Outcomes of children, adolescents, and young adults following allogeneic stem cell transplantation for secondary acute myeloid leukemia and myelodysplastic syndromes-The MD Anderson Cancer Center experience.

We conducted a retrospective analysis of outcomes for children and young adults with sAML/sMDS who underwent HSCT at our institution. Thirty-two patients (median age 20 years) with sAML (n=24) and sMDS (n=8) received HSCT between 1990 and 2013. The median time from sAML/sMDS diagnosis to HSCT was 4.

Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells.

Preclinical studies using bone marrow derived cells to treat traumatic brain injury have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe traumatic brain injury demonstrated safety and potentially a central nervous system structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design.

Long-Term Outcomes after Treatment with Clofarabine ± Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome.

Pretransplant conditioning regimens critically determine outcomes in the setting of allogeneic stem cell transplantation (allo-SCT). The use of nucleoside analogs such as fludarabine (Flu) in combination with i.v.

Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children.

Objectives: The devastating effect of traumatic brain injury is exacerbated by an acute secondary neuroinflammatory response, clinically manifest as elevated intracranial pressure due to cerebral edema. The treatment effect of cell-based therapies in the acute post-traumatic brain injury period has not been clinically studied although preclinical data demonstrate that bone marrow-derived mononuclear cell infusion down-regulates the inflammatory response. Our study evaluates whether pediatric traumatic brain injury patients receiving IV autologous bone marrow-derived mononuclear cells within 48 hours of injury experienced a reduction in therapeutic intensity directed toward managing elevated intracranial pressure relative to matched controls.

Exploring the Cancer Experiences of Young Adults in the Context of Stem Cell Transplantation.

Background: Cancer is the leading cause of nonaccidental morbidity and mortality among young adults (YAs) in the United States. Stem cell transplantation (SCT), a treatment modality for a variety of YA malignancies, often requires prolonged hospitalization and immune-compromising treatment regimens. Stem cell transplantation may isolate YAs physically and emotionally, contributing to uncertainty about treatment processes, outcomes, and long-term sequelae.

The development of a myeloablative, reduced-toxicity, conditioning regimen for cord blood transplantation.

Cord blood transplantation is being used with increasing frequency for patients with high-risk hematologic malignancies. Myeloablative preparative regimens provide antitumor efficacy and facilitate engraftment but are associated with higher morbidity and nonrelapse mortality rates than nonablative regimens. We evaluated 3 sequential myeloablative regimens in the cord blood transplant setting.

Feasibility of allografting in patients with advanced acute lymphoblastic leukemia after salvage therapy with inotuzumab ozogamicin.

Background: No highly effective salvage therapy exists for patients with relapsed acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody attached to calicheamycin that targets B lymphocytes in early stages of development, successfully inducing remission in patients with multiply relapsed ALL.

Methods: We describe our findings in 26 patients who received allogeneic hematopoietic stem cell transplantation (SCT) after treatment with IO between September 2010 and October 2011.

Cord-blood engraftment with ex vivo mesenchymal-cell coculture.

Background: Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells.

Methods: We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells.

High-dose infusional gemcitabine combined with busulfan and melphalan with autologous stem-cell transplantation in patients with refractory lymphoid malignancies.

We developed a new high-dose combination of infusional gemcitabine with busulfan and melphalan for lymphoid tumors. Gemcitabine dose was escalated by extending infusions at a fixed rate of 10 mg/m(2)/min in sequential cohorts, in daily, 3-dose or 2-dose schedules. Each gemcitabine dose immediately preceded busulfan (adjusted targeting area under the curve 4,000 μM/min(-1)/day × 4 days) or melphalan (60 mg/m(2)/day × 2 days).

Fludarabine, melphalan, thiotepa and anti-thymocyte globulin conditioning for unrelated cord blood transplant.

Unrelated cord blood transplant (CBT) is an alternative treatment option for patients who lack a matched donor. However, the optimal type and intensity of the preparative regimen remains unclear. We evaluated the toxicity and outcomes of a conditioning regimen consisting of melphalan 140 mg/m(2) (day - 8), thiotepa 10 mg/kg (day - 7), fludarabine 160 mg/m(2) over 4 days (days - 6 to - 3) and rabbit antithymocyte globulin (ATG) 1.

Long-term follow-up of allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: impact of tyrosine kinase inhibitors on treatment outcomes.

The introduction of tyrosine kinase inhibitors (TKI) has revolutionized therapy for patients with acute lymphoblastic leukemia (ALL) who have the Philadelphia (Ph) chromosome. A retrospective analysis was conducted on 102 adults and 11 children who received a first-matched related (n = 60), matched unrelated (n = 40), mismatched cord blood (n = 12), or haploidentical (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for Ph-positive (Ph+) ALL in first complete remission (n = 71), second complete remission (n = 11), or with active disease (n = 31) between 1990 and 2009. Sixty-seven patients received TKI with upfront ALL therapy, and 32 patients received TKI maintenance following HSCT.

Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children.

Background: Severe traumatic brain injury (TBI) in children is associated with substantial long-term morbidity and mortality. Currently, there are no successful neuroprotective/neuroreparative treatments for TBI. Numerous preclinical studies suggest that bone marrow-derived mononuclear cells (BMMNCs), their derivative cells (marrow stromal cells), or similar cells (umbilical cord blood cells) offer neuroprotection.

Clofarabine ± fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS.

Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem.

Fludarabine, cyclophosphamide, and antithymocyte globulin for matched related and unrelated allogeneic stem cell transplant in severe aplastic anemia.

Twenty severe aplastic anemia (SAA) patients underwent allogeneic stem cell transplantation (allo-SCT) with fludarabine (FLU), cyclophosphamide and antithymocyte globulin from a matched related (n=7, age ≥ 40) or unrelated donor (n=13, any age). Median age was 34 years (range 1–59). Median time from diagnosis to allo-SCT was 12 months (range 2–244).

Cell therapies for traumatic brain injury.

Preliminary discoveries of the efficacy of cell therapy are currently being translated to clinical trials. Whereas a significant amount of work has been focused on cell therapy applications for a wide array of diseases, including cardiac disease, bone disease, hepatic disease, and cancer, there continues to be extraordinary anticipation that stem cells will advance the current therapeutic regimen for acute neurological disease. Traumatic brain injury is a devastating event for which current therapies are limited.

Infections in 100 cord blood transplantations: spectrum of early and late posttransplant infections in adult and pediatric patients 1996-2005.

Cord blood-derived stem cells are successfully used in the treatment of cancer and congenital disorders in children. This alternative source of stem cells is also explored for adult cancer patients with limited donor options. However, delayed engraftment, prolonged neutropenia, secondary graft loss, and graft-versus-host disease (GVHD) in recipients of cord blood transplantation (CBT) make opportunistic infections a serious concern.

Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing.

Advances in immune assessment, including the development of T-cell receptor excision circle (TREC) assays of thymopoiesis, cytokine-flow cytometry assays of T-cell function, and higher-order phenotyping of T-cell maturation subsets have improved our understanding of T-cell homeostasis. Limited data exist using these methods to characterize immune recovery in adult cord blood (CB) transplant recipients, in whom infection is a leading cause of mortality. We now report the results of a single-center prospective study of T-cell immune recovery after cord blood transplantation (CBT) in a predominantly adult population.

Corruption of the Fas pathway delays the pulmonary clearance of murine osteosarcoma cells, enhances their metastatic potential, and reduces the effect of aerosol gemcitabine.

Purpose: Pulmonary metastases continue to be a significant problem in osteosarcoma. Apoptosis dysfunction is known to influence tumor development. Fas (CD95, APO-1)/FasL is one of the most extensively studied apoptotic pathways.

Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells.

Chemoresistance is a major reason that patients with osteosarcoma fail to achieve a lasting chemotherapy response, and it contributes to disease relapse, progression, and death. Human glutathione S-transferase P1 (GSTP1), a phase II detoxification enzyme, contributes to chemoresistance in many cancers. However, the role of GSTP1 in osteosarcoma chemoresistance is ill defined.

Production of VEGF165 by Ewing's sarcoma cells induces vasculogenesis and the incorporation of CD34+ stem cells into the expanding tumor vasculature.

The Ewing's sarcoma cell line TC71 overexpresses vascular endothelial growth factor isoform 165 (VEGF165), a potent proangiogenic molecule that induces endothelial cell proliferation, migration, and chemotaxis. CD34+ bone marrow stem cells can differentiate into endothelial and hematopoietic cells. We used a transplant model to determine whether CD34+ cells migrate from the bone marrow to Ewing's sarcoma tumors and participate in the neovascularization process that supports tumor growth.

Interleukin-12 up-regulates Fas expression in human osteosarcoma and Ewing's sarcoma cells by enhancing its promoter activity.

Interleukin-12 (IL-12) has shown significant antitumor activity in several preclinical animal tumor models. Our previous studies showed that IL-12 inhibited tumor growth in human osteosarcoma and Ewing's sarcoma animal model. Decreased Fas expression in osteosarcoma increased the lung metastatic potential.

Increased Fas expression reduces the metastatic potential of human osteosarcoma cells.

Purpose: The process of metastasis requires the single tumor cell that seeds the metastatic clone to complete a complex series of steps. Identifying factors responsible for these steps is essential in developing and improving targeted therapy for metastasis. Resistance to receptor-mediated cell death, such as the Fas/Fas ligand pathway, is one mechanism commonly exploited by metastatic cell populations.

Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation.

We investigated the pharmacokinetics (PK) of a recently approved intravenous busulfan (IVBU) formulation as a part of the preparative regimen in 20 children with advanced hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Seventeen patients received a thiotepa, IVBU, and cyclophosphamide-based regimen, and 3 patients received an IVBU and cyclophosphamide-based regimen. All patients received IVBU 0.

Fludarabine and once-daily intravenous busulfan for allogeneic bone marrow transplantation for Chediak-Higashi syndrome.

An HLA-identical sibling bone marrow transplant was done for a patient with Chediak-Higashi syndrome. The preparative regimen included intravenous fludarabine (40 mg/m2/dx4) and busulfan (130 mg/m2/dx4). Busulfan was given once daily.

Aerosol gene therapy with PEI: IL-12 eradicates osteosarcoma lung metastases.

Purpose: We determined whether polyethylenimine (PEI), a polycationic DNA carrier, can be used to deliver the interleukin (IL) 12 gene by aerosol to treat established osteosarcoma (OS) lung metastases in a nude mouse model.

Experimental Design: Tumor response was assessed using our OS lung metastases model. Treatment with aerosolized PEI containing the murine IL-12 gene (PEI:IL-12; 600 microl PEI and 2 mg IL-12) was given twice weekly for 5-6 weeks.