Purpose
Complete signal transducer and activator of transcription 1 (STAT1) deficiency is a rare autosomal recessive condition characterized by impairment of intracellular signaling from both type I ...and type II interferons (IFN). Affected patients are prone to early severe mycobacterial and viral infections, which usually result in death before 18 months of age. We previously reported a patient affected by complete STAT1 deficiency who underwent hematopoietic stem cell transplantation (HSCT). Here, we describe the transplantation procedures and long-term outcomes.
Methods
The patient, who had suffered multiple life-threatening mycobacterial and viral infections in the first years of life, underwent HSCT at 4 years of age from a partially matched (HLA compatibility 8/10) unrelated donor after a myeloablative conditioning regimen consisting of busulfan, cyclophosphamide, and anti-thymocyte globulin.
Results
Hematological reconstitution was detected at d+15, with full donor engraftment demonstrated by molecular analysis of leukocytes. Several complications occurred in the post-transplantation phase, including acute graft versus host disease, posterior reversible encephalopathy, thrombotic thrombocytopenic purpura, bilateral keratoconjunctivitis with complete loss of vision, and chronic lower limb lymphedema. Analysis of STAT1 in CD3
+
cells at 90 and 120 days after HSCT by flow cytometry showed normal STAT1 phosphorylation levels in response to IFN-α.
Conclusions
Notably, no severe infections occurred after discharge (day + 90) during a 9-year follow-up, suggesting that normal response to IFNs in hematopoietic cells is sufficient to provide protection in humans.
Minimal residual disease (MRD) monitoring is an important tool to optimally address post-transplant management of acute myeloid leukemia (AML) patients.
We retrospectively analyzed the impact of bone ...marrow CD34+ molecular chimerism and
on the outcome of a consecutive series of 168 AML patients submitted to allogeneic stem cell transplantation.
The cumulative incidence of relapse (CIR) was significantly lower in patients with donor chimerism on CD34+ cells ≥ 97.5% and
< 213 copies/ABL x 10^4 both at 1
month (p=0.008 and p<0.001) and at 3
month (p<0.001 for both). By combining chimerism and
at 3
month, 13 patients with chimerism < 97.5% or
> 213 showed intermediate prognosis. 12 of these patients fell in this category because of molecular chimerism < 97.5% at a time-point in which
was < 213.
Our results confirm that lineage-specific molecular chimerism and
after allo-SCT (1
and 3
month) are useful MRD markers. When considered together at 3
month, CD34+ molecular chimerism could represent an earlier predictor of relapse compared to
. Further studies are necessary to confirm this preliminary observation.
Aims There is increasing evidence that stem cell (SC) mobilization to the heart and their differentiation into cardiac cells is a naturally occurring process. We sought to assess the safety and ...feasibility of granulocyte-colony stimulating factor (G-CSF) administration in humans to enhance SC mobilization and left ventricle (LV) injury repair during myocardial infarction (MI). Methods and results Twenty patients with STEMI (mean age, 61±10 years), of whom 14 were submitted to primary percutaneous coronary intervention, were randomized to G-CSF (5 µg/kg/day s.c. for 4 consecutive days) or placebo. At entry and then at months 3 and 6, 99mTc-sestamibi gated-SPECT was performed to estimate extension of perfusion defect (PD) and LV function. The study drug was well tolerated and induced a significant increase of white blood count, CD34+ cells, and CD34+ cells coexpressing AC133 and VEGFR-2. At follow-up, treated and placebo groups did not differ for the angiographic coronary late loss and showed a similar pattern of PD recovery, whereas in the former at 6 months LVEF and especially LVEDV tended to be relatively higher (P=0.068) and lower (P=0.054), respectively. Conclusion G-CSF administration in acute MI patients was feasible and did not lead to any clinical or angiographic adverse events and resulted in CD34+ and CD34+AC133+VEGFR2+ cell mobilization.
Background Currently, hematopoietic stem cell transplantation allows long-term survival in a high proportion of infants with congenital severe T-cell immunodeficiency. However, relatively little is ...known of their long-term quality of life. Objective We sought to assess the long-term immune reconstitution and clinical status in children treated with stem cell transplantation for severe T-cell immunodeficiency. Methods Immune function and clinical status have been analyzed in a cohort of 40 patients with severe T-cell immunodeficiency who are alive at a follow-up of at least 5 years after transplantation. Results Most patients have attained normal T- and B-cell function. Weight and height were normal at last follow-up in most patients. Endocrine and severe neurologic abnormalities have been observed in 17.5% and 10% of the patients, respectively. Conclusions These data indicate that with current management strategies, stem cell transplantation can lead to long-term survival and good quality of life in the majority of patients with severe T-cell immunodeficiency. Clinical implications Prompt recognition of congenital severe T-cell immunodeficiency, followed by stem cell transplantation, allows excellent perspectives of long-term survival and good quality of life for these otherwise fatal disorders.
Primary immunodeficiencies (PID) are characterized by recurrent infections and increased risk of malignancies because of the reduced immunological surveillance against cancer cells and oncogenic ...viruses.
We report the incidence of tumors among 690 patients with PID, diagnosed from 1990 until 2017 in Brescia.
Out of 690 patients, 25 patients (3.6%) developed 33 tumors. Of the 25 affected patients, 8 patients suffered from common variable immunodeficiency (CVID), 5 from combined immunodeficiency (CID), 3 from Ataxia-telangectasia (AT), 2 from Hermanksy-Pudlak type 2 (HSP2), 2 from gammaglobulinemia X-linked (XLA), 2 from Wiskott-Aldrich syndrome (WAS), 2 from Hyper IgE syndrome (HIES), 1 from severe combined immunodeficiency (SCID). The age at diagnosis ranged from 1 to 52 years, with a median age of 19.6 years. The time between the diagnosis of PID and onset of tumor was short, often <1 year between diagnosis and the appearance of cancer in the case of CID. Moreover, in two cases of CID, the diagnosis of cancer was made before the diagnosis of PID, so cancer was the onset clinical manifestation. Hematological malignancies were prevalent (22/33, 66.7%) with a minority of solid tumors (11/33, 33.33%). In particular Non-Hodgkin lymphomas were the most frequent (16/33, 48.48%). In total 13 patients survived (52%) and tumor was the main cause of death (7 cases). Two patients underwent BMT once the disease was in remission.
Therefore, the correct management of tumors that arise in patients with primitive immunodeficiency still represents a challenge in the pediatric field. For this reason now it is mandatory to collect in a unique international registry the cases of malignancies in PID that could lead to a better understanding of the etiopathogenesis and of the biological and clinical characteristics of these tumors, with the aim of defining adequate preventive measures and guaranteeing an early diagnosis which also creating a shared and specific therapeutic strategy, with the prospect of obtaining a better prognosis for these patients.
High-dose therapy (HDT) and peripheral-blood stem-cell transplantation (PBSCT) in HIV-associated lymphoma (HIV-Ly) has been recently reported in selected patients. We describe the results of a ...multi-institutional program of HDT and PBSCT as salvage therapy in HIV-Ly responsive to highly active antiretroviral therapy (HAART) in unselected patients.
Patients with resistant or relapsed HIV-Ly after first-line chemotherapy (CT) underwent PBSC collection after a course of second-line CT or cyclophosphamide and granulocyte colony-stimulating factor. Patients with chemotherapy-sensitive disease received carmustine, etoposide, cytarabine, and melphalan (BEAM regimen) and PBSC reinfusion. Effective HAART was maintained during the entire program.
Sixteen consecutive patients entered the program. Adequate collection of PBSC was obtained in 80% of patients (median CD34+ cells 6.8 x 106/kg). Three patients had early progression. Ten patients (62%) received PBSCT with prompt engraftment in all patients (neutrophils and platelet engraftment after a median of 10 days range, 8 to 10 days and 13 days range, 8 to 18 days, respectively). No patients died as a result of opportunistic or other infections or treatment-related complications. Eight of nine assessable patients achieved complete remission (one patient after radiotherapy for residual disease) and one patient achieved partial remission. Two patients experienced relapse and died at +10 and +14 months. Six patients are alive and disease free at a median of 8 months after transplantation.
Our data confirm that HDT plus PBSCT is feasible and active as salvage therapy in HIV-Ly on a multi-institutional basis and in unselected HAART-responding patients. HIV infection should no longer preclude the opportunity of HDT in patients with lymphoma.
We describe a previously healthy 14-year-old girl with acute onset autoimmune hemolytic anemia, associated with severe but transient lymphopenia during corticosteroid therapy, without infectious ...episodes during follow-up. After detailed investigations to rule out an underlying immunodeficiency, we detected a heterozygous
gene mutation. This was associated with slightly increased blood levels of adenosine and deoxyadenosine nucleotides and with reduced ADA activity in red blood cells, but within the normal range. This observation suggests that heterozygous ADA mutation might be a predisposing factor for lymphopenia in patients receiving corticosteroid therapy.
Levels of Kappa-deleting recombination excision circles (KRECs), T-cell receptor excision circles (TRECs), and T-cell repertoire diversity were evaluated in 1038 samples of 124 children with primary ...immunodeficiency, of whom 102 (54 with severe combined immunodeficiency and 48 with other types of immunodeficiency) underwent hematopoietic stem cell transplantation. Twenty-two not transplanted patients with primary immunodeficiency were used as controls. Only data of patients from whom at least five samples were sent to the clinical laboratory for routine monitoring of lymphocyte reconstitutions were included in the analysis. The mean time of the follow-up was 8 years. The long-lasting posttransplantation kinetics of KREC and TREC production occurred similarly in patients with severe combined immunodeficiency and with other types of immunodeficiency and, in both groups, the T-cell reconstitution was more efficient than in nontransplanted children. Although thymic output decreased in older transplanted patients, the degree of T-cell repertoire diversity, after an initial increase, remained stable during the observation period. However, the presence of graft-versus-host disease and ablative conditioning seemed to play a role in the time-related shaping of T-cell repertoire. Overall, our data suggest that long-term B- and T-cell reconstitution was equally achieved in children with severe combined immunodeficiency and with other types of primary immunodeficiency.
Leukocyte Adhesion Deficiency type 1 (LAD-1) is a rare primary immunodeficiency due to mutations in the gene encoding for the common β-chain of the β2 integrin family (CD18). Herein, we describe ...clinical manifestations and long-term complications of eight LAD-1 patients. Four LAD-1 patients were treated with hematopoietic stem cell transplantation (HSCT), while the remaining four, including two with moderate LAD-1 deficiency, received continuous antibiotic prophylaxis. Untreated patients presented numerous infections and autoimmune manifestations. In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved. Other two LAD-1 patients developed type 1 diabetes and autoimmune cytopenia after HSCT, suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications.
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