Treosulfan‐based reduced toxicity hematopoietic stem cell transplantation in X‐linked agammaglobulinemia: A cost‐effective alternative to long‐term immunoglobulin replacement in developing countries

X‐linked agammaglobulinemia (XLA) is a primary antibody disorder due to a mutation in the Bruton tyrosine kinase gene that requires lifelong immunoglobulin replacement resulting in a significant economic burden and treatment abandonment. Hematopoietic stem cell transplantation (HSCT) offers an alternative option for complete cure. In our series, two children with XLA underwent successful HSCT using a myeloablative conditioning with thiotepa, treosulfan, and fludarabine from a matched sibling donor. The second child had rejected his first graft following a busulfan‐based regimen with resultant autologous reconstitution. At 6 months post‐HSCT, serum IgG were normal, off IVIG, and had no infections. Both children after a median follow‐up of 20 months have 100% chimerism. Treosulfan‐based reduced toxicity myeloablative HSCT has encouraging results with a positive impact on the socioeconomics in developing countries.     

异基因造血干细胞移植治疗儿童急性髓系白血病临床研究

目的评估应用异基因造血干细胞移植(allo-HSCT)治疗儿童急性髓系白血病(AML)的临床疗效及相关影响因素。方法回顾分析2002年1月至2017年11月49例确诊中、高危及复发AML行allo-HSCT患儿的临床资料,分析危险度分级、HLA分型、移植前状态、移植方式、干细胞来源及急慢性移植物抗宿主病(GVHD)等对allo-HSCT治疗效果的影响。结果 49例患儿中男35例、女14例,中位年龄9岁。三年总体存活率(OS)为(59.2±7.3)%,无白血病存活率(LFS)为(50.9±7.4)%。其中第1次缓解状态移植、非血缘移植、外周血干细胞移植、中危组移植的三年LFS分别为69.8%、69. 2%、73. 7%、65. 8%。19例死亡,分别为复发13例、严重感染5例、多器官衰竭1例。COX回归模型结果显示,急性GVHD是影响移植OS的独立危险因素(RR=3. 16,95%CI:1. 23～8. 09,P=0. 017),移植前状态为部分缓解及未缓解是影响移植LFS的独立危险因素(RR=4.76,95%CI:1.52～14.94,P=0.008;RR=5.28,95%CI:1.68～16.58,P=0.004)。结论移植前状态及急性GVHD是影响Allo-HSCT治疗儿童AML疗效的关键因素;白血病复发及感染是导致死亡的主要原因。     

Allogeneic hematopoietic cell transplantation in chemotherapy‐induced aplasia in children with high‐risk acute myeloid leukemia or myelodysplasia

Relapse remains the most common cause of treatment failure after hematopoietic cell transplantation for acute myeloid leukemia. Inability to achieve hematologic complete remission has been a barrier to transplant for patients with refractory disease. We describe six children with refractory myeloid disease undergoing transplant in chemotherapy‐induced aplasia, as a strategy to facilitate curative therapy in refractory patients. Clofarabine‐ or high‐dose cytarabine‐based chemotherapy regimens were used to achieve marrow aplasia, followed by reduced‐intensity conditioning and allogeneic transplant before hematologic recovery. Long‐term disease control was achieved in five, with one transplant‐related mortality, suggesting the feasibility of this approach.     

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.     

Unrelated donor hematopoietic stem cell transplantation for pediatric de novo acute myeloid leukemia with intermediate‐ or high‐risk cytogenetics

The role of unrelated donor HSCT for children with de novo AML in CR1 is controversial. We performed this study to investigate the feasibility of unrelated donor HSCT who initially had intermediate‐ or high‐risk cytogenetics. We retrospectively reviewed medical records of patients with AML who received unrelated HSCT in CR1 at Samsung Medical Center between November 2001 and January 2012. Patients were allocated based on karyotype at diagnosis as follows: (a) low‐risk: inv(16), t(16;16), t(8;21), and t(15;17); (b) high‐risk: ‐5, 5q‐, ‐7, 3q abnormalities, t(8;16), t(6;9), t(6;11), t(6;21), t(10;11), complex karyotype (≥3 abnormalities), and acute megakaryocytic leukemia without t(1;22); and (c) IR: all the other karyotypes including normal. Patients in intermediate‐ or high‐risk group who were transplanted with either unrelated CB or matched unrelated BM/mobilized PB in their CR1 were included in this study. The projected OS and EFS rates were 74.9% and 71.1%, respectively, with a median follow‐up of 87.3 months after transplantation. The EFS was 70.1%, 80.7%, and 73.9% for CB, BM, and mobilized PB groups, respectively (P = 0.89), and 73.9% and 70.6% for IR and high‐risk groups (P = 0.76). The leading cause of death was relapse (n = 8), and only one patient died from non‐relapse cause. Unrelated donor HSCT seems a feasible approach for children with intermediate‐ or high‐risk AML in CR1. Relapse remains the leading cause of treatment failure among these patients.     

Haploidentical bone marrow transplantation in a patient with sickle cell disease and acute myeloid leukemia

Myeloid neoplasms in children with sickle cell disease have been rarely reported, and the exact underlying connection between these two conditions is not clearly understood. Whether the acute myeloid leukemia in hydroxyurea‐treated sickle cell patients is co‐incidental or related to therapy remains an unanswered question. Herein, we report a 14‐year‐old girl of Haitian descent with sickle beta zero thalassemia on chronic hydroxyurea therapy who developed FMS‐like tyrosine kinase 3 (FLT3)‐mutated acute myeloid leukemia and underwent a complete disease remission following a combination chemotherapy with sorafenib and was subsequently treated using a T cell replete unmanipulated haploidentical bone marrow transplantation followed by post‐transplant cyclophosphamide.     

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??Objective??To analyze the effectiveness and the practicability of Nordic Society for Pediatric Hematology and Oncology??NOPHO?? AML 2004 protocol combined with hematopoietic stem cell transplantation??HSCT?? in treating childhood acute myeloid leukemia??AML?? in China. Methods??The clinical data of 53 children??aged under 14?? with AML??not including acute promyelocytic leukemia?? treated with NOPHO AML 2004 protocol??some children followed by HSCT?? between Dec. 2009 and Dec. 2015 was retrospectively analyzed. Survival was evaluated by Kaplan Meier analysis and Log-Rank test. Results??Complete remission??CR?? rate reached 86.8%. Totally 36 patients??67.9%?? finished 6 courses of chemotherapy??14 patients??26.4%??underwent HSCT after 1-3 courses of consolidation chemotherapy??3 patients gave up treatment after 1-3 courses of chemotherapy. The proleptic overall survival??pOS?? at 5 years and leukemia-free survival??pLFS?? was 72% and 56% respectively during a follow-up period of 12 to 82 months??median 29 months??. For standard-risk patients??the pLFS at 5 years reached 58%?? while high-risk patients had 46%??P??0.779??. The pLFS at 5 years in patients who only underwent chemotherapy and those with additional hematopoietic stem cell transplantation was 48% and 77% respectively??P??0.1268??. The pLFS in patients with good response??intermediate response and poor response on day 15 bone marrow examination was 75%??29% and 53% respectively??P??0.0071??. Conclusion??NOPHO AML 2004 protocol is effective and feasible for Chinese patients with childhood AML. The evaluation of blast in bone marrow on day 15 can be used as an important prognostic indicator.     

Low‐dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high‐risk pediatric acute myeloid leukemia

The dismal prognosis of pediatric acute myeloid leukemia (AML) relapsing after hematopoietic stem cell transplantation (HSCT) requires exploration of novel strategies to prevent relapse. Azacitidine (AZA) maintenance therapy could potentially reduce the recurrence rate post HSCT. Here, we presents the cases of three children with high‐risk AML post HSCT who were treated with low‐dose AZA maintenance therapy, demonstrating the feasibility of this therapy. Currently, all three are in complete remission for 13–41 months despite their high‐risk characteristics. Our encouraging data warrant larger prospective studies to assess the efficacy and safety of low‐dose AZA maintenance therapy post HSCT for pediatric patients with high‐risk AML.     

Donor cell-derived acute myeloid leukemia after second allogenic cord blood transplantation in a patient with Fanconi anemia

DCL following hematopoietic stem cell transplantation has been reported in approximately 5% of all leukemic relapses. There have been several reports on DCL, mainly AML after umbilical cord blood transplantation. In this case study, we present a young boy diagnosed with Fanconi anemia who underwent an umbilical cord blood transplantation. Because of the graft failure, he was retransplanted one month later, also with a cord blood transplant. Two years after the second transplant, he developed AML, where 100% of the cells were of female donor origin. The donor, a now 14-yr-old female, was recently reported healthy.     

Haploidentical hematopoietic stem cell transplantation for a case with X‐linked chronic granulomatous disease

CGD is a rare primary immunodeficiency with high mortality rates when treated conventionally, especially for the X‐chromosome‐linked form. HSCT is the only curative therapy for CGD; however, haploidentical transplantation in CGD is rare. Here, we report a case of X‐linked CGD treated successfully by haploidentical HSCT. The patient showed a positive result with full donor chimerism, good quality of life, and the absence of recurrent infectious diseases at follow‐up (68 months). Thus, haploidentical HSCT may serve as an acceptable treatment approach for patients who have CGD, but no HLA‐matched related or unrelated donor.     

Multiple extramedullary relapses without bone marrow involvement after second allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

EMR without BM involvement after allogeneic HSCT is extremely rare, especially in children; only a few cases have been reported. A two-yr-old boy was diagnosed with AML (M4) and underwent allogeneic HSCT in first complete remission with BM from HLA-matched unrelated donor without GVHD. Four yr later, he had a BM relapse and after induction and consolidation chemotherapy, he received a second HSCT from an unrelated donor using peripheral blood stem cells. His second post-transplant course was complicated by extensive chronic GVHD involving the skin, oral cavity, and lungs, which was treated with tacrolimus and corticosteroid. Two yr later, he noticed a mild swelling in the right cheek area. The BM showed a complete remission marrow and a soft tissue biopsy was compatible with granulocytic sarcoma. PET-CT showed multifocal bone involvements. He received chemotherapy, and the chloromas decreased in size. We report a case of diffuse EMR of AML without BM involvement after a second allogeneic HSCT.     

Azacitidine as a bridge to allogeneic hematopoietic cell transplantation in a pediatric patient with Fanconi anemia and acute myeloid leukemia

HCT is the definitive therapy for patients with FA and AML. Conventional cytotoxic agents cause potential DNA damage, and currently, there is no established regimen for these patients prior to HCT. A 13‐year‐old male with FA and refractory AML was given azacitidine, achieved morphologic remission and underwent HCT. At 95 days after HCT, he relapsed. Azacitidine along with DLI was used as first salvage therapy. Azacitidine was overall well tolerated with minimal side effects. In patients with AML and FA, azacitidine can be considered an alternative to conventional chemotherapy.     

The outcome of children with acute myeloid leukemia (AML) post-allogeneic stem cell transplantation (SCT) is not improved by the addition of etoposide to the conditioning regimen

BACKGROUND: Relapse remains a concern for children with AML undergoing allogeneic SCT, so in an effort to reduce the risk of relapse in these patients, we intensified our pre-SCT preparation by adding etoposide to the standard busulfan and cyclophosphamide regimen. PROCEDURE: We retrospectively analyzed the collected data and compared the two groups; Group A (n = 18) included patients who received busulfan 16 mg/kg plus cyclophosphamide 200 mg/kg (Bu/Cy), and Group B (n = 48) included patients who received busulfan 12 mg/kg, cyclophosphamide 90 mg/kg in addition to etoposide 60 mg/kg (Bu/Cy/VP). The patients' characteristics were similar in the two groups. RESULTS: No significant difference in the overall outcome was noted; the 5-year overall survival was 50% and 53.3% for Groups A and B, respectively (P = 0.9). Similarly, the 5-year probability of relapse was 64.1% and 46.1% for Groups A and B, respectively (P = 0.38). The use of etoposide was not associated with increased toxicity. CONCLUSION: The addition of etoposide to the Bu/Cy regimen was well tolerated, but did not appear to improve the outcome.