Changing outcomes for children requiring intensive care following hematopoietic stem cell transplantation

Past literature has shown that respiratory failure following hematopoietic stem cell transplant is associated with a universally poor outcome with mortality rates approaching 100%. More recent studies have suggested that patient survival is improving. We report our experience with the patients from our institution, a large children's hospital, who were admitted to the intensive care unit (ICU). Medical records of 183 patients, who received a bone marrow transplant between 1992 and early 2004, who were <20 yr of age, were retrospectively reviewed. Various factors that might influence mortality were examined. Over the course of the study, the ICU survival increased from 18% during the period 1992-1999 to 59% between 2000 and early 2004. In the latter period, 54% of the patients discharged from the ICU were alive at 100 days post-transplant. Factors that were significant predictors of poor outcome were malignancy as the reason for transplant, dialysis during the ICU stay, or extreme respiratory failure with a ratio of arterial oxygen tension (PaO2)/inspired oxygen concentration (FiO2) <300. Analysis of patients who required a high positive end-expiratory pressure or were ventilated with permissive hypercapnia showed that they also had a higher mortality. The impact on survival of factors such as age at time of transplant, graft-vs.-host disease, pneumonia, bacteremia, sepsis, post-transplant days, Pediatric Risk of Mortality III score, engraftment status, or veno-occlusive disease did not reach statistical significance in this cohort. Survival has improved for children who require intensive care following a bone marrow transplant, even for those who require mechanical ventilation. Patients with extreme respiratory failure and those requiring dialysis continue to have poor outcome. Because of an overall improvement in survival, children whose condition following transplant requires intensive care should be treated aggressively.     

Haploidentical hematopoietic stem cell transplantation with post‐transplant high‐dose cyclophosphamide in high‐risk children: A single‐center study

Recently, haploidentical transplantations have been performed with unmanipulated BM or PBSC. This approach is becoming more widely adopted with the use of PTCY. However, there is limited evidence about this approach in children. We present 15 children who received 16 haploidentical HSCT with unmanipulated BM or PBSC using PTCY for GVHD prophylaxis. Post‐transplant CY(50 mg/kg IV) was given on the third and fifth day, and CsA or tacrolimus with MMF or MP was also used for GVHD prophylaxis. All patients engrafted at a median of 16 and 18 days for neutrophil and thrombocyte recovery, respectively. Grades II–III acute GVHD developed in seven patients, and mild chronic GVHD was found in two patients. Two patients died within the first 100 days due to sepsis (TRM 12.5%). Eleven patients are currently alive, with a median follow‐up of 12 months (range 6–22 months). The 12‐month OS and DFS were 75 ± 10.8% and 68.8 ± 11.6%, respectively. Our results with these high‐risk patients are encouraging for haploidentical HSCT in pediatric patients. Future studies should continue to assess haploidentical HSCT, including comparison of other modalities, in a primary pediatric population.     

Cytomegalovirus infection in children who underwent hematopoietic stem cell transplantation at a single center: A retrospective study of the risk factors

Abstract:  CMV infection is one of the major causes of morbidity and mortality after HSCT. The aim of this single center retrospective study was to analyze risk factors for CMV infection in pediatric patients who underwent HSCT. We retrospectively reviewed the medical records of 117 pediatric patients who underwent allogeneic HSCT at Asan Medical Center between December 2000 and January 2007. After HSCT, CMV antigenemia was detected by identifying CMV pp65 early antigen in white blood cells. The incidence of CMV antigenemia was 24% (28/117) at a median of 38 days (range: 19–123 days) after HSCT. In multivariate analysis, CMV antigenemia occurred significantly more often in CMV seropositive recipients, patients who received grafts from alternative donors, T-cell depleted grafts, patients on ATG-containing conditioning regimens, or patients who received steroid for acute GVHD (p < 0.05). CMV antigenemia tend to develop earlier in patients who received ATG-containing conditioning regimens (p = 0.09). A second episode of CMV antigenemia was observed in three out of 28 patients (11%). The incidence of CMV disease was 5.9% (7/117) at a median of 97 days (range: 34–120 days). Manifestation of CMV disease included retinitis in two, pneumonitis in two, hepatitis in one, hepatitis with colitis in one, and gastritis in one. Six of the 12 patients (50%) with HG antigenemia (CMV pp65 antigen positivity ≥40 cells) developed clinical CMV disease, a rate that was significantly higher than seen in patients with LG antigenemia (6.25%; p < 0.01). We recommend that patients with these risk factors should carefully undergo regular evaluations for CMV infection. We also suggest that earlier and more aggressive preemptive treatment and serial follow-up of CMV disease is necessary in patients with HG-antigenemia.     

儿童造血干细胞移植后巨细胞病毒感染的临床研究

目的了解儿童造血干细胞移植后巨细胞病毒的感染率和防治方法。方法对从2001年8月到2007年3月北京儿童医院血液病中心37例作造血干细胞移植的血液肿瘤及先天遗传性疾病患儿进行回顾性分析。结果31例可研究病例中,5例自体造血干细胞移植及5例同基因造血干细胞移植患儿无人类巨细胞病毒（HCMV）感染,21例异基因造血干细胞移植患儿,发生HCMV感染7例,感染率为33.3%,大剂量阿昔洛韦加丙种球蛋白预防及早期更昔洛韦加大剂量静脉丙种球蛋白治疗,仅1例发生巨细胞病毒相关性间质性肺炎（CMV-IP）,无1例发生巨细胞病毒感染相关死亡。结论巨细胞病毒感染是儿童造血干细胞移植术后的主要并发症,临床上进行定期监测、前瞻性预防、早期诊断和及时合理治疗,对降低移植术后巨细胞病毒感染和提高移植成功率至关重要。     

Hematopoietic stem cell transplantation in CD40 ligand deficiency: A single‐center experience

Deficiency of the CD40L, expressed on the surface of T lymphocytes, is caused by mutations in the glycoprotein CD40L (CD154) gene. Resulting defective humoral and cellular responses cause a clinical presentation that includes recurrent sinopulmonary bacterial infections, opportunistic infections, sclerosing cholangitis, neutropenia, and autoimmune manifestations. HSCT represents the only curative treatment modality. However, the therapeutic decision to use HSCT proves challenging in many cases, mainly due to the lack of a phenotype‐genotype correlation. We retrospectively reviewed patients with CD40L deficiency who were transplanted in Antalya and Göztepe MedicalPark Pediatric HSCT units from 2014 to 2019 and followed by Akdeniz University School of Medicine Department of Pediatric Immunology. The records of eight male cases, including one set of twins, were evaluated retrospectively. As two transplants each were performed on the twins, a total of ten transplants were evaluated. Conditioning regimens were predominantly based on myeloablative protocols, except for the twins, who received a non‐myeloablative regimen for their first transplantation. Median neutrophil and platelet engraftment days were 13 (range 10‐19) and 14 (range 10‐42) days, respectively. In seven of ten transplants, a CMV reactivation was developed without morbidity. None of the patients developed GVHD, except for one mild case of acute GVHD. All patients survived, and the median follow‐up was 852 days. Our data show that HSCT for patients with CD40 ligand deficiency is a potentially effective treatment for long‐term disease control.     

Transplant‐related mortality and survival in children with malignancies treated with allogeneic hematopoietic stem cell transplantation. A multicenter analysis

The aim of the study was to assess the risk of TRM in pediatric patients treated for malignant disorders with allogeneic HSCT, according to different risk factors. The treatment outcome was analyzed in 299 pediatric patients treated in pediatric transplant departments from 2006 to 2015. To compare the outcome, patients were analyzed all together and in groups according to the diagnosis, age at transplant, donor type, disease status, stem cell source, and pediatric TRM score. At the end of the observation time, 82 patients were alive, 82 died, of which 40 due to transplant‐related reasons. The most frequently observed causes of TRM were toxic complications effecting with organ failure (38%), followed by infections (26%), PTLD (14.3%), and GvHD (16.7%). There was no statistical difference in the incidence of TRM depending on stem cell source (P = .209) and primary diagnosis (P = .301). According to TRM score, TRM was significantly higher in high‐risk group (P = .006). High‐risk patients had lower survival comparing to low/intermediate group (P = .0001). OS did not differ between ALL, AML, and MDS/JMML groups. The study confirmed the utility of factors included in TRM score stratification in assessing the risk of transplant procedure in pediatric patients transplanted for malignancies.     

Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita

DC is an inherited bone marrow failure syndrome mainly characterized by nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Bone marrow failure is the most common cause of death in patients with DC. Because previous results of HSCT with a myeloablative regimen were disappointing, we used a reduced-intensity conditioning regimen for two patients with classic DC, and one patient with cryptic DC who harbored the TERT mutation. Graft sources included two mismatched-related bone marrow (BM) donors and one unrelated BM donor. Successful engraftment was achieved with few regimen-related toxicities in all patients. They were alive 10, 66, and 72 months after transplantation, respectively. Long-term follow-up is crucial to determine the late effects of our conditioning regimen.     

儿童异基因造血干细胞移植后淋巴细胞增殖性疾病的临床研究

目的探讨儿童异基因造血干细胞移植（allo-HSCT）后淋巴细胞增殖性疾病（PTLD）的诊治及预后。方法回顾性分析4例allo-HSCT后EBV相关性PTLD（EBV．PTLD）患儿的临床资料。其中,急性淋巴细胞白血病（高危）（ALL—HR）2例,重型再生障碍性贫血（SAA）2例。异基因外周血造血干细胞移植（allo-PBSCT）3例,异基因脐血造血干细胞移植（allo-UCBSCT）1例。结果4例患儿分别于allo．HSCT后第53、101、22、42d发生PTLD。临床表现为发热、鼻塞、扁桃体肿大、淋巴结肿大和肝脾肿大,移植前均EBNA-1-IgG（＋）、VCA．IgG（＋）;移植后EBV．DNA1．69×10^4～8．62×10^8 copies／mL。经淋巴结病理活检确诊为EBV-PTLD,其中1例为T细胞来源,3例为B细胞来源。例1予减停免疫抑制剂、使用利妥昔单抗、联合COP方案化疗及供者淋巴细胞输注（DU）治疗,PTLD反复且发生严重皮肤GVHD、肺部感染,移植后第193d死亡。余3例予减停免疫抑制剂及利妥昔单抗治疗,临床表现消失且EBV．DNA转阴,分别随访17、12、7个月均无病存活。结论动态监测EBV—DNA对PTLD早期发现具有重要意义。减停免疫抑制剂联合利妥昔单抗治疗EBV-PTLD疗效明显。化疗可导致严重感染,DLI治疗存在严重GVHD危险,不宜作为一线治疗。     

Hematopoietic stem cell transplantation without in vivo T‐cell depletion for pediatric aplastic anemia: A single‐center experience

For young patients, HLA‐MRD HSCT is the first‐line treatment of SAA. However, due to China's birth control policy, few patients could find suitable sibling donors and HLA‐MUD. More and more transplantation centers have used Haplo‐D as the donor source for young adult and pediatric patients. However, studies with larger amount of pediatric patients are rare. We retrospectively analyzed the data of children with AA who were treated with allogeneic HSCT and compared the therapeutic efficacy of Haplo‐HSCT and MRD/MUD group. A total of 62 patients were enrolled. Implantation was successfully performed in 58 patients. There was no significant difference in the time for reconstruction of hematopoietic function between patients in the two groups. Thirty‐two had grade I‐IV aGVHD with incidence of 51.61%. The incidence of aGVHD was 79.41% for patients in the Haplo‐HSCT, significantly higher than that of 17.86% for patients in the MRD/MUD group (P < .01). However, the incidence of cGVHD was not significantly different between patients in the two groups (26.47% vs 10.71%, P = .09), the incidence of CMV infection was 28.57% and 52.94% for patients in the MRD/MUD and Haplo group, respectively, showing no significant difference (P = .053). The incidence of EBV infection was 47.06% for patients in the Haplo group and 28.57% for patients in the MRD/MUD group, showing no significant difference (P = .11). However, the 3‐ and 5‐year cumulative OS and FFS rates showed statistically significant difference in the two groups, P = .012 and .045, respectively. Compared to Haplo‐HSCT, MRD/MUD is more economic. In this study, we achieved good Haplo transplantation results. The incidences of cGVHD and CMV/EBV were not significantly different between Haplo group and MRD/MUD group. Although OS and FFS of the Haplo group were not as good as those of the MRD/MUD group, it is still acceptable as an alternative treatment under emergency.     

Bullous pemphigoid after allogeneic hematopoietic stem cell transplantation

Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by subepidermal blisters due to deposit of autoantibody against dermal basement membrane protein. It has been reported that BP can occur after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a patient with BP having autoantibody against BP180 after unrelated‐donor HSCT against T lymphoblastic leukemia. The patient was treated with steroid leading to complete resolution of BP, but T lymphoblastic leukemia progressed rapidly after steroid hormone treatment. Given that immunosuppressant may reduce graft‐versus‐tumor effect, immunomodulatory agents such as nicotinamide and tetracycline, erythromycin, and immunoglobulin may be appropriate as soon as typical blister lesions are seen after HSCT.     

异基因造血干细胞移植并发致死性间质性肺炎

目的探讨小儿异基因造血于细胞移植并发间质性肺炎（IP）的发病病因、临床特点、危险因素及防治措施。方法根据尸解病理检查及聚合酶键反应技术对病毒病原学检测结果，结合临床移植资料综合分析。结果14例移植患儿中并发IP3例（3／14），分别死于十19天、＋76天、＋150天;3例IP中2例移植前后外周血及尸解肺组织直到CMV包涵体;4例3～4应急性GVHD患儿中3例并发IP，10例0～2度急性GVHD无1例并发IP。结论IP是移植早期死亡的重要原因之一，巨细胞病毒感染是IP的主要病原，GVHD严重程度与移植后并发IP密切相关.     

Non‐sibling hematopoietic stem cell transplantation using myeloablative conditioning regimen in children with Maroteaux‐Lamy syndrome: A brief report

Maroteaux‐Lamy syndrome is a rare inherited lysosomal storage disorder with a progressive course. HSCT is a curable option for treatment in these patients. The following report describes our experience in HSCT for three patients with Maroteaux‐Lamy syndrome using non‐sibling donors. All of the patients received the same myeloablative regimen consisting of intravenous busulfan, cyclophosphamide, and rabbit antithymocyte globulin. Patients underwent HSCT from haploidentical other‐related (n=1), full‐matched other‐related (n=1), and one‐locus‐mismatched unrelated donor. Stem cell sources included bone marrow (n=1), peripheral blood (n=1), and cord blood (n=1). Currently, two patients who received transplant from other‐related donors showed full engraftment and regression of the symptoms of the disease, while for the patient with unrelated cord blood donor, graft failure resulted in progression of the disease and death. The result of our study showed beneficial effects of HSCT even from heterozygote donor. Due to rarity of the disease, future multicenter studies are recommended to find the best treatment approaches based on the patients’ status.     

Home care during neutropenia after allogeneic hematopoietic stem cell transplantation in children and adolescents is safe and may be more advantageous than isolation in hospital

After ASCT, children are isolated in hospital to prevent neutropenic infections. Patients living within two‐h drive from the hospital were given the option of treatment at home after ASCT. Daily visits by an experienced nurse and phone calls from a physician from the unit were included in the protocol. We compared 29 children and adolescents treated at home with 58 matched hospital controls. The children spent a median time of 13 days at home (range 2–24 days) and 6 (0–35) days in hospital. The cumulative incidence of acute GVHD grades II–IV was 21% in the home‐care children and 39% in the controls (p = 0.1). Chronic GVHD and probability of relapse were similar in the two groups. TRM at five yr was 11% in the home‐care patients and 18% in the controls. Overall survival at three yr was 77% and 62%, respectively (p = 0.33). None of the patients died at home. Median costs were 38 748 euros in the home‐care patients and 49 282 euros in those treated in the hospital (p = 0.2). We conclude that it is safe for children and adolescents to be treated at home during the pancytopenic phase after ASCT.     

Idiopathic hyperammonemia after hematopoietic stem cell transplantation: A case report

IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT. We describe a case of a patient with FA that developed acute idiopathic hyperammonemia after the preparative regimen for HSCT.