Severe cytokine release syndrome in a patient receiving PD‐1‐directed therapy

Cytokine release syndrome (CRS) is a phenomenon of immune hyperactivation described in the setting of cellular and bispecific T‐cell engaging immunotherapy. Checkpoint blockade using anti‐programmed cell death 1 (anti‐PD‐1) inhibitors is an approach to antitumor immune system stimulation. A 29‐year‐old female with alveolar soft part sarcoma developed severe CRS after treatment with anti‐PD‐1 therapy. CRS was characterized by high fevers, encephalopathy, hypotension, hypoxia, hepatic dysfunction, and evidence of coagulopathy, and resolved after infusion of the interleukin‐6 inhibitor tocilizumab and corticosteroids.     

Fulminant recurrence of atypical hemolytic uremic syndrome during a calcineurin inhibitor-free immunosuppression regimen

Recurrence of hemolytic uremic syndrome (HUS) after kidney transplantation is frequent, occurring almost exclusively in patients with atypical HUS, which is not caused by Escherichia coli gastroenteritis and in which diarrhea is absent. Calcineurin inhibitors are associated with recurrence of HUS. In two children who underwent living donor kidney transplantation for atypical HUS, we pre-emptively employed sirolimus in a calcineurin inhibitor-free immunosuppression regimen. Both children had excellent early graft function, yet both developed severe recurrent disease and subsequently lost their grafts. Avoidance of calcineurin inhibitors did not prevent recurrence of severe HUS and graft loss. Transplantation for severe atypical HUS remains problematic.     

Long-term follow-up of children treated with daclizumab for steroid-refractory gastrointestinal GvHD in a prospective study

Hamidieh AA, Hadjibabaie M, Taghizadeh Ghehi M, Jalili M, Hosseini A, Pasha F, Behfar M, Ghavamzadeh A. Long‐term follow‐up of children treated with daclizumab for steroid‐refractory GI GvHD in a prospective study. Abstract: Daclizumab, a humanized MoAB to IL‐2Ra, has been found to be safe and effective in adults with refractory GvHD; however, data in children are limited. The aim of this prospective study was to evaluate the long‐term safety and efficacy of daclizumab in children with steroid‐refractory GI aGvHD. This study included 13 children who developed steroid‐refractory GI GvHD between 2007 and 2009. When first‐line treatment failed, daclizumab was given in a regimen of 1 mg/kg intravenously and then repeated on a 10‐ to 14‐day interval for maximum five doses if necessary. Daclizumab was well tolerated, but infections were common. Ten patients responded to daclizumab completely, one patient responded partially, and two patients failed to respond. With a median follow‐up of 630 days, 10 patients were alive and free of severe infections, but among them, four patients were suffering from cGvHD. Of the three remaining patients, one died because of bacterial meningitis, and the other two patients died because of severe refractory GI GvHD. This long‐term evaluation showed that daclizumab could be an effective and relatively safe treatment in most of the pediatric patients with severe steroid‐refractory GI GvHD.     

Development of common variable immunodeficiency in a patient with Evans syndrome treated by autologous stem cell transplantation

We describe a case report of a patient who developed common variable immunodeficiency (CVID) after autologous haematopoietic stem cell transplantation (SCT) for recurrent Evans syndrome. The disease manifested as attacks of haemolytic anaemia, thrombocytopenia and neutropenia from the age of 12 years. Presence of autoantibodies to blood elements was confirmed together with C4 deficiency. The patient also suffered from dermatitis herpetiformis Duhring without signs of coeliac disease. Autologous T cell-depleted peripheral blood stem cell (PBSC) transplant following conditioning regimen was performed at the age of 20 years. Immunological reconstitution was incomplete and 2 years after SCT he fulfilled laboratory criteria for common variable immunodeficiency (CVID). The patient was found to be a carrier of a risk haplotype for development of CVID DRB1*03/DQB1*0201. We conclude that T cell-depleted SCT here performed for autoimmune manifestations can hasten development of CVID in genetically predisposed patients.     

造血干细胞移植治疗Wiskott-Aldrich综合征一例报告及文献复习

目的 Wiskott-Aldrich综合征(WAS)是一种原发性免疫缺陷性疾病,严重病例预后不良.采用人类白细胞抗原(HLA)全相合的同胞骨髓移植成功治疗1例,特此总结并进行文献复习.方法 采用流式细胞仪检测WAS蛋白(WASP)表达和基因分析确诊WAS.患儿姐姐为人类白细胞抗原全相合骨髓供者,所采集骨髓单个核细胞数为4.38×108/kg,CD34+细胞3.78×106/kg患儿体重.采用白消安/环磷酰胺全清髓的预处理方案,环孢菌素单用预防移植物抗宿主病.移植后检测WASP表达和短串联重复序列(STR)作为植入证据.结果 患儿诊断:WAS,WASP(-IVS9+2T>C,WASP阴性).白消安/环磷酰胺预处理后骨髓回输;移植13 d中性粒细胞(ANC)绝对值0.8×109/L,移植15 d起血小板>50×109/L,1个月后正常.移植50 d起患儿WASP表达阳性,STR显示为供者DNA完全嵌合;随访至移植后510 d,患儿健康,WASP稳定表达.结论 结合病例和文献复习,人类白细胞抗原相合同胞骨髓移植治疗典型WAS近期预后较好.     

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children

Abstract

CD19 chimeric antigen receptor T (CD19CAR-T) cell therapy has shown striking response in treating relapsed and refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, side-effects including cytokine release syndrome (CRS) and neurotoxicity can be fatal to patients. In this report, five patients with r/r B-ALL were treated with CD19CAR-T cells. Cytokine release syndrome experienced by four patients who achieved complete remission (CR) with minimal residual disease (MRD) negative. One patient who did not response to the treatment had no CRS. Acute toxicities including fever, hypotension and other neurological toxicities occurred in responding patients within 2?weeks post infusion and managed properly with tocilizumab and/or steroids according to the “real-time” monitoring of a simple 6 Th1/Th2 cytokine pattern. In conclusion, our study demonstrates that CD19CAR-T cell therapy can be safely administered for patients with relapsed and refractory leukemia under the “real-time” monitoring of a simple 6-cytokine pattern.     

Chronic active Epstein-Barr virus infection with mosquito allergy successfully treated with reduced-intensity unrelated allogeneic bone marrow transplantation in a boy

Abstract:  EBV-infected T-/NK cells play an important role in the pathogenesis of mosquito allergy, and the prognosis of most patients with mosquito allergy is poor without proper treatment. We describe a 13-yr-old boy who had CAEBV with mosquito allergy and was successfully treated with BMT from an unrelated donor after reduced-intensity preconditioning. Because combination chemotherapy failed to achieve CR, we performed unrelated BMT to reconstitute normal immunity and eradicate any residual EBV-infected cells. To reduce complications after BMT, we selected a reduced-intensity preconditioning regimen consisting of fludarabine, l -phenylalanine mustard, and antithymocyte Ig instead of a conventional myeloablative preconditioning. Although grade II acute GVHD developed, it was successfully controlled with immunosuppressive therapy. After 27 months, the patient has been well without any signs of CAEBV, and the EBV DNA has been undetectable with real-time PCR analysis. We conclude that RIST from the bone marrow of an unrelated donor is indicated for some patients who have CAEBV that is refractory to chemotherapy and who have no HLA-matched related donors or cord blood as a source of stem cells.     

Hematopoietic stem cell transplantation with a reduced‐intensity conditioning regimen in pediatric patients with Griscelli syndrome type 2

Partial albinism with variable immunodeficiency are the two major characteristics of Griscelli syndrome type 2 (GS‐2). This syndrome is usually associated with a high mortality rate and commonly results in early childhood death. Patients suffer from different infections and experience crisis of HLH. HSCT remains the sole curative treatment for GS‐2. We prospectively analyzed the outcomes of transplantation with RIC regimen in five patients. The median age at transplantation was 21.6 months (range: 12–30). All of the patients underwent HSCT from HLA‐matched related donors. Currently, four patients are cured, and symptoms of recurrent infections and HLH crisis are not seen in them. The only patient who died had undergone HSCT in the accelerated phase of HLH. One patient who developed acute GvHD had a favorable response to therapy. No chronic GvHD occurred in patients. It seems that the use of RIC regimen as a method of transplant preparation is effective and tolerable in this group of patients with various comorbidities. It is recommended to carry out HSCT in these patients at lower ages, before presentations of different infections and HLH crisis.     

Unrelated partially matched lymphocyte infusions in a patient with complete DiGeorge/CHARGE syndrome

We present an infant with cDGS overlapping with CHARGE syndrome, who suffered from T-cell deficiency treated with screened healthy DLI from an unrelated donor (8/10 match). The first dose of DLI (1.1 x 10(6) CD3+/kg) was administered at the age of six months, the second one (0.9 x 10(6) CD3+/kg) 36 days later. No conditioning was employed, GvHD prophylaxis consisting of CsA was used only during the second infusion. Since day+10 after the first DLI, split chimerism showing T-cell engraftment has been documented. Proliferative response to PHA was detected on day+145. The treatment was complicated by severe acute GvHD (grade II-III) after the first DLI and prolonged chronic liver cholestatic GvHD developing after the second DLI. Vigorous EBV proliferation four wk after the second DLI was accompanied by peripheral expansion of CD8+ donor cells. The patient, 26-months old, is clinically well and has slowly started to gain his developmental milestones. We believe that infusions of small doses of DLI from an unrelated donor represent a potentially helpful therapeutic option in patients with cDGS/CHARGE phenotype.     

Accelerated phase in partial albinism with immunodeficiency (Griscelli syndrome): genetics and stem cell transplantation in a 2-month-old girl

A 2-month-old girl presented with fever, hepatosplenomegaly, pancytopenia, hypertriglyceridaemia and silvery-greyish hair, suggesting the diagnosis of Griscelli syndrome (partial albinism with immunodeficiency). This diagnosis was confirmed by the characteristic agglomeration of melanin in the hair shaft and accumulation of melanosomes in melanocytes of the skin. The patient was homozygous for polymorphic markers around the myosin-Va gene on chromosome 15q21, which co-localize to the Griscelli disease locus. Natural-killer cells were in the lower range. The stimulation of lymphocytes with antigen and mitogen was normal. The patient's accelerated phase, characterized by haemophagocytosis was treated with prednisolone, rabbit anti-thymocyte globulins, and intrathecal methotrexate. Remission was maintained with cyclosporin A until HLA-compatible peripheral blood stem cell transplantation from her mother. Conclusion The silvery-greyish hair associated with fever, pancytopenia and hypertriglyceridaemia is the clue to early diagnosis of Griscelli syndrome and important to prevent death before stem cell transplantation. Received: 6 April 1999 / Accepted: 19 July 1999     

Epidemiology,risk factors,and prognosis of capillary leak syndrome in pediatric recipients of stem cell transplants: a retrospective single‐center cohort study

CLS involves sudden loss of intravascular fluids into the interstitial spaces. CLS was described as a possible complication after SCT. Few studies report the incidence of CLS in pediatric populations. We aimed to assess CLS incidence, its risk factors, and impact on the survival. The clinical charts of patients <18 years of age transplanted at our institution between 2002 and 2012 were reviewed. CLS was defined by weight gain >3% in 24 hours and positive intake balance despite furosemide administration. In total, 234 patients underwent 275 allogeneic SCT procedures in the analyzed time frame. Fifteen patients developed CLS (5.4%). The probability of developing CLS was significantly increased in patients suffering from sepsis (14.3% vs 0.6%, P<.001). Patients with CLS exhibited an increased risk of acute GvHD in the first 30 days after SCT (10.8% vs 1.8%, P=.002). Ten of the patients with CLS required intensive care. CLS strongly impacts OS at day +100 after SCT and is a predictive factor of TRM at the same date (42.9% vs 5%, P<.0001). The biological relation among sepsis, GvHD, and CLS development in terms of cytokine release and endothelial damage warrants further studies.     

减停免疫抑制剂诱发移植物抗宿主病治疗儿童ABO血型不合移植后纯红细胞再生障碍性贫血1例及文献复习

目的探讨ABO血型不合移植后合并纯红细胞再生障碍性贫血(PRCA)的发生机制及治疗对策。方法报道1例重型地中海贫血患儿接受ABO血型不合的无关供者外周血造血干细胞移植(URD-PBSCT)后合并PRCA病例并进行文献复习。结果患儿接受ABO血型不合的URD-PBSCT获得成功后出现PRCA,依赖红细胞输注伴ABO血型抗体滴度显著升高,通过减停免疫抑制剂诱发移植物抗宿主病(GVHD)后,ABO血型抗体滴度显著下降,网织红细胞、血红蛋白和骨髓象随之恢复正常。结论免疫紊乱及ABO血型抗体是ABO血型不合移植后PRCA的最可能原因,减停免疫抑制剂诱发GVHD是治疗ABO血型不合移植后PRCA的一种优先考虑的选择,但需要注意GVHD的有效控制。