Decitabine prior to salvaged unrelated cord blood transplantation for refractory or relapsed childhood acute leukemia

No clinical studies have investigated the role of decitabine as a part of the myeloablative conditioning regimen prior to UCBT for refractory or relapsed childhood AL in patients in NR status. The aim of this study was to identify the potential benefits of decitabine as a prior therapy before salvaged unrelated UCBT for refractory or relapsed childhood AL. Eight consecutive patients with childhood refractory/relapsed AL were enrolled in our study between 2013 and 2014. All patients were in NR status before the time of transplant and had features associated with poor outcomes, such as CNSL, MDS‐AML, high WBC count at diagnosis, and hypodiploid status (FLT3+/ITD+). Additionally, all patients had one of the following disease statuses: PIF, multiple relapse, or early relapse. All transplants were performed with decitabine as part of the myeloablative conditioning regimen, which was decitabine+Flu/Bu/CY±BCNU or decitabine+Ara‐c/BU/CY2±BCNU. A total of seven patients (7 of 8) achieved neutrophil engraftment and platelet engraftment, and one patient experienced primary graft failure. All eight patients (100%) developed PES at a median of 7 days. Three patients developed stage II‐IV acute GVHD at a median of 18 days. Additionally, three patients developed chronic GVHD, but it was not extensive in any of those three patients. The median follow‐up time after CBT was 19.9 months (range, 9.2–30.7 months). The estimated probability of OS was 75%. Two patients (2 of 8) experienced a testis relapse, and two patients (2 of 8) died. Our experience suggests that the additional application of decitabine as part of the myeloablative conditioning regimen prior to UCBT for refractory or relapsed childhood AL among patients who are not in remission is safe and might be an effective treatment option.     

Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation

A 2-month-old girl presented for treatment with a diffuse rash, interstitial pneumonia, otorrhea, and lymphadenopathy. Skin biopsy confirmed Langerhans cell histocytosis by electron microscopy. After receiving multiple courses of chemotherapy, only marginal improvement was achieved, with progressive marrow and liver involvement. The decision was made to pursue a human leukocyte antigen-identical unrelated cord blood transplantation. Two years after transplant, the bone marrow was clear of Langerhans cell histocytosis and 100% donor engraftment. The poor prognosis of patients with an inadequate response to therapy and the presence of organ dysfunction (marrow and liver) substantiated the decision to pursue an unrelated cord blood transplantation.     

人类白细胞抗原不全相合非血缘脐血移植治疗儿童难治性复发急性白血病

脐血移植治疗血液系统恶性肿瘤的疗效仍需观察。我科于2001年4月～2003年3月应用非血缘脐血移植(UD-UCBT)治疗儿童难治性复发急性白血病患儿3例,现报告如下。     

人类白细胞抗原配型一个位点不合非血缘脐血移植治疗急性淋巴细胞性白血病一例

近年脐血已成为造血干细胞重要来源之一并用于血液病的治疗。我们于2002年11月进行了一例人类白细胞抗原(HLA)配型一个位点不合的非血缘脐血移植(unrelated umbilical cord blood transplantation,UCBT),获得成功。现报告如下。     

Successful cord blood transplantation with reduced-intensity conditioning for childhood cerebral X-linked adrenoleukodystrophy at advanced and early stages

Childhood cerebral ALD is a rapidly progressive and neurodegenerative disorder for which HSCT is the curative therapy if carried out at early stages. We successfully treated two patients of childhood cerebral ALD by CBT with RIC. The proband was a seven-yr-old boy whose brain MRI severity score (Loes score) was 14.5. Unrelated CBT was performed in five wk. To minimize conditioning regimen-related neurotoxicity, the combination of fludarabine (125 mg/m(2)), melphalan (140 mg/m(2)), and 4 Gy of brain-sparing TBI was used. The second patient was a six-yr-old brother of the proband. Four wk after the detection of a single small lesion (Loes score 1), he received unrelated CBT with the same RIC as the proband. In both patients, the engraftment was fast and stable, and severe complications were not observed. Furthermore, gadolinium-enhanced inflammation on brain MRI rapidly disappeared after CBT. Now, 20 and 13 months have passed after CBT, respectively, and both patients are neurologically stable. The RIC we used was sufficient for stable engraftment of cord blood and also tolerable even to the patient with advanced ALD. RIC-CBT should be considered for the patients with cerebral ALD at advanced stages, as well as those at early stages.     

Five-month marrow aplasia in a child with refractory acute myeloid leukemia: successful management with continuous granulocyte support and reduced-intensity conditioning followed by matched unrelated bone marrow transplantation

A 10-year-old girl diagnosed with acute myeloid leukemia FAB M4 failed to achieve remission following several courses of induction chemotherapy. From the first course of chemotherapy the patient had continuous marrow aplasia, managed by a total of 57 granulocyte transfusions. After reinduction and reduced-intensity conditioning including fludarabine, Campath-1H, and melphalan, the patient received unmanipulated marrow from an HLA-matched unrelated donor. Leukocyte and platelet engraftment was observed on day +18 and +50, respectively. Graft-versus-host disease did not occur. The patient is alive and well in complete remission 18 months after transplantation with complete donor chimerism.     

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.     

Successful treatment of refractory immune hemolysis following unrelated cord blood transplant with Campath-1H

Immune-mediated hemolytic anemia is a well-recognized complication of hematopoietic stem cell transplantation. We report on a 6-year-old boy with X-linked adrenoleukodystrophy who developed severe delayed alloimmune hemolytic anemia associated with immune-mediated neutropenia and thrombocytopenia following major ABO incompatible unrelated cord blood transplantation. The patient's cytopenias were refractory to treatment with corticosteroids, cyclosporine, intravenous immune globulin, rituximab, and pentostatin. After one course of Campath-1H his hematologic parameters normalized, suggesting that the compound may be an effective therapy for complex immunohematologic disorders complicating hematopoietic stem cell transplantation. The case also emphasizes the importance of T-cells in transplant associated immune cytopenias.     

Induction of a transient graft vs. leukemia effect following unrelated cord blood transplantation

Umbilical cord blood (UCB) has become a frequent source of allogeneic hematopoietic stem cells for transplantation. Of theoretical concern is a potential decrease in the graft vs. leukemia (GvL) effect, given the lesser degree of graft vs. host disease (GvHD) with this donor source. We report a case of recurrent acute non-lymphoblastic leukemia (ANLL) following stem cell transplantation with unrelated mismatched UCB, which responded to the induction of GvHD. The response was documented both morphologically and by evaluation of chimeric engraftment by molecular DNA techniques. In addition, WT-1, a purported marker of minimal residual disease in acute leukemia, correlated with remission status in this patient. In summary, the GvL effect is seen with allogeneic UCB transplantation and has the potential to be induced along with GvHD.     

Successful unrelated donor cord blood transplantation for Glanzmann’s thrombasthenia

Kitko CL, Levine JE, Matthews DC, Carpenter PA. Successful unrelated donor cord blood transplantation for Glanzmann’s thrombasthenia.
Pediatr Transplantation 2011: 15: e42–e46. © 2009 John Wiley & Sons A/S. Abstract: GT, a rare disorder of platelet function, can lead to life‐threatening bleeding, particularly following the development of antiplatelet antibodies. Curative therapy includes HCT but previous reports are limited predominantly to matched siblings and have excluded CBT. Delayed or non‐engraftment of platelets because of antiplatelet antibodies might be particularly concerning after CBT for GT. Here, we report two successful unrelated cord blood transplants for GT. Recurrent life‐threatening bleeding was the primary indication for HCT, with one patient developing antiplatelet antibodies pre‐HCT. Bleeding risks associated with delivery of the conditioning regimen and the toxicity that follows should be carefully considered, including tunneled central venous line catheter placement, inclusion of B cell‐specific therapy to potentially decrease antiplatelet antibody production, and targeted busulfan dosing. This is the first report of successful unrelated cord blood HCT for GT and indicates that modifications to supportive care can improve the safety of this potentially curative therapy for patients with severe, life‐threatening disease manifestations.     

Successful allogeneic unrelated bone marrow transplantation using reduced-intensity conditioning for the treatment of X-linked adrenoleukodystrophy in a one-yr-old boy

Abstract:  The childhood cerebral form of X-linked ALD is a demyelinating disorder of the central nervous system, which rapidly leads to total disability and death. Allogeneic stem cell transplantation benefits patients who show early evidence of the demyelination. We report here a one-yr-old boy with ALD who received HLA-matched unrelated BMT in an early stage of the disease after careful planning and observation since his birth. BMT was performed when MRI began to show slight signal intensity changes in the white matter of the brain. Pretransplant conditioning consisted of fludarabine, l -PAM and TBI (2 Gy). GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. The patient showed an uneventful BMT course with fast and stable engraftment. Following BMT, the plasma levels of VLCFA decreased gradually and MRI changes improved. The patient did not have any evidence of further neurological deterioration 22 months following the transplant. Although this is still a short follow-up, it has been shown that BMT should be considered when a child has a biochemical diagnosis and MRI findings of ALD without any neurological signs. RIST should be considered as a pretransplant conditioning for ALD.     

Successful unrelated cord blood transplantation in a child with beta-thalassemia major

We report here the first successful transplant of unrelated umbilical cord blood (UCB) for a child with beta-thalassemia major in Taiwan. A total of 2.48 x 10(5)/kg CD34 cells were infused into a 3(1/2)-year-old girl following conditioning with a pre-transplant cytoreductive/immunosuppressive regimen of busulfan and cyclophosphamide. The absolute neutrophil count first exceeded 0.5 x 10(9)/l on day 17, and the patient became red cell- and platelet-independent on days 34 and 49, respectively. Engraftment of donor hematopoietic populations was documented by cytogenetic analysis, hemoglobin electrophoresis, Southern blot analysis for thalassemia markers, and molecular analysis of short tandem repeats sequences. The patient was ex-thalassemic for more than 15 months post transplant. From this experience, it is postulated that UCB will indeed allow us to expand the available donor pool for recipients with an HLA DRB1 mismatched at one locus and reduce the risk of graft-versus-host disease.     

Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation

Wolman disease is a rapidly fatal lysosomal storage disease caused by the complete absence of lysosomal acid lipase activity. We report the cure of an infant with Wolman disease following transplantation of unrelated HLA-mismatched umbilical cord blood-derived stem cells. Umbilical cord blood was chosen as the stem-cell source because of its immediate availability and reduced tendency to cause graft-versus-host disease. The transplantation resulted in restoration of normal acid lipase levels before the onset of permanent end-organ damage. Four years after transplantation, the patient is thriving and has normal levels of acid lipase in peripheral blood cells. To our knowledge, this is the first report of a successful unrelated cord blood transplant in a patient with Wolman disease. Umbilical cord stem cells transplantation can restore acid lipase levels in Wolman disease, and if performed early, can cure the disease.     

Successful report of reduced-intensity stem cell transplantation from unrelated umbilical cord blood in a girl with chronic active Epstein-Barr virus infection

We describe an 8-year-old girl with chronic active Epstein-Barr virus (EBV) infection (CAEBV) who was treated successfully by reduced-intensity stem cell transplantation (RIST) from unrelated cord blood (CB). She had been suffering from fever, abdominal pain, and interstitial lymphadenopathy, and CAEBV was diagnosed. After chemotherapy that included etoposide, the amount of EBV decreased transiently below the detection level. However, the disease due to CAEBV worsened despite the chemotherapy, and she finally needed chemotherapy every week. Therefore, instead of conventional myeloablative transplantation, we performed CB transplantation with reduced-intensity conditioning regimens consisting of low-dose total body irradiation, fludarabine, and etoposide. CB, for which human leukocyte antigen (HLA) was 2-loci mismatched on the DR loci from an unrelated donor, was infused after conditioning. Although grade III acute graft-versus-host disease (GVHD) in the gut and chronic GVHD in the lung developed, the symptoms of GVHD disappeared with immunosuppressive therapy. After 15 months, the patient remained a complete chimera, with undetectable levels of EBV in peripheral blood and bone marrow. We conclude that RIST from unrelated CB can be indicated for some cases of CAEBV who are refractory to chemotherapy and have no HLA-matched related and unrelated donors as the source of bone marrow or peripheral blood stem cells.     

Graft versus leukemia effect against juvenile myelomonocytic leukemia after unrelated cord blood transplantation

A 13-month-old female underwent unrelated cord blood transplantation (CBT) for juvenile myelomonocytic leukemia (JMML). In spite of progression of the disease after a conditioning regimen with high-dose chemotherapy, a complete remission was induced in concordance with development of acute GVHD after reduction of the immunosupressant. She has been in complete remission for 1 year after transplantation. This case illustrates that CBT can provide a potent graft versus leukemia (GVL) effect against JMML.     

Successful unrelated mismatched cord blood transplantation in a child with malignant infantile osteopetrosis

Allogeneic hematopoietic stem cell transplantation represents the only curative option for malignant infantile osteopetrosis (MIOP), a rare disease of infants and young children, characterized by excessive accumulation of mineralized bone and abnormal hematopoiesis. We report a case of successful engraftment and stable full-donor chimerism in a patient with MIOP who underwent unrelated donor cord blood transplantation (CBT). The donor was 2-loci human leukocyte antigen (HLA)-mismatch. After a conditioning regimen based on the combination of busulfan, cyclophosphamide, total body irradiation, and antithymocyte globulin, the patient received a dose of 3.85 x 10(7)/kg of nucleated cells. Neutrophil and platelet engraftment had been achieved by day +33 and +82, respectively, and the patient was discharged home on day +89. A successful engraftment of donor hematopoiesis was demonstrated and the child experienced grade II acute graft-vs.-host disease (GVHD) involving the skin only. A remarkable but non-progressive decrease in lumbar spine bone mineral density was observed in the first nine months post-transplant. This case suggests that unrelated donor CBT may be a feasible option in case of unavailability of a fully HLA-matched related or unrelated donor.     

Successful treatment of refractory Langerhans cell histiocytosis with pulmonary aspergillosis by reduced‐intensity conditioning cord blood transplantation

Hatakeyama N, Hori T, Yamamoto M, Inazawa N, Hirako Y, Tsutsumi H, Suzuki N. Successful treatment of refractory Langerhans cell histiocytosis with pulmonary aspergillosis by reduced‐intensity conditioning cord blood transplantation.
Pediatr Transplantation 2010: 14: E4–E10. © 2009 Wiley Periodicals, Inc. Abstract: The prognosis of multisystem LCH in children with risk organ involvement is extremely poor when they fail to respond to conventional chemotherapy. In such patients, allogeneic SCT may produce complete and sustained remission; however, high‐dose myeloablative regimens are frequently associated with treatment‐related morbidity and mortality. More recently, allogeneic SCT following an RIC regimen has been performed as an alternative salvage approach. We describe a nine‐month‐old boy with refractory multisystem LCH with pulmonary aspergillosis who was successfully treated with reduced‐intensity cord blood transplantation.     

Fulminant septicaemia caused by multi-drug-resistant Streptococcus mitis following unrelated cord blood transplantation

Streptococcus mitis (a common and usually harmless bacterium found in the nose, mouth and throat) can have an unusually high level of resistance to beta-lactam antibiotics. We report a patient who developed fatal Streptococcus mitis septicaemia following unrelated cord blood transplantation. Administration of vancomycin to patients with recurrent fever during allogeneic stem cell transplantation might be indicated.