Hyery Kim

Efficacy and safety of micafungin for the prophylaxis of invasive fungal infection during neutropenia in children and adolescents undergoing allogeneic hematopoietic SCT

The objective of this study was to evaluate the efficacy and safety of micafungin for the prevention of invasive fungal infection (IFI) during the neutropenic phase of allogeneic hematopoietic SCT (allo-HSCT) in children and adolescents. This was a prospective, multicenter, open-label, single-arm study. Micafungin was administered i.v. at a dose of 1 mg/kg/day (max 50 mg) from the beginning of conditioning until neutrophil engraftment. Treatment success was defined as the absence of proven, probable, possible or suspected IFI through to 4 weeks after therapy. From April 2010 to December 2011, 155 patients were enrolled from 11 institutions in Korea, and 147 patients were analyzed. Of the 147 patients, 121 (82.3%) completed the protocol without premature interruption. Of the 132 patients in whom micafungin efficacy could be evaluated, treatment success was achieved in 119 patients (90.2%). There was no proven fungal infection in any patient. The number of patients with probable, possible and suspected IFI was two, two and nine, respectively. Thirty-five patients (23.8%) experienced 109 adverse events (AEs) possibly related to micafungin. No patients experienced grade IV AEs. Two patients (1.4%) discontinued micafungin administration due to adverse effects. None of the deaths were related to the study drug.

Impact of CD34 + cell dose in children who receive unrelated PBSCT with in vivo T-cell depletion for hematologic malignancies

PBSCs are increasingly being chosen as the mode of donation among unrelated donors. Pediatric patients, in particular, may receive very high CD34+ and CD3+ doses during unrelated PBSCT. In this work, we analyzed survival and GVHD outcomes in a cohort of 81 children who received unrelated PBSCT with uniform antithymocyte globulin (ATG)-based in vivo T-cell depletion for treatment of hematologic malignancy, with emphasis on the impact of cell dose on transplant outcomes. EFS was 61.5±5.6%, with higher CD34+ dose (>10.0 × 106/kg) and lower patient risk status predicting improved survival in multivariate study. Cumulative incidence of relapse was 30.2±5.2%; a low CD34+ dose was the only significant factor for relapse. Neither CD34+ nor CD3+ dose was a significant determinant of acute or chronic GVHD. Importance of CD34+ dose was reaffirmed in a subcohort of younger patients who received greater median cell doses than the overall cohort. In summary, for children who received unrelated PBSCT with ATG-based T-cell depletion for treatment of hematologic malignancy, the CD34+ dose was the most important factor for relapse and EFS, and neither the CD34+ nor the CD3+ dose influenced incidence of acute or chronic GVHD.

Outcome of Reinduction Chemotherapy with a Modified Dose of Idarubicin for Children with Marrow-Relapsed Acute Lymphoblastic Leukemia: Results of the Childhood Acute Lymphoblastic Leukemia (CALL)-0603 Study

This multicenter, prospective trial was conducted to develop an effective and safe reinduction regimen for marrow-relapsed pediatric acute lymphoblastic leukemia (ALL) by modifying the dose of idarubicin. Between 2006 and 2009, the trial accrued 44 patients, 1 to 21 years old with first marrow-relapsed ALL. The reinduction regimen comprised prednisolone, vincristine, L-asparaginase, and idarubicin (10 mg/m2/week). The idarubicin dose was adjusted according to the degree of myelosuppression. The second complete remission (CR2) rate was 72.7%, obtained by 54.2% of patients with early relapse < 24 months after initial diagnosis and 95.0% of those with late relapse (P = 0.002). Five patients entered remission with extended treatment, resulting in a final CR2 rate of 84.1%. The CR2 rate was not significantly different according to the idarubicin dose. The induction death rate was 2.3% (1/44). The 5-year event-free and overall survival rates were 22.2% ± 6.4% and 27.3% ± 6.7% for all patients, 4.2% ± 4.1% and 8.3% ± 5.6% for early relapsers, and 43.8% ± 11.4% and 50.0% ± 11.2% for late relapsers, respectively. Early relapse and slow response to reinduction chemotherapy were predictors of poor outcomes. In conclusion, a modified dose of idarubicin was effectively incorporated into the reinduction regimen for late marrow-relapsed ALL with a low toxic death rate. However, the CR2 rate for early relapsers was suboptimal, and the second remission was not durable in most patients.

Depletion of αβ+ T cells for a haploidentical hematopoietic stem cell transplantation in children

A consistent and reproducible depletion technique is crucial for the successful transplantation of an ex vivo depleted graft. Our aim was to evaluate the efficacy of an ex vivo technique for depletion of αβ+ T cells using a biotinylated anti‐TCRαβ monoclonal antibody, which was performed by one clinical nurse specialist. Between 2012 and 2017, 119 depletion procedures from 216 apheresis using the anti‐TCRαβ monoclonal antibody were performed on 105 pediatric patients. The median log depletion of αβ+ T cells was 4.0 (range, 2.5‐5.0). The median recovery rates of CD34+, NK, and γδ+ T cells were 90.4%, 74.9%, and 75.9%, respectively. The efficacy of depletion of αβ+ T cells significantly improved over time and the duration of the depletion procedure significantly decreased over time. Our study demonstrated that this procedure for depletion of αβ+ T cells by skilled staff is highly effective at depleting target cells and obtaining CD34+ progenitor cells.

αβ T-cell-depleted haploidentical hematopoietic cell transplantation and zoledronate/interleukin-2 therapy in children with relapsed, high-risk neuroblastoma

Outcomes in patients with relapsed, high-risk neuroblastoma have an extremely poor prognosis and novel treatment options are required [1]. For those patients, haploidentical hematopoietic cell transplantation (haplo-HCT) can be a potential option as it is expected to induce graftversus-tumor (GVT) effects on neuroblastoma [2, 3]. Limited reports investigating the use of haplo-HCT for neuroblastoma suggested a potential GVT effect, but this was not potent enough to prevent tumor progression in patients with a high tumor burden prior to transplant [4–6]. Haplo-HCT using αβ T-cell depletion provides grafts containing many γδ T lymphocytes and other effector cells. γδ T cells can kill tumor cells in an MHC-unrestricted manner without significant risk of graft-versus-host disease (GVHD) [7, 8]. In addition, it can provide a platform for further post-transplant immunotherapy to maximize the GVT effect. Zoledronate, a potent aminobisphosphonate, augments the cytolytic activity of γδ T cells [9]. Interleukin (IL)-2 is also required for the expansion of γδ T cells [10]. Therefore, zoledronate in combination with IL-2 can potentially augment the anti-neuroblastoma activity of γδ T cells, which can be enriched after αβ T-cell-depleted haplo-HCT. In this prospective pilot study of patients with relapsed, high-risk neuroblastoma, we aimed to use high-dose I-metaiodobenzylguanidine (MIBG) to reduce pretransplant tumor burden, followed by αβ T-cell-depleted haplo-HCT using RIC to utilize alloimmunity with minimal transplant-related toxicity. In addition, post-transplant immunotherapy using a combination of zoledronate and IL-2 was adopted to enhance the GVT effect of γδ T cells. The study was approved by the Institutional Review Board at the Asan Medical Center, Seoul, Korea. Between June 2015 and March 2016, four patients with relapsed, high-risk neuroblastoma after HDCT/ASCT, who showed at least partial response (PR) to salvage treatment, were enrolled and assigned a unique patient number (UPN 1–4). Patient characteristics are summarized in Table 1. Patients had received a median of six (range, 5–6) cycles of salvage chemotherapy after relapse prior to haplo-HCT. The median intervals between initial diagnosis and haplo-HCT, and relapse and haplo-HCT were 36.5 (range, 29–48) months, and 7 (range, 6–9) months, respectively. At 21 days prior to haplo-HCT, all patients received a single intravenous infusion of I-MIBG at a median dose of 11.8 (range, 10.5–11.9) mCi/kg. No immediate adverse events were observed. The RIC regimen comprised fludarabine (40 mg/m/day, days −8 to −5), thiotepa (10 mg/kg/ day, day −4), melphalan (70 mg/m/day, days −3 to −2) and rabbit anti-thymocyte globulin (ATG, Thymoglobulin, 2 mg/kg at day −9 and 1 mg/kg at day −8). RIC was well-tolerated and caused no serious regimen-related adverse events during the first 100 days post transplant. Peripheral blood stem cells were processed for αβ T-cell depletion using the CliniMACS system (Miltenyi Biotec). The target dose of CD34 cells were 5 × 10/kg and the minimum required dose was 3 × 10/kg. The efficacy of depletion was expected to be a 3to 4-log reduction in the αβ T cells. Graft manipulation and composition data are * Kyung-Nam Koh pedkkn@amc.seoul.kr

Neurocognitive Function and Health-Related Quality of Life in Pediatric Korean Survivors of Medulloblastoma

The neurocognitive function and quality of life of 58 Korean survivors of childhood medulloblastoma were assessed after surgery, cranial radiation and chemotherapy. All patients were evaluated with a battery of neurocognitive function tests and the Pediatric Functional Assessment of Cancer Therapy-Brain Tumor Survivors, which consists of self-report questionnaires on quality of life. The mean full-scale intelligence quotient (IQ), verbal IQ, and performance IQ scores were 90.2, 97.1, and 84.16, respectively. The mean memory quotient (MQ) score was 86.78, which was within 1 standard deviation of the average score of 100. Processing speed, attention, and executive function showed mild to moderate deficits. Intelligence, memory, executive function, visuospatial function, and simple motor function were significantly lower in the patients diagnosed before 8 years of age compared with those diagnosed after 8. The cognitive deficits in the patients diagnosed at younger ages might be related to earlier exposure to craniospinal irradiation and chemotherapy. The patient and parent proxy evaluations of attention, fine motor function, and quality of life did not differ. We found significant neurocognitive changes in a wide range of neurocognitive functional domains in Korean survivors of childhood medulloblastoma. Long-term follow-up studies of survivors of childhood medulloblastoma beginning at the time of their first diagnosis are required to better understand the deficits exhibited by survivors of childhood medulloblastoma, so that intervention strategies and treatment refinements that reduce the long-term neurocognitive decline can be developed.

Simultaneous rearrangements of TAL1 and LMO2 in T-cell acute lymphoblastic leukemia.

Sir, T-cell acute lymphoblastic leukemia (T-ALL) shows recurrent chromosomal rearrangements that activate several oncogenic transcription factors, such as TAL1, LYL1, LMO1, LMO2, HOXA, TLX1, and TLX3. Activation of these oncogenes results from translocations with TCR loci and some deletions or insertions. T-ALL cases showing a rearrangement affecting TAL or LMO oncogenes are common, although T-ALL cases showing rearrangements affecting both TAL and LMO have rarely been reported. Here, we report a pediatric T-ALL patient with simultaneous TAL1 and LMO2 rearrangements. A 9-year-old male patient presented with persistent fever. A peripheral blood smear revealed 89% lymphoblasts with a white blood cell count of 378.0 9 10/L. Bone marrow (BM) aspirates showed 96.6% lymphoblasts of medium size, irregularly shaped nuclei, inconspicuous nucleoli, and a miniscule to a small amount of cytoplasm. Flow cytometric immunophenotyping revealed a blast cell population positive for TdT, CD2, cytoplasmic CD3, CD4, CD5, CD7, and CD8 and negative for CD34, CD10, CD19, CD20, CD13, CD33, MPO, and CD56. These findings were consistent with a diagnosis of cortical T-cell ALL. A