution is highly stochastic and likely does not depend on the evaluation of the most expanded TCR clones in any individual recipient but instead depends on a complex polyclonal architecture.


2020 ◽  
Vol 221 (Supplement_1) ◽  
pp. S23-S31 ◽  
Author(s):  
Ghady Haidar ◽  
Michael Boeckh ◽  
Nina Singh

Abstract This review focuses on recent advances in the field of cytomegalovirus (CMV). The 2 main strategies for CMV prevention are prophylaxis and preemptive therapy. Prophylaxis effectively prevents CMV infection after solid organ transplantation (SOT) but is associated with high rates of neutropenia and delayed-onset postprophylaxis disease. In contrast, preemptive therapy has the advantage of leading to lower rates of CMV disease and robust humoral and T-cell responses. It is widely used in hematopoietic cell transplant recipients but is infrequently utilized after SOT due to logistical considerations, though these may be overcome by novel methods to monitor CMV viremia using self-testing platforms. We review recent developments in CMV immune monitoring, vaccination, and monoclonal antibodies, all of which have the potential to become part of integrated strategies that rely on viral load monitoring and immune responses. We discuss novel therapeutic options for drug-resistant or refractory CMV infection, including maribavir, letermovir, and adoptive T-cell transfer. We also explore the role of donor factors in transmitting CMV after SOT. Finally, we propose a framework with which to approach CMV prevention in the foreseeable future.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2838-2838 ◽  
Author(s):  
Margaret L. MacMillan ◽  
Arleen D. Auerbach ◽  
John E. Wagner

Abstract Fanconi anemia patients with biallelic BRCA2 mutations have an exceptionally high risk of developing hematological malignancies, Wilms tumors and medulloblastoma at a very young age. We report on the hematopoietic cell transplant (HCT) results of 6 patients from 4 kindreds, all of whom have biallelic BRCA2 mutations. Two patients (800/2 and 984/2) were found to have a Wilms tumor at time of work-up for HCT despite normal previous renal ultrasounds. One was a stage 1 favorable histology, the second a stage II poorly differentiated tumor with diffuse anaplasia. In each case, the patient underwent nephrectomy and proceeded to HCT 3 weeks later. All unrelated or mismatched related donor marrow grafts were T cell depleted either by elutriation in patient 632/1, or CD34 selection with Isolex in the remaining cases. Five of 6 patients achieved neutrophil engraftment. Only one patient developed severe regimen related toxicity and one patient GVHD. Two of 6 patients are alive and well after HCT, both whom had T-cell ALL, which is uncommon in FA patients. Patient and Transplant Characteristics Kindred, IFAR No. Age/Gender Clinical Hx Donor Preparative Rx Day to ANC&gt;500 Toxicity, GVHD Outcome 1, 632/1 3.7 yr/F AML at 36 mo, chemotherapy refractory 6/6 URD BM x 2 CY, TBI, ATG, CSA, MP; CY, ATG, MP, CSA graft failure; +31 None AML relapse after both HCT, died day +76 after 2nd HCT 1, 632/2 1.9 yr/F AML at 21 mo, chemotherapy refractory 6/6 MSD BM CY, TBI, FLU, ATG, CSA, MP Engrafted None AML relapse, died day +288 2, 800/1 1.8 yr/M AML at 11 mo, chemotherapy refractory 6/6 URD TCD BM CY, TBI, ATG, CSA, MP +11 Grade II aGVHD AML relapse day +110, died day +124 2, 800/2 0.8 yr/M Neutropenia at 5 mo, Wilms tumor at 9 mo 6/6 URD TCD BM CY, TBI, FLU, ATG, CSA, MP +9 Resp and renal failure Died day +60 from pulmonary hemorrhage 3, 900/1 4.9 yr/M T cell ALL at 5.2 yr, CR after chemotherapy 5/6 Mat TCD BM BU, CY, FLU, ATG, CSA, MP +10 None Alive and well 19 mo after HCT 4, 900/2 6.7 yr/F T cell ALL at 4.9 yr, remission with chemotherapy, relapse with AML 17 mo later, Wilms at 6.6 yr 6/6 URD UCB BU, CY, FLU, ATG, CSA, MP +13 None Alive and well 3 mo after HCT In summary, HCT has limited effectiveness after the onset of leukemia in patients with Fanconi anemia. While these patients have tolerated chemoradiotherapy well in most cases, refractoriness of the leukemia is the principle obstacle to success. Therefore, patients with biallelic BRCA2 mutations should be screened for solid tumors and referred for HCT as soon as possible, prior to the onset of leukemia. In addition, these patients require routine screening for solid tumors after HCT, the incidence of which remains to be determined.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 327-327
Author(s):  
Lauri Burroughs ◽  
Rainer F. Storb ◽  
Wendy Leisenring ◽  
Michael Pulsipher ◽  
Michael R. Loken ◽  
...  

Abstract Myeloablative conditioning regimens may cause significant life threatening transplant related toxicities in patients with immunodeficiency disorders, particularly in patients with co-morbid conditions. This current study was designed to determine whether an immunosuppressive nonmyeloablative regimen would safely enable stable donor engraftment of hematopoietic cells in patients with immunodeficiency disorders who were ineligible for myeloablative conditioning regimens because of life-threatening infections or organ dysfunction. Fourteen patients with severe combined immunodeficiency disorder (SCID; n=3), common variable immunodeficiency (CVID; n=1), T-cell immunodeficiency disorder (TCD; n=3), Wiskott-Aldrich syndrome (WAS; n=2), CD40 Ligand deficiency (CD40LD; n=2), immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX; n=1), X-linked agammaglobulinemia (XLA; n=1) and chronic granulomatous disease (CGD; n=1) received HLA-matched related (n=7) or unrelated (n=7) hematopoietic cell grafts from marrow (n = 8), peripheral blood stem cell (n = 5), or umbilical cord blood (n = 1). All patients were given postgrafting immunosuppression with MMF and CSP. Two patients had no pre-transplant conditioning, whereas host immunosuppression was provided by 200 cGy TBI alone (n=3) or in combination with 90 mg/m2 fludarabine (n=9) before hematopoietic cell transplantation (HCT). Mixed (n=5) or full (n=5) donor cell chimerism was established in 10 patients. Four patients required second HCT (n=3) or donor lymphocyte infusion (n=1) due to either T cell graft rejection (n=1), loss of the granulocyte graft (n=1), or low levels of T cell chimerism (n=2). Mortality by days 100 and 180 was 0%. The cumulative incidences of grade II–IV and III–IV acute graft versus host disease (GVHD) were 79% and 14%, respectively. The 1-year incidence of extensive chronic GHVD was 64%. Median follow up for the living recipients was 3 (range, 0.8–6.4) years. The 2 year overall survival, event free survival and transplant related mortality were 68%, 60%, and 16%, respectively. In 7 of the 10 patients with stable donor engraftment correction of immune dysfunction was documented. Specifically, the 4 patients with SCID (n=3) and CVID (n=1) had normal T cell numbers and function following HCT. One patient with WAS had correction of T cell function and platelet numbers after HCT; however subsequently died of B cell non-EBV lymphoma. In addition, 1 patient with CD40LD showed increases in functional CD40 ligand expressing T-cells and response to a neoantigen. Finally, 1 patient with CGD exhibited a normal neutrophil oxidative burst following HCT. Three patients (TCD n=2, CD40LD n=1) were not evaluable for disease response due to continued immunosuppression for chronic GVHD. These results indicate that postgrafting immunosuppression plus nonmyeloablative HCT markedly reduces early HCT related mortality among high-risk patients with immunodeficiency disorders.


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