Matched related donor hematopoietic stem cell transplantation results in a long‐term follow‐up of a pediatric acquired severe aplastic anemia subset: A stem cell source perspective

HSCT has substantially improved pediatric acquired SAA patients' outcomes. Retrospectively, we attempted to assess the outcome of MRD HSCT in 65 pediatric patients referred to a single center from 1992 to 2012. We were particularly interested to find out whether source of SC (PB, n = 40 and BM, n = 25) significantly impacts EFS and GVHD incidence. With a median follow‐up of 45 months, total EFS was 87.7%; EFS for PB and BM groups was 87.5% and 88%, respectively. Acute GVHD (grades 3–4) occurred in 13 patients (PB, n = 10 [25%] and BM, n = 3 [12%]), acute GVHD (grades 2–4) occurred in 24 (PB, n = 16 [40%] and BM, n = 8 [32%]). Extensive chronic GVHD occurred in five patients (PB, n = 3 [7.5%] and BM, n = 2 [8%]). Cox regression revealed that elapsed time of <10 months between diagnosis and HSCT is associated with improved survival (hazard ratio, 95% CI = 1.204, 1.010–1.434, p = 0.038). SC source did not significantly affect EFS, incidence of acute GVHD (grades 3–4), or extensive chronic GVHD (p = 0.938, 0.121, and 0.487, respectively). Based on our findings, pediatric acquired SAA patients are benefitted most if MRD‐HSCT is carried out early in disease process and SC source does not affect outcome of MRD‐HSCT in these patients.     

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.     

Favorable outcome with allogeneic hematopoietic stem cell transplantation in pediatric acquired aplastic anemia patients

The data of allogeneic HSCT in nine children with acquired AA between June 1998 and July 2006 were analyzed retrospectively. The median duration of time to neutrophil and platelet engraftment was 18 and 25 days, respectively. None of the patients had primary graft failure. Two (22.2%) patients developed acute GVHD and of these, one (11.1%) was Grade 1, and the other (11.1%) was Grade 3. Although the study group was composed of higher risk patients, including six of nine resistant to previous immunosuppressive treatment, eight had multiple not irradiated or filtered transfusion histories and one of the cases was only 5/6 HLA-compatible with his donor, the five-yr overall and EFS was 100%, and all recipients are alive without any graft failure. This may be attributed to the dose adjusted use of ATG according to individual transfusion history and gradual tapering of CsA and cessation at least nine months after allogeneic HSCT.     

异基因造血干细胞移植治疗儿童再生障碍性贫血临床分析

目的探讨异基因造血干细胞移植在儿童再生障碍性贫血治疗中的作用。方法10例再障患儿中,5例行HLA相合同胞供者异基因外周造血干细胞移植,3例行无关供者异基因外周造血干细胞移植,1例行无关供者骨髓移植,1例行脐血移植。结果1例接受脐血移植者未植活,其余9例均植入。中位植入时间14d（8～24d）,中性粒细胞〉0.5×10^9/L中位时间12d（8～19d）,血小板〉20×10^9/L中位时间17d（9～40d）。2例发生排斥,1例接受了第二次移植,1例移植后3个月血象开始自行恢复。结论如有HLA相合的同胞供者,异基因造血干细胞移植可作为儿童再障的一线治疗;临床重症感染无法控制的患儿,并非移植绝对反指征,相反可通过移植后的造血重建控制感染。     

Successful treatment of disseminated mixed invasive fungal infection after hematopoietic stem cell transplantation for severe aplastic anemia

Concomitant infections are frequent and usually the causes of death in patients with severe AA. HSCT can restore hematopoiesis in AA, but it is usually life threatening when patients simultaneously have an IFI. Mixed IFIs have been reported on rare occasions. The exact diagnosis of IFIs is difficult because of low fungus culture rate, difficultly obtaining tissue specimens in severely immunocompromised patients or those with bleeding tendencies. Otherwise, treatment with anti-fungal drugs alone for DMIFI was always lethal in previous reports. Surgical resection is crucial for invasive zygomycosis, but severe pancytopenia and bleeding tendency make therapy difficult. Herein, we report that with a combination of aggressive anti-fungal drugs, HSCT, and surgery, we successfully treated a 10-yr-old boy with severe AA and pulmonary zygomycosis before HSCT and disseminated mixed invasive zygomycosis and aspergillosis after HSCT.     

Fludarabine based reduced intensity conditioning regimens in children undergoing allogeneic stem cell transplantation for severe aplastic anemia

Fourteen children with a median age of 9.8 yr with SAA (10 males, four females) underwent related HLA identical allogeneic stem cell transplantation using Flu, Cy +/- ATG between 2004 and 2006. GVHD prophylaxis consisted of cyclosporine +/- mini methotrexate. Graft source included PBSCs (seven) or BM (seven). One patient expired <7 days post-transplant, while 12 (85.7%) patients engrafted with median neutrophil and platelet engraftment times of 13.8 and 14.5 days each. One patient had primary graft failure and expired on Day +27. Acute GVHD was seen in 25% of evaluable patients while limited chronic GVHD was seen in 33%. At a mean follow-up of 18 months, 12 patients (85.7%) are alive and well. Compared with a historical cohort of 12 children transplanted using Cy/ATG, there was faster engraftment (13.8 vs. 16.4 days; p = 0.002) with lower rejection rates (7.1 vs. 36.3%; p = 0.133) and improved event free (85.7 vs. 54.5%; p = 0.177) and overall survival (85.7 vs. 63.6%; p = 0.350). Flu with Cy +/- ATG reduces rejection and improves overall and event free survival in children with aplastic anemia.     

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.     

Related donor hematopoietic stem cell transplantation for Fanconi anemia without radiation: a single center experience in Turkey

Abstract:  Eight children with FA underwent allogeneic HSCT without using irradiation for the conditioning regimen. Patients received two different conditioning regimens: first two patients received BU 1.5 mg/kg/day for four days and CY 10 mg/kg/day for four days and the other regimen was: Flu 30 mg/m²/day for five days, CY 10 mg/kg/day for two days, and ATG-Fresenius 9–10 mg/kg/day for four days. GVHD prophylaxis consisted of CsA + MTX for the first two patients and only CsA for the others. All patients received HLA-identical stem cells from related donors. Primary engraftment was demonstrated in all patients. No patient developed acute GVHD and one patient had chronic GVHD. Only one patient who received BU based regimen died because of VOD. Overall, seven patients (87.5%) are alive with stable full donor chimerism at a median follow-up time of 2.5 yr (range: 1.7–8.9 yr). None of the patients developed secondary malignancy. Based on our data, we conclude that Flu-based, non-irradiation conditioning regimen was safe with low organ toxicity and stable engraftment in FA patients undergoing HSCT from matched related donors.     

Outcomes of pediatric living donor kidney transplantation: A single‐center experience

Renal transplantation is the treatment of choice for children with ESRD offering advantages of improved survival, growth potential, cognitive development, and quality of life. The aim of our study was to compare the outcomes of LDKT vs DDKT performed in children at a single center. Retrospective chart review of pediatric patients who underwent kidney transplantation from 2005 to 2014 was performed. Ninety‐one renal transplants were accomplished, and 31 cases (38.27%) were LDKT, and in 96.7% of the cases, the graft was obtained through laparoscopy. Thirty‐four receptors weighted <25 kg. LDKT group had statistically significant lower cold ischemia times than DDKT one. Complication rate was 9.67% for LDKT and 18.33% for DDKT. eGFR was better in LDKT. Patient survival rate was 100% for LDKT and 98.3% for DDKT, and graft survival rate was 96.7% for LDKT and 88.33%‐80% for DDKT at a year and 5 years. Our program of pediatric kidney transplantation has achieved optimal patient and graft survival rates with low rate of complications. Living donor pediatric kidney transplants have higher patient and better graft survival rates than deceased donor kidney transplants.     

Hematopoietic stem cell transplantation for Diamond-Blackfan anemia: a report from the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology

Transfusion-dependent Diamond-Blackfan anemia (DBA) patients opt for allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy. Clinical outcomes of 19 transplanted Japanese patients were analyzed. Prior to HSCT, 10 patients (53%) suffered hemosiderosis with organ dysfunction, and all eight with short stature (42%) had adverse effects of prednisolone. Median age at the time of HSCT was 56 months. Transplantation sources were 13 bone marrow [six human leukocyte antigen (HLA)-matched siblings, and six HLA-matched and one HLA-mismatched unrelated donors], five cord blood (two HLA-matched siblings and three HLA-mismatched unrelated donors), and one peripheral blood from haploidentical mother. All 13 patients with bone marrow transplantation (BMT) and two with sibling cord blood transplantation (CBT) had successful engraftment. Of three patients who underwent unrelated CBT, one died after engraftment, and the other two had graft failure but succeeded in a second BMT from an HLA-disparate father and unrelated donor, respectively. One died shortly after haploidentical PBSCT. The five-yr failure-free survival rate after BMT was higher than CBT (100%: 40%, p=0.002). Platelet recovery was slower in seven unrelated BMT than in six sibling BMT (p=0.030). No other factors were associated with engraftment and survival. These results suggest that allogeneic BMT, but not unrelated CBT, is an effective HSCT for refractory DBA.     

Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia

Pillai A, Hartford C, Wang C, Pei D, Yang J, Srinivasan A, Triplett B, Dallas M, Leung W. Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia.
Pediatr Transplantation 2011: 15: 628–634. © 2011 John Wiley & Sons A/S. Abstract: To assess whether a tolerance‐induction regimen could be applied for unrelated (MUD) HCT in SAA, we retrospectively reviewed our HCT experience using unmanipulated 10/10 HLA‐matched bone marrow grafts from MSD vs. MUD donors. Conditioning was CTX 200 mg/kg (CTX) + rabbit ATG 10 mg/kg (ATG) for MSD (n = 9) and TLI (800 cGy) + CTX/ATG for MUD HCT (n = 5). Immunoprophylaxis was CSA and short‐course MTX. Median patient age was 14.7 yr, median time to HCT 1.5 yr, and median follow‐up 3 yr. Outcome measures included EFS, time to engraftment, and cumulative incidence of GVHD (CIN of GVHD) for MSD and MUD cohorts. EFS and stable engraftment rate were 100%. CIN of acute GVHD was: MSD, Grade I–II: 1 (11%), Grade III–IV: 0%; MUD, Grade I–II: 1 (20%), Grade III–IV: 1 (20%). CIN of chronic GVHD was: MSD, limited: 1 (11%), extensive: 0%; MUD, limited: 0%, extensive: 0%. All immunosuppressive‐compliant patients successfully weaned immunosuppression. Although in limited patients, our results suggest that immunomodulatory TLI added to backbone CTX/ATG conditioning is a promising option for MUD HCT in SAA patients, which we will examine in a prospective clinical trial.     

Ibrutinib for the treatment of chronic graft‐vs‐host disease in pediatric hematopoietic stem cell transplant patients: A single‐center experience

cGVHD is a significant cause of morbidity and mortality after transplant. Ibrutinib has been studied as treatment for cGVHD in the adult population. Pediatric dosing and safety of ibrutinib are unknown. We conducted a retrospective review on the use of ibrutinib in 22 children with cGVHD at Cincinnati Children's Hospital Medical Center. All patients received a dose of 250 mg/m² orally, once daily. Responses were measured at 6 months after drug initiation using the 2014 NIH consensus panel response criteria. Twenty‐two patients of median age 13.5 years received ibrutinib. cGVHD grades were severe (n = 15), moderate (n = 6), and mild (n = 1). Eight patients stopped ibrutinib prior to 3 months due to adverse events or death and could not be evaluated for 6‐month response. Of the 14 evaluable patients, 12 achieved a partial response at 6 months and two patients had progressive disease. Seven evaluable patients with lung involvement had stable lung function at 6 months. One patient had EBV reactivation, and one patient developed pneumococcal sepsis despite appropriate prophylaxis while on ibrutinib therapy. No fungal infections occurred while on ibrutinib. Adverse events leading to discontinuation included recurrent fevers without a source, extensive bruising, oral bleeding, gastrointestinal distress, lower GI bleeding, dizziness, elevated transaminases, and pneumococcal sepsis. Ibrutinib administration of 250 mg/m² oral daily shows promising responses in pediatric cGVHD. Pediatric‐focused pharmacokinetic‐directed studies are needed to establish optimal dosing and define efficacy in children.     

Hematopoietic stem cell transplantation in pediatric patients with acute myeloid leukemia without favorable cytogenetics

Intensified chemotherapy, HSCT, and supportive care improve the survival of pediatric patients with AML. However, no consensus has been reached regarding the role of HSCT in patients without favorable cytogenetics. We evaluated OS and EFS according to prognostic factors that affect clinical outcomes, including cytogenetics risk group, conditioning regimen, donor type, disease status at the time of HSCT, and number of chemotherapy cycles prior to HSCT in 65 pediatric patients with AML without favorable cytogenetics who underwent HSCT. Fifteen of the 65 patients died: three of TRM and 12 of disease‐related mortality. The 5‐year OS and EFS were 78.0% and 72.0%, respectively, and the 5‐year cumulative relapse and TRM rates were 26.9% and 5.1%, respectively. Survival rates were not influenced by cytogenetic group (intermediated vs. poor), donor type (related vs. unrelated), transplant type (myeloablative vs. reduced‐intensity conditioning), or number of pretransplant chemotherapy cycles (≤3 vs. >3 cycles). The low TRM rate and encouraging outcomes suggest that HSCT may be a feasible treatment for pediatric patients with AML without favorable cytogenetics.     

Hematopoietic stem cell transplantation from non‐sibling matched family donors for patients with thalassemia major in Jordan

There are limited data on the outcome of patients with thalassemia receiving HSCT from non‐sibling matched family donors. Of the 341 patients with thalassemia major that underwent donor search at our center from January 2003 to December 2011, 236 (69.2%) had fully matched family donor of which 28 patients (8.2%) had non‐sibling matched family donors identified. We report on seven patients with a median age of eight yr (4–21) who underwent myeloablative (n = 4) or RIC (n = 3) HSCT. The median age of the donors was 33 yr (4–47), three were parents, two first cousins, one paternal uncle, and one paternal aunt. All patients achieved primary neutrophil and platelet engraftment at a median of 18 (13–20) and 16 days (11–20), respectively. One patient developed grade II acute GVHD, and two patients developed limited chronic GVHD. One patient experienced secondary GF requiring a second transplant. At a median follow‐up of 69 months (7–110), all patients are alive and thalassemia free. Our data emphasize the need for extended family HLA typing for patients with thalassemia major in regions where there is high rate of consanguinity. Transplant from non‐sibling matched family donor can result in excellent outcome.     

Hematopoietic stem cell transplantation for children with primary immunodeficiency diseases: Single center experience in Jordan

HSCT can be curative for many PID. Little is known about the outcome of HSCT for patients with PID in the developing countries. We retrospectively reviewed all children with PID who received HSCT at KHCC in Jordan between August 2003 and October 2011. Twenty‐eight patients were identified. The median age was 16 months (3 months–17 yr). Patients' diagnoses were SCID (n = 16), CHS (n = 3), HLH (n = 3), WAS (n = 2), Griscelli syndrome (n = 1), ALPS (n = 1), Omenn's syndrome (n = 1), and DiGeorge syndrome (n = 1). Seventeen patients received HLA‐matched related HSCT, eight received maternal un‐manipulated haploidentical HSCT, and three received unrelated cord blood transplantation. Nine patients (32%) developed BCGosis secondary to reactivation of pretransplant vaccination. Three died while still receiving anti‐tuberculosis drugs, one still on treatment, and all others have recovered. Six patients had graft failure; four of them received no conditioning regimens. At a median follow up of 32 months (range 1‐67), 21 patients are alive, with overall survival of 72%. We conclude that HSCT for PID patients can be performed with a good outcome in developing countries; however, delayed diagnosis or referral and BCG reactivation are unique challenges.     

Long‐term outcome of pediatric kidney transplantation: A single‐center experience from Greece

Pediatric kidney Tx has critically altered the outcome in ESRD pediatric patients. The aims of this study were to determine long‐term graft and patient survival in a homogeneous ethnic population. We reviewed the medical charts of pediatric kidney Tx performed between 1990 and 2012 in Greece. Seventy‐five kidney Txs were performed from LRD and 62 from DD. The 10‐ and 20‐yr graft survival was higher in LRD Tx compared with DD Tx. Both patient and graft survival at 10 and 20 yr after Tx were similar in LRD Tx from grandparents compared with parents (92.9% vs. 93.4% 20‐yr patient survival, 71.4% vs. 78.7% and 57.1% vs. 72.1%, 10‐ and 20‐yr graft survival, respectively). However, there was a decreasing tendency in LRD Tx rates in period 2001–2012 compared with period 1990–2000 (47.1% vs. 62.7%). Risk factors for poor five‐yr graft survival were DD Tx, and induction treatment with ALG compared with basiliximab, but their effect attenuated at 10 yr after Tx. In conclusion, Tx from LRD may offer efficient survival outcomes irrespective of donor age, suggesting that even older LRD could be an excellent option for the 1st kidney Tx in children and adolescents.     

T‐cell‐rich HLA‐haploidentical hematopoietic stem cell transplantation for relapsed/refractory pediatric Philadelphia chromosome‐positive acute lymphoblastic leukemia without posttransplant tyrosine kinase inhibitor therapy

Intensive chemotherapy with tyrosine kinase inhibitor (TKI) improves the prognosis of patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph‐ALL). However, the prognosis of cases of relapsed or refractory Ph‐ALL remains poor. Here, we aimed to assess the efficacy of T‐cell‐rich HLA‐haploidentical hematopoietic stem cell transplantation (TCR‐haplo‐HSCT) in eight patients with relapsed or refractory pediatric Ph‐ALL. Transplant‐related mortality was observed in two patients. All patients discontinued TKI after receiving TCR‐haplo‐HSCT. The 3‐year probability of overall survival and event‐free survival was 75.0 and 62.5%, respectively. These results indicate the efficacy of TCR‐haplo‐HSCT for relapsed/refractory pediatric Ph‐ALL.