Kuang-Yueh Chiang

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

Abstract:  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.

Clinical outcomes and graft characteristics in pediatric matched sibling donor transplants using granulocyte colony-stimulating factor-primed bone marrow and steady-state bone marrow.

Abstract:  Matched sibling donor (MSD) transplant is a life‐saving procedure for children with various hematological malignancies and non‐malignancies. Traditionally, steady‐state bone marrow (S‐BM) has been used as the source of stem cells. More recently, peripheral blood stem cell (PBSC) after granulocyte‐colony stimulating factor (G‐CSF) mobilization has gained popularity. Adult studies of G‐CSF‐primed BM (G‐BM) have shown that it produces rapid white blood cell engraftment like PBSC, but with less chronic graft‐vs.‐host disease. No such study has been published in pediatric patients. We conducted a pilot clinical trial of G‐BM for pediatric patients. Ten patients were enrolled and were compared to a contemporaneous group of 12 patients who received S‐BM. Patients in the G‐BM group received a higher dose of total nucleated cells/kg (7.01 vs. 3.76 × 108, p = 0.0009), higher granulocyte–macrophage colony‐forming units (CFU‐GM)/kg (7.19 vs. 3.53 × 105, p = 0.01) and had shorter inpatient length of stay (28 vs. 40 days, p = 0.04). The engraftment, transfusion requirement and disease‐free survival between the two groups were similar. We concluded that G‐BM should be considered as an alternative graft source to S‐BM, with the benefits of larger graft cell dose, higher CFU‐GM dose and shorter length of stay.

Tandem stem cell rescue as consolidation therapy for high-risk neuroblastoma.

Despite aggressive treatment for high‐risk neuroblastoma (NB), event‐free survival (EFS) remains <40%. In single arm studies, intensifying therapy with high‐dose chemotherapy and tandem autologous stem cell rescue (HDC/SCR) improved outcome. We retrospectively describe our institutional experience in using HDC/SCR for patients with high‐risk NB, focusing on outcome and acute toxicities.

Is the updated Schwartz formula appropriate for assessing renal function prior to hematopoietic stem cell transplantation

Assessing renal function is an integral part of evaluating pediatric patients for hematopoietic stem cell transplantation (HSCT). The most accurate method is DTPA‐Tc‐99m GFR testing. However, it is costly and time consuming. The Schwartz formula, which was recently updated, represents an inexpensive and readily available alternative. We assessed agreement between the original and updated formula and DTPA‐Tc‐99m in 107 patients who were being evaluated for HSCT. Agreement between both formulas and DTPA‐Tc‐99m was poor, although the updated formula performed marginally better. The Schwartz formulas do not appear to be accurate enough to be used for pre‐transplant kidney function evaluation. Pediatr Blood Cancer 2010;55:199–201.

Inhibition of MDM2 by nilotinib contributes to cytotoxicity in both Philadelphia-positive and negative acute lymphoblastic leukemia.

Nilotinib is a selective BCR-ABL tyrosine kinase inhibitor related to imatinib that is more potent than imatinib. Nilotinib is widely used to treat chronic myelogenous leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). The present study identifies Mouse double minute 2 homolog (MDM2) as a target of nilotinib. In studying ALL cell lines, we found that the expression of MDM2 in both Philadelphia positive (Ph+) and Philadelphia negative (Ph-) ALL cells was remarkably inhibited by nilotinib, in a dose- and time-dependent manner. Further studies demonstrated that nilotinib inhibited MDM2 at the post-translational level by inducing MDM2 self-ubiquitination and degradation. Nilotinib-mediated MDM2 downregulation did not result in accumulation and activation of p53. Inhibition of MDM2 in nilotinib-treated ALL cells led to downregulation of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP), a translational target of MDM2, resulting in activation of caspases. Inhibition of XIAP following nilotinib-mediated downregulation of MDM2 resulted in apoptosis of MDM2-expressing ALL; however, similar nilotinib treatment induced stronger apoptosis in Ph+/MDM2+ ALL than in Ph-/MDM2+ or Ph+/MDM2- ALL. The ALL cells that were Ph-/MDM2- were totally resistant to nilotinib. These results suggested that nilotinib can inhibit MDM2 and induce a p53-independent apoptosis pathway by downregulating XIAP; thus, nilotinib can treat not only Ph+, but also Ph- ALL patients whose cancer cells overexpress MDM2.

Factors Influencing Pulmonary Toxicity in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation in the Setting of Total Body Irradiation-Based Myeloablative Conditioning

PURPOSE This study evaluated factors associated with increased risk of pulmonary toxicity (PT) from any cause in pediatric patients after myeloablative conditioning, using total body irradiation (TBI), followed by allogeneic hematopoietic stem cell transplantation (HSCT). METHODS AND MATERIALS The records of 129 consecutive pediatric patients (range: 1-21 years of age) who underwent TBI-based myeloablative conditioning for hematologic malignancies at our institution between January 2003 and May 2014 were reviewed. Although total TBI doses ranged from 10.5 to 14 Gy, lung doses were limited to 10 Gy with partial transmission blocks. TBI dose rates ranged from 5.6 cGy/min to 20.9 cGy/min. PT was classified using clinical symptoms, radiographic evidence, and ventilatory defects on pulmonary function tests. Noninfectious (idiopathic) pneumonia syndrome (IPS) was characterized by patients exhibiting PT while demonstrating no signs of infection throughout the follow-up period. RESULTS PT from any cause developed in 70.5% of patients and was significantly associated with increased transplantation-related mortality (TRM) (P=.03) and decreased overall survival (OS) (P=.02). IPS developed in 23.3% of patients but was not associated with increased TRM (P=.6) or decreased OS (P=.5). Acute graft-versus-host disease (GVHD) significantly affected PT (P=.001) but did not significantly influence the development of IPS (P=.4). Infection was a leading cause of PT (75.8%). TBI dose rate significantly affected development of overall PT (P=.02) and was the sole factor to significantly influence the incidence of IPS (P=.002). TBI total dose, dose per fraction, disease type, transplantation chemotherapy, age of patient, sex, and donor type did not significantly impact overall PT or IPS. CONCLUSIONS A high incidence of PT was noted in this large series of homogeneously treated pediatric patients undergoing TBI for allogeneic HSCT. TBI dose rates affected overall PT and strongly influenced IPS. TBI dose rate is a contributing factor influencing pulmonary toxicity and rates less than 15 cGy/min should be considered to decrease the risk of IPS.

Relative Defects in Mucosal Immunity Predict Acute Graft-Versus-Host Disease

Impairment of gut mucosal immunity by the transplant process could facilitate translocation of commensal bacteria and thereby augment the graft-versus-host response. To begin to assess the influence of gut mucosal immunity on the development of acute graft-versus-host disease (GVHD), we conducted a prospective study in 24 pediatric allogeneic hematopoietic cell transplant recipients, assessing 4 fecal markers of mucosal immunity: calprotectin, soluble CD8 (sCD8), soluble intracellular adhesion molecule 1, and β-defensin-2. Stool samples were collected prospectively on transplant days 0, +5, +10, and +15 and analyzed by ELISA. Lower levels on day +5 (calprotectin and β-defensin-2) and day +10 (calprotectin, β-defensin-2, and sCD8) were associated with subsequent acute GVHD. The most striking difference was with calprotectin on day +10. Patients with levels below 424 mg/kg had an incidence of 77.8%, whereas those with levels above this threshold had a cumulative incidence of 0% (P = .002). Relative defects in gut mucosal immunity may be important in the pathogenesis of acute GVHD.

Rifaximin for preventing acute graft-versus-host disease: impact on plasma markers of inflammation and T-cell activation.

In murine allogeneic hematopoietic cell transplantation models, inhibiting bacterial translocation stemming from conditioning-induced damage to the gut mucosa abrogates inflammatory stimulation of donor T cells, preventing acute graft-versus-host disease (AGVHD). We conducted a phase I trial to begin testing the hypothesis that rifaximin, a broadly acting oral antibiotic, would reduce systemic inflammation and T-cell activation. We administered rifaximin to 20 adolescents and younger adults (day –10 through day +30) receiving intensive conditioning. We measured the plasma level of interleukin-6, as a marker of conditioning-induced inflammation, and the levels of soluble tumor necrosis factor receptor-1 and soluble interleukin-2 receptor, as surrogate markers of AGVHD. We formed a historical control group (n=24), from a previous study of biomarkers in AGVHD. The increase in the treatment group’s mean interleukin-6 level from baseline to day 0 was 73% less than that in the control group (P=0.006). The increase from baseline to day 15 in the treatment group’s mean soluble tumor necrosis factor-1 and soluble interleukin-2 receptor levels was similar to the control group. Incidences of grade 2 to 4 AGVHD also did not differ. This suggests that rifaximin may abrogate bacterial translocation and resultant inflammation, but in alternative donor transplants this does not prevent downstream activation of donor T cells.

Early blood stream infection following allogeneic hematopoietic stem cell transplantation is a risk factor for acute grade III–IV GVHD in children and adolescents

Graft‐versus‐host disease (GVHD) remains a major cause of mortality and morbidity in allogeneic hematopoietic stem cell transplantation (HSCT). In adults, early blood stream infection (BSI) and acute GVHD (AGVHD) have been reported to be related. The impact of BSI on risk for AGVHD, however, has not been assessed in pediatric patients.

Infusion hemolysis after pediatric major ABO-mismatched bone marrow transplant: Comparison of two red blood cell depletion techniques

During major ABO‐mismatched bone marrow transplant (BMT), the infusion of incompatible red blood cells (RBCs) that are present in the bone marrow graft can cause adverse events from hemolysis. RBC depletion of the bone marrow graft can decrease this risk, but the optimal method to prevent hemolysis is unclear.