Unrelated cord blood transplantation in children with severe congenital neutropenia

Abstract:  SCN is an inherited hematological disorder with severe neutropenia and recurrent infections. Although there are some reports that recombinant rhG-CSF improves clinical outcome, allogeneic HSCT appears to be the only curative treatment for these patients. We report here two children with SCN successfully treated by CBT from unrelated donors. They were refractory to rhG-CSF treatment and have no identical family donor. Bu + CY were given as conditioning. Case 1 and Case 2 received 6/6 and 5/6 HLA-matched unrelated umbilical cord blood, respectively. The number of infused nucleated cells was 6, 18 × 10⁷/kg and CD34⁺  cell number was 3, 74 × 10⁵/kg in Case 1. Those cell numbers were 8, 8 × 10⁷/kg and 5, 34 × 10⁵/kg for Case 2, respectively. Neutrophil/platelet engraftments were 45/49 days in Case 1 and 24/36 days in Case 2. Grade II cutaneous acute GVHD was seen in Case 2 that was treated successfully with prednisolone. Both patients are well with normal hematological findings and full donor chimerism for post-transplant 20 and 24 months, respectively. We conclude that UCB can be considered as a safe source of stem cell in patients with SCN who need urgent HSCT.     

Non-myeloablative transplantation for severe congenital neutropenia

Severe Congenital Neutropenia is a rare condition characterized by a very low neutrophil count, which pre-disposes the affected child to recurrent bacterial infections. Treatment with granulocyte colony stimulating factor (G-CSF) has dramatically improved the prognosis of these children; but in patients who have become G-CSF refractory, hematopoeitic stem cell transplant is still the only effective curative treatment. We describe a patient who was unresponsive to escalating doses of G-CSF and underwent a successful reduced intensity conditioning, matched unrelated donor allograft resulting in cure.     

Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: An analysis of 18 Japanese cases

Oshima K, Hanada R, Kobayashi R, Kato K, Nagatoshi Y, Tabuchi K, Kato S; for the Hematopoietic Stem Cell Transplantation Committee of the Japanese Society of Pediatric Hematology. Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: An analysis of 18 Japanese cases.
Pediatr Transplantation 2010: 14:657–663. © 2010 John Wiley & Sons A/S. Abstract: We studied the outcome of allogeneic HSCT in patients with SCN. Between 1989 and 2005, 18 patients with SCN in Japan received HSCT for reasons other than malignant transformation, i.e., because of the lack of or a partial response to treatment with r‐HuG‐CSF. The median age of the patients at the first HSCT was three and a half yr (range 0.2–16.7 yr). Nine patients received stem cells from an HLA‐identical sibling donor and nine from an alternative donor. Twelve and six patients received myeloablative and non‐myeloablative conditioning regimens, respectively. Engraftment occurred at the first HSCT in 12 patients, four patients received a second HSCT for graft failure, and two patients died. The cause of death was renal failure and graft failure at the first and second HSCT, respectively. The cumulative incidence of grade II–IV acute GVHD and TRM at the first transplantation was 11% and 5.6%, respectively. Of our patients, 16 are alive and in complete remission, with a median follow‐up of six and a half yr. Our results suggest that HSCT is beneficial for patients with SCN refractory to r‐HuG‐CSF treatment.     

Unrelated donor cord blood transplantation for childhood severe aplastic anemia after a modified conditioning

Treatment of severe aplastic anemia (SAA) patients who lack human leukocyte antigen (HLA)-matched donors and failed immunosuppressive therapy (IST) is challenging. Recently, umbilical cord blood transplantation (CBT) after non-myeloablative therapy has been reported in adult but not in childhood SAA. However, most cases resulted in mixed donor chimerism and incomplete hematological recovery. We reported an 11-yr-old girl with recurred SAA 5 yr after IST who underwent unrelated donor CBT after a modified regimen. This patient had renal and cardiac dysfunction, and lacked suitable bone marrow donors. The 3.9 x 10(7)/kg CB cells from an HLA one-locus mismatched unrelated donor were infused after conditioning with total body irradiation (5 Gy), melphalan (120 mg/m(2)), and fludarabin (120 mg/m(2)). Hematological recovery was favorable in complete chimerism. A major complication was only skin graft-versus-host disease (grade I). CB could be an alternate stem cell source for childhood SAA after modified preparative regimen.     

Successful long‐term hematological and immunological reconstitution by autologous cord blood transplantation combined with post‐transplant immunosuppression in two children with severe aplastic anemia

aUCBT is a valuable curative option in pediatric patients with refractory idiopathic SAA and no available matched sibling or unrelated donors. Experience in the use of autologous cord blood units in patients with SAA is limited and private for‐profit cord blood‐banking programs are controversial. We report the successful treatment of two patients with SAA, aged 15 and 24 months, with autologous cord blood combined with immunosuppression. After conditioning with 200 mg/kg cyclophosphamide and ATG, 7.5 mg/kg, 32.2 × 10⁷/kg, and 3.8 × 10⁷/kg autologous cord blood nucleated cells were infused, respectively. One of our patients underwent transplantation after failure of IST. Both patients received post‐transplant immunosuppression with cyclosporine for 12 months. They remain disease‐free 6 years post‐transplantation.     

Unrelated cord blood transplantation in children with sickle cell disease: review of four-center experience

UCBT was performed in seven children with SCD and stroke (HLA match 4/6 n=5; 5/6 n=2). Four received myeloablative regimens (BU, CY, ATG plus FLU in one patient). One had primary graft failure, three had sustained engraftment, two with grade III-IV GVHD (one died, one developed chronic GVHD), one with stable mixed chimerism. Three patients treated with reduced-intensity regimens (FLU, BU or CY, ATG, TLI) failed to engraft; one engrafted after second UCBT (HU, TT, RXA, ALZ, TBI). Four patients (57%) developed viral infections. Engraftment, GVHD, and infection remain challenges.     

非血缘相关脐血移植治疗儿童高危白血病的临床观察

目的：非血缘脐血具有快速寻求、容易得到和HLA配型不严格的特点，该文进行了非血缘相关脐血移植（UD-UCBT）治疗儿童恶性白血病的研究并探讨其疗效问题。方法：对6例难治性白血病患儿，包括3例急性淋巴细胞白血病（2例高危CR1，1例标危CR2），2例幼年慢性粒单细胞白血病（1例缓解期，1例加速期）和1例急性髓系白血病（AML- M5，CR1）进行了非血缘相关脐血移植，HLA高分辨1例全相合，1例5个位点相合，1例4个位点相合，3例3个位点相合。预处理选用白消安/环磷酰胺/ATG或全身放疗/环磷酰胺/ATG为主方案。于 0 d 回输脐血，有核细胞中位数为8.51×107/kg，CD34+细胞中位数为1.81×105/kg。预防移植物抗宿主病（GVHD）采用环孢霉素A、甲基泼尼松龙和骁悉或CD25单抗。结果：中性粒细胞绝对值（ANC）≥0.5×109/L和PLT≥20×109/L的中位天数分别是+13 d、+30 d，移植证据均为供者型。4例出现Ⅰ~Ⅲ度GVHD，均控制。随访中位时间12个月，未发生慢性GVHD，现存活4例血型均转为供者型，无复发。结论：脐血提供快速有效的造血干细胞，为治疗儿童白血病提供良好时机，非血缘相关脐血移植能耐受HLA多个位点不相合。急性GVHD发生率也较高，存在移植物抗白血病作用。     

Reduced‐intensity conditioning umbilical cord blood transplantation in Nijmegen breakage syndrome

NBS is a rare autosomal recessive congenital disorder associated with chromosome instability caused by a mutation in the NBN gene (8q21). Clinical manifestations include microcephaly, growth retardation, combined immunodeficiency, and a strong predisposition to develop (mainly lymphatic) malignancies. There is no specific treatment for patients with NBS, and the prognosis is generally poor. The therapeutic option for some patients with NBS may be HSCT. We present a case of safe and successful non‐myeloablative UCB transplantation in the 19th month of the life of a female child with NBS concomitant with SCID.     

严重先天性中性粒细胞减少症2 例报告及文献复习

目的探讨罕见的严重先天性中性粒细胞减少症的临床及基因突变特点。方法回顾分析2例经基因检测确诊为严重先天性中性粒细胞减少患儿的临床资料,并复习相关文献。结果男女各1例,均有反复感染病史。男孩,1岁9个月,中性粒细胞绝对计数(ANC)最低0.17×10~9/L,伴有发育异常,全外显子基因检测示VPS13B基因杂合突变,Exon47,c.8531delG(p.Ser2844fs)移码突变,来自父亲;Intron 38(c.6940+1GT)内含子突变,来自母亲,结合临床确诊Cohen综合征。女孩,2岁,ANC长期波动在0.4×10~9/L左右,全外显子基因检测示CSF3R基因杂合突变,Intron3,c.64+5GA内含子突变,来自父亲;Exon7,c.690delC(p.Met231Cysfs*32)移码突变,来自母亲,结合临床考虑为严重先天性粒细胞减少症7型(SCN7)。女性患儿对粒细胞集落刺激因子(G-GSF)治疗无效,改用粒细胞巨噬细胞集落刺激因子(GM-CSF)有效。结论严重先天性中性粒细胞减少可导致严重或反复感染,为某类综合征的特征表现,部分可向骨髓增生异常综合征或急性髓细胞性白血病转变,需长期随访及治疗,基因检测有助诊断。     

Second transplant with two unrelated cord blood units for early graft failure after cord blood transplantation for thalassemia

Abstract:  Early GF is a frequent complication following hematopoietic stem cell transplantation for patients with thalassemia. We report the outcome of double-unit CBT in three patients who developed early GF after CBT. The initial conditioning regimen consisted of i.v. Bu 14 mg/kg (day −9 to −6), i.v. Cy 200 mg/kg (day −5 to −2) and ATG at 120 mg/kg (day −4 to −1). They received GVHD prophylaxis with cyclosporine-A from day −3 and a short course of methylprednisolone (1 mg/kg i.v., every 12 h on days 5–19 with a taper, thereafter 25% decrease every other day). The interval between two transplants was seven and 10 months. The retransplant recipients were preconditioned with i.v. Bu 14 mg/kg (day −7 to −4), i.v. Cy 120 mg/kg (day –3 to –2) and ATG at 150 mg/kg (day −5 to −1 and +1 to +5). GVHD prophylaxis regimen was the same as the first transplant. Neutrophil engraftment were observed in all patients between day +15 and +26. All are alive, between nine and 11 months after retransplant. Our group reported successful utilization of double umblical cord blood grafts in thalassemia patients with early GF.     

Kostmann syndrome or infantile genetic agranulocytosis, part one: celebrating 50 years of clinical and basic research on severe congenital neutropenia

Congenital neutropenia in man was first reported 50 years ago by the Swedish paediatrician Rolf Kostmann. He coined the term “infantile genetic agranulocytosis” for this condition, which is now known as Kostmann syndrome. Recent studies have demonstrated a lack of antibacterial peptides and severe periodontitis in these patients despite recombinant growth factor treatment. Moreover, an increased degree of apoptosis of myeloid progenitor cells in the bone marrow has been shown.

Conclusion: Future studies should aim to clarify the underlying molecular genetic defect in Kostmann syndrome.     

Lymphadenopathy as the primary manifestation of malignant transformation in two patients with severe congenital neutropenia

We present the cases of two patients with severe congenital neutropenia (SCN) who both developed generalized adenopathy. Although both had recent histories that placed infection high on the differential of causes for the adenopathy, biopsies demonstrated acute myeloid leukemia (AML) as the etiology. The risk of malignant transformation in SCN is known to be significantly elevated, and these cases illustrate the need for physicians of such patients to keep myelodysplastic syndrome (MDS) and AML high on the differential when patients manifest atypical symptoms.     

Hematopoietic cell transplantation with autologous cord blood in patients with severe aplastic anemia: an opportunity to revisit the controversy regarding cord blood banking for private use

The controversy surrounding private banking of umbilical cord blood units (CBU), as a safeguard against future malignancy or other life-threatening conditions, raises many questions in pediatric clinical practice. Recent favorable experiences with autologous transplantation for severe aplastic anemia using privately stored CBU, suggested a possible utility. While private banking is difficult to justify statistically or empirically, there may exist rare cases where autologous transplant of stored umbilical CBU could be beneficial. The reality of privately banked CBU and the possibility for future discovery of additional indications for autologous cord blood transplant, motivated us to re-examine our attitudes towards private cord blood banking.     

Successful unrelated umbilical cord blood cell transplantation without conditioning for a neonate with severe combined immunodeficiency

Taga T, Itoh E, Noda Y, Kato H, Maruo Y, Takano T, Ohta S, Takeuchi Y, Kumaki S. Successful unrelated umbilical cord blood cell transplantation without conditioning for a neonate with severe combined immunodeficiency.
Pediatr Transplantation 2011: 15: E152–E155. © 2010 John Wiley & Sons A/S. Abstract: A neonate was diagnosed as having SCID from his umbilical cord blood cells immediately after birth because his older brother had died of SCID eight months earlier. One locus‐mismatched unrelated umbilical cord blood cell transplantation without conditioning was performed at the age of 30 days. The CD3‐positive cells were detected on day 14 post‐transplantation. There were no peri‐transplantation complications. Four yr after transplantation, the boy is in excellent condition and T and NK cell engraftments are complete. His peripheral B cells with a common gamma chain were not detected by flow cytometry, and he still needs IgG replacement; however, his IgM and IgA levels have gradually increased, and the dosage of IVIG per body weight has gradually decreased. We speculate that the very few B cells that proliferate from transplanted cord blood cells produce gamma globulin. Unrelated cord blood cell transplantation, even though mismatched, without conditioning would be a treatment option for neonates with severe combined immunodeficiency.     

Kostmann syndrome or infantile genetic agranulocytosis, part two: Understanding the underlying genetic defects in severe congenital neutropenia

Congenital neutropenia in man was first reported 50 years ago by the Swedish paediatrician Rolf Kostmann. He coined the term 'infantile genetic agranulocytosis' for this condition, which is now known as Kostmann syndrome. Recent studies have revealed mutations in ELA-2, encoding the neutrophil granule protease, neutrophil elastase, in autosomal dominant neutropenia, and mutations in HAX-1, encoding an anti-apoptotic protein, in autosomal recessive neutropenia. Conclusion: Future studies should aim to clarify the mechanisms underlying the evolution of secondary malignancies in these patients.     

Unrelated umbilical cord blood transplantation and unrelated bone marrow transplantation in children with hematological disease: A meta-analysis

Abstract:  UCB has been used as an alternative source of HSC. Both unrelated donor BM and UCB are available as potential options for transplantation. However, there have been limited comparisons of the outcomes of unrelated donor UCBT vs. UBMT in the unrelated setting. Our aim is to observe the therapeutic efficacy of UCBT and UBMT for treatment of pediatric hematological diseases. We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and critically appraised all relevant articles (1989.1–2008.5). Comparative studies were carried out on clinical therapeutic effect of UCBT and UBMT with research on stem cells engraftment, complications, earlier mortality, and survival rate. We performed a meta-analysis using review manager 5.0 software (RevMan, The Nordic Cochrane Center, The Cochrane Collaboration) and adopted funnel plot regression to assess the publication bias. We obtained 324 records. Seven trials totaling 1453 patients have been assessed. Pooled comparisons of studies of UCBT and UBMT in children found that the incidence of engraftment failure and earlier transplantation-related mortality were higher with UCBT because of its delay of hematological recovery [OR = 4.96, 95% CI (3.25, 7.59), p < 0.00001 and OR = 2.36, 95% CI (1.79, 3.11), p < 0.00001 respectively], but CMV infection didn't increase obviously. There was no difference in long disease-free survival rate [OR = 0.85, 95% CI (0.65, 1.01), p = 0.06] between UCBT and UBMT due to the decrease of GVHD in UCBT [OR = 0.45, 95% CI (0.34, 0.60), p < 0.0001]. Our meta-analysis confirmed that UCBT in children is also an effective way to treat children with hematological disease and has equivalent survival outcomes compared with UBMT.     

Post‐transplant EBV‐related lymphoproliferative disorder complicating umbilical cord blood transplantation in patients of adrenoleukodystrophy

EBV‐associated post‐transplant lymphoproliferative disorder (PTLD) is a well‐recognized complication following solid organ transplantation and hematopoietic stem cell transplantation (HSCT) using bone marrow or peripheral blood as stem cell sources, but rarely reported in umbilical cord blood transplantation (UCBT). We report two cases in unrelated UCBT setting and added the following new information to the literature: (i) EBV‐related PTLD can be presented late in recipients of unrelated UCBT; (ii) in contrast to reported literatures that PTLD is a serious complication with unfavorable outcome, especially in monomorphic form, our cases showed that the clinical course may be relatively benign if treatment is initiated promptly. Pediatr Blood Cancer 2009; 53:1329–1331. © 2009 Wiley‐Liss, Inc.