Hack Ki Kim

Long-term outcome after immunosuppressive therapy with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in children

Some prospective studies showed that rabbit antithymocyte globulin was inferior to horse antithymocyte globulin as first-line therapy for patients with severe aplastic anemia. We retrospectively analyzed the clinical outcome of 455 children with severe aplastic anemia who received horse antithymocyte globulin (n=297) or rabbit antithymocyte globulin (n=158) combined with cyclosporine as first-line therapy between 1992 and 2010. The response rates were comparable between the horse and rabbit antithymocyte globulin groups at 3 months [46% (136/294) versus 42% (66/153), P=0.55] and 6 months [60% (178/292) versus 55% (87/143), P=1.0]. Using multivariate analysis, differences in antithymocyte globulin preparations were not associated with response rates. However, 2-year and 10-year overall survival rates in the horse antithymocyte globulin group were significantly better than those in the rabbit antithymocyte globulin group (2-year overall survival: 96% versus 87%, 10-year overall survival: 92% versus 84%, P=0.004). On the basis of multivariate analysis, use of rabbit antithymocyte globulin was a significant adverse factor for overall survival (hazard ratio = 3.56, 95% confidence interval, 1.53 – 8.28, P=0.003). Rabbit antithymocyte globulin caused more profound immunosuppression, which might be responsible for the higher incidence of severe infections. Considering that there are no studies showing the superiority of rabbit antithymocyte globulin over horse antithymocyte globulin, horse antithymocyte globulin should be recommended as a first-line therapy. However, our results justify the use of rabbit antithymocyte globulin as first-line therapy if horse antithymocyte globulin is not available.

Successful Engraftment with Fludarabine, Cyclophosphamide, and Thymoglobulin Conditioning Regimen in Unrelated Transplantation for Severe Aplastic Anemia: A Phase II Prospective Multicenter Study

Antithymocyte globulin (ATG) has been used in severe aplastic anemia (SAA) as part of the conditioning regimen. Among the many kinds of ATG preparations, thymoglobulin had been found to be more effective for preventing graft-versus-host disease (GVHD) and the rejection of organ transplants. After the promising results of our preliminary study, we conducted a phase II prospective multicenter clinical trial using a fludarabine (Flu), cyclophosphamide (Cy), and thymoglobulin conditioning regimen to allow good engraftment in patients who underwent unrelated transplantation for SAA. Twenty-eight patients underwent bone marrow (N = 15) or mobilized peripheral blood (N = 13) transplantation from HLA-matched unrelated donors with Cy (50 mg/kg once daily intravenously (i.v.) on days -9, -8, -7, and -6), Flu (30 mg/m² once daily i.v. on days -5, -4, -3, and -2), and thymoglobulin (2.5 mg/kg once daily i.v. on days -3, -2, and -1). Donor-type hematologic recovery was achieved in all patients. The estimated survival rate (SR) was 67.9%, and all the events were treatment-related mortality (TRM), which included thrombotic microangiopathy (N = 2), pneumonia (N = 1), myocardiac infarction (N = 1), posttransplantation lymphoprolifarative disease (N = 3), and chronic GVHD-associated complications (N = 2). The SR of patients who received bone marrow (60.0%) was not different from that of patients who received mobilized peripheral blood (76.9%) (P = .351), but the SR of patients who received more than 15 units of red blood cells before transplantation (45.5%) was significantly lower than that of the other patients (82.4%) (P = .048). The Flu, Cy, and thymoglobulin conditioning regimen achieved promising results for successful engraftment, but the TRM was high. This study was registered at www.clinicaltrials.gov (NCT00737685), and now we are performing a new multicenter study (NCT00882323) to decrease the TRM by reducing the dose of Cy.

Expression of Functional Markers in Acute Nonlymphoblastic Leukemia

Multidrug resistance parameters, tissue infiltration parameters, receptors for colony-stimulating factors (CSFr) and cell cycle parameters were analyzed using flow cytometry in 145, 109 initial and 36 relapsed or refractory, acute nonlymphoblastic leukemia (ANLL) patients to find out clinically more reliable functional parameters. Lung resistance-associated protein (LRP) was most frequently expressed in ANLL (44.1%) followed by P-glycoprotein (PGP) (35.9%) and multidrug resistance-associated protein (MRP) (8.3%). LRP and PGP were expressed more frequently in relapsed or refractory ANLL than initial ANLL cases. Complete remission rate after standard chemotherapy falls in PGP-positive cases (p = 0.001). CD44-positive ANLL cases relapsed more frequently. The organ tropism is different depending on the infiltration parameters, vascular cell adhesion molecule to splenomegaly, matrix metalloprotease-2 to hepatomegaly and to extramedullary infiltration other than spleen, liver or lymph node. The percentage of the granulocyte-macrophage-CSFr expression was high in M4 and M5, and granulocyte-CSFr-positive ANLL showed less extramedullary infiltration (p = 0.007) and more PGP expression. Ki-67 was expressed significantly less in refractory ANLL than initial ANLL and DNA topisomerase IIα was expressed significantly more in the surviving patients group. In conclusion, analysis of these new functional parameters could help to predict and overcome the clinical behavior of each ANLL at the time of diagnosis.

Predisposing Factors of Posterior Reversible Encephalopathy Syndrome in Acute Childhood Leukemia

A retrospective chart review was performed on 19 patients aged <18 years who developed posterior reversible encephalopathy syndrome as a complication during treatment of acute childhood leukemia. Posterior reversible encephalopathy syndrome was most often observed during acute lymphoblastic leukemia induction chemotherapy (n = 9, 47.4%) and after hematopoietic stem cell transplantation (n = 8, 42.1%). Among eight patients with the complication of posterior reversible encephalopathy syndrome after hematopoietic stem cell transplantation, five (62.5%) had a history of hypertension. In contrast, among 11 patients with the complication of posterior reversible encephalopathy syndrome without hematopoietic stem cell transplantation, only one (9.1%) had a history of hypertension. Moreover, unlike other leukemia induction chemotherapy, posterior reversible encephalopathy syndrome developed only in patients who received acute lymphoblastic leukemia induction chemotherapy. Posterior reversible encephalopathy syndrome patients required long-term anticonvulsant therapy (n = 9, 50.0%) and manifested intractable seizures (n = 3, 16.7%). Sequelae were evident in long-term follow-up magnetic resonance images (n = 5, 26.3%). Acute lymphoblastic leukemia chemotherapy regimens apparently comprised the main predisposing factors for posterior reversible encephalopathy syndrome complicated during induction chemotherapy, compared with hypertension and immunosuppressive agents after hematopoietic stem cell transplantation.

Clinical features and treatment outcomes of Langerhans cell histiocytosis: a nationwide survey from Korea histiocytosis working party.

A nationwide survey was conducted to clarify the clinical features and outcomes of Korean children with Langerhans cell histiocytosis (LCH). Korea Histiocytosis Working Party analyzed the data of 603 patients who were diagnosed with LCH between 1986 and 2010 from 28 institutions in Korea. Median age at diagnosis was 65 months (range, 0 to 276 mo). Bone was the most frequently affected organ (79.6%) followed by skin (19.2%). Initially, 419 patients (69.5%) had single-system involvement (SS), 85 (14.1%) with multisystem (MS) disease without risk organ involvement (MS-RO−), and 99 (16.4%) multisystem disease with risk organ involvement (MS-RO+). The 5-year overall survival (OS) rates in the SS, MS-RO−, and MS-RO+ groups were 99.8%, 98.4%, and 77.0%, respectively (P<0.001), and the 5-year reactivation rates were 17.9%, 33.5%, and 34.3%, respectively (P<0.001). The OS rate was lower in patients with RO involvement (P=0.025) and lack of response to initial treatment (P=0.001). MS involvement (P=0.036) was an independent risk factor for reactivation. Permanent consequences were documented in 99 patients (16.4%). Reactivation of disease, MS involvement, and age at diagnosis ⩽2 years were associated with higher incidence of permanent consequences. This study emphasized that further efforts are required to improve survival of MS-RO+ patients and reduce reactivation in younger patients with MS involvement.

Current status of pediatric umbilical cord blood transplantation in Korea: A multicenter retrospective analysis of 236 cases

We report the outcome of 236 pediatric umbilical cord blood transplantations (UCBT) performed in Korea. Given that the sources of the grafts were mostly unrelated donors (n = 226; 95.8%), only the results of unrelated UCBT were included for all statistics. The most frequent primary disease was acute leukemia (n = 167). In total, 91.7% of recipients were seropositive for cytomegalovirus (CMV). The median doses of nucleated cells and CD34+ cells were 4.84 × 107/kg and 2.00 × 105/kg, respectively. The median times to neutrophil (>0.5 × 109/L) and platelet recovery (>20 × 109/L) were 18 and 45 days, respectively. Grade 2–4 acute graft‐versus‐host‐disease (GVHD) and chronic GVHD developed in 41.1 and 36.1% of cases, respectively. Forty‐five patients developed CMV disease. The 5‐year overall and event‐free survival were 47.5 and 36.9%, respectively. Multivariate analysis revealed that adverse factors for survival of the whole cohort were total body irradiation‐based conditioning (P = 0.007), salvage transplant (P = 0.001), failure to achieve early complete chimerism (P < 0.0005), and CMV disease (P = 0.001). The outcomes of the single‐ and double‐unit UCBT (n = 64) were similar, while double‐unit recipients were heavier (P < 0.0005) and older (P < 0.0005). We conclude that double‐unit UCBT is a reasonable option for older or heavier children and that the thorough surveillance of CMV infection and the development of an effective CMV therapeutic strategy may be especially important for Korean children, whose CMV seroprevalence exceeds 90%. Am. J. Hematol., 2011.

Recombinant urate oxidase (Rasburicase) for the treatment of hyperuricemia in pediatric patients with hematologic malignancies: Results of a compassionate prospective multicenter study in Korea†

Hyperuricemia accompanying tumor lysis syndrome is a serious complication in neoplasia with rapid proliferation and destruction. To confirm the efficacy of recombinant urate oxidase (rasburicase) and its safety profile, a phase IV compassionate use prospective study was performed in Korean pediatric patients with hematologic malignancies.

Subcutaneous panniculitis-like T-cell lymphoma in a child: whole-body MRI in the initial and follow-up evaluations

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is classified as an unusual subtype of peripheral T-cell lymphoma that preferentially infiltrates the subcutaneous tissue without overt lymph node involvement. SPTCL is particularly rare in children, and there have been only a few case reports describing the US and CT findings of SPTCL. To our knowledge, the use of whole-body (WB) MRI as the initial and follow-up diagnostic method to assess the extent of disease and relapse of SPTCL has not been reported in children. In our case report involving one child, WB MRI was useful as both the initial and follow-up diagnostic method to assess the extent of disease and to monitor the patient’s response to therapy for SPTCL.

Endocrine Complications after Hematopoietic Stem Cell Transplantation during Childhood and Adolescence

Long-term survivors of hematopoietic stem cell transplantation (HSCT) during childhood and adolescence are at risk of developing endocrine complications. The purpose of this study was to evaluate the long-term endocrine complications and their associated risk factors among such patients. We reviewed the data from 111 patients (59 males and 52 females) who underwent HSCT at the mean age of 8.3±4.1 yr. Thirty patients (27.0%) had growth impairment, and seven (21.2%) out of 33 patients who attained final height reached final height below 2 standard deviation (SD). The final height SD score of the patients conditioned with total body irradiation (TBI) was significantly lower than that of the patients conditioned without TBI (-1.18±1.14 vs. -0.19±0.78, P=0.011). Thirteen patients (11.7%) developed hypothyroidism (11 subclinical, 2 central) 3.8±1.8 (range 1.6-6.2) yr after HSCT. Nineteen (65.5%) out of 29 females had evidence of gonadal dysfunction, and 18 (64.3%) out of 28 males had evidence of gonadal dysfunction. The risk for gonadal dysfunction was significantly higher in females conditioned with busulfan/cyclophosphamide (P=0.003). These results suggest that the majority of patients treated with HSCT during childhood and adolescence have one or more endocrine complications. Therefore, multiple endocrine functions should be monitored periodically after HSCT until they reach adult age.

Three-way complex translocations in infant acute myeloid leukemia with t(7;12)(q36;p13): The incidence and correlation of a HLXB9 overexpression

The t(7;12)(q36;p13) is one of the recurrent cytogenetic abnormalities that involves the ETV6 gene. It is found in patients suffering with infantile acute myeloid leukemia (AML). We reviewed the cytogenetic and clinical findings of 215 pediatric patients (ages </=17) who were diagnosed with AML to check for abnormalities of 7q and/or 12p. Fluorescence in situ hybridization (FISH) analysis using an ETV6 (12p13) break-apart probe was done to confirm the breakage of the ETV6 gene on 12p. We also performed immunohistochemistry to verify the upregulated expression of the HLXB9 protein, which is coded by the HLXB9 gene at 7q36. Three patients (1.4%) with t(7;12) were detected and they made up 15.8% of the patients who were less than 24 months old. New three-way complex translocations were found in two cases - t(5;7;12)(q31;q36;p13) and t(1;7;12)(q25;q36;p13) - and we detected these by performing FISH. All three patients died early during treatment due to multiple organ failure or relapse. HLXB9 overexpression was proven by immunohistochemistry for the first time in this study. In connection with this, we prudently propose that downregulation of the HLXB9 expression may be a new treatment strategy for AML patients with t(7;12).