Eun Seok Choi

Successful rescue of early graft failure in pediatric patients using T-cell-depleted haploidentical hematopoietic SCT

Graft failure (GF) is a significant complication after allogeneic hematopoietic stem cell transplantation (HCT) and is associated with a high mortality rate. We performed re-transplantation using haploidentical-related donors to rescue children with early GF. Between 2008 and 2013, 10 patients received re-transplantation from haploidentical family donors. The median age at HCT was 13.5 years and the median time between transplantations was 52.5 days. Conditioning regimen with fludarabine and CY was used in seven patients, and TBI was added in three patients. All 10 patients received T-cell-depleted grafts using CD3 or CD3/CD19 MoAb. The median numbers of CD34+ and CD3+ cells were 5.52 × 106/kg and 1.08 × 106/kg, respectively. For GVHD prophylaxis, mycophenolate mofetil (MMF) and tacrolimus or MMF and CYA were used. All 10 patients achieved a sustained neutrophil engraftment and maintained a complete donor chimerism at the time of analysis (median 23 months, range 6–62 months). Nine of 10 patients were alive, and one patient with moyamoya disease with AML died of encephalopathy 7 months post transplant. This study suggests that fludarabine- and CY-based conditioning with T-cell-depleted haploidentical HCT is a feasible option to rescue pediatric patients with primary GF.

Refinement of treatment strategies in ex vivo T-cell-depleted haploidentical SCT for pediatric patients

We evaluated the feasibility of T-cell-depleted haploidentical hematopoietic SCT (HHCT) in pediatric patients. Between July 2008 and January 2013, 28 patients underwent ex vivo T-cell-depleted HHCT; 9 had hematologic malignancy, 18 had nonmalignant hematologic disease, and 1 had refractory neuroblastoma. Twenty-six patients achieved neutrophil engraftment at a median of 11 days (range, 9–15 days). Two patients failed to achieve primary engraftment and five experienced graft rejection after primary engraftment. These seven patients achieved stable engraftment after a second HHCT. The cumulative incidences (CIs) of⩾grade II and⩾grade III acute GVHD were 33.3% and 14.3%, respectively, and the 1-year CI of extensive chronic GVHD was 11.1%. Four patients died of non-relapse-related causes (two of CMV disease, one of encephalopathy and one of autoimmune hemolytic anemia) and one of leukemia relapse. Non-relapse mortality at 100 days, 1 year and 2 years was 0.0%, 10.7% and 14.3%, respectively. At a median follow-up of 32.8 months (range, 17.0–72.5 months), the 2-year OS was 82.1%. OSs for nonmalignant diseases and malignant diseases were 94.4% and 60.0%, respectively (P=0.019). Thus, HHCT is a realistic alternative for patients with malignant or nonmalignant diseases who lack a suitable donor.

Unrelated hematopoietic stem cell transplantation for children with acute leukemia: experience at a single institution.

We evaluate the outcomes in children with acute leukemia who received allogeneic hematopoietic stem cell transplantation (HCT) using unrelated donor. Fifty-six children in complete remission (CR) received HCT from unrelated donors between 2000 and 2007. Thirty-five had acute myeloid leukemia, and 21 had acute lymphoid leukemia. Stem cell sources included bone marrow in 38, peripheral blood in 4, and cord blood (CB) in 14. Four patients died before engraftment and 52 engrafted. Twenty patients developed grade II-IV acute graft-versus-host disease (GVHD) and 8 developed extensive chronic GVHD. With median follow-up of 39.1 months, event free survival and overall survival were 60.4% and 67.5%, respectively, at 5 yr. Events included relapse in 10 and treatment-related mortality (TRM) in 10. The causes of TRM included sepsis in 4, GVHD in 4 (1 acute GVHD and 3 chronic GVHD), veno-occlusive disease in 1 and fulminant hepatitis in 1. Patients transplanted with CB had event free survival of 57.1%, comparable to 63.2% for those transplanted with other than CB. In conclusion, HCT with unrelated donors is effective treatment modality for children with acute leukemia. In children with acute leukemia candidate for HCT but lack suitable sibling donor, unrelated HCT may be a possible treatment option at the adequate time of their disease.

Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ + cells by add-back after a reduced intensity preparative regimen containing low-dose TBI

Between 2012 and 2015, 42 pediatric patients underwent haploidentical hematopoietic cell transplantation using an αβ+ T-cell-depleted graft with targeted αβ cells at 1–5 × 105/kg by add-back; 31 had hematologic malignancy (HM), 8 had non-malignant disease (NM) and 3 had solid tumors. All patients received uniform reduced-intensity conditioning with fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin and low-dose TBI. All 42 patients achieved neutrophil engraftment at a median of 10 days. The cumulative incidences (CIs) of ⩾grade II and ⩾grade III acute GvHD were 31±7.1% (SE) and 12±5.0%, respectively, and 1-year CI of chronic GvHD was 15±5.8%. One patient died of CMV pneumonia, leading to transplant-related mortality (TRM) of 2.6±2.5%. Sixteen patients relapsed and 11 died of disease. At a median follow-up of 19 months (range, 5–43 months), the estimated 2-year event-free survival for NM and HM were 88±11.7 and 50±10.1%, respectively. Our study demonstrated that haploidentical hematopoietic cell transplantation after ex vivo depletion of αβ+ T cells with targeted dose noticeably reduced the graft failure rate and TRM in pediatric patients and could be applied to patients lacking a suitable related or unrelated donor.

Successful use of brentuximab vedotin for refractory anaplastic large cell lymphoma as a bridging therapy to haploidentical stem cell transplantation and maintenance therapy post-transplantation

Brentuximab vedotin (BV) is a monoclonal antibody‐drug conjugate that targets CD30, and has been reported to be effective for relapsed/refractory anaplastic large cell lymphoma. We here report a patient who experienced multiple relapses after conventional chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). He achieved a complete metabolic response with BV and proceeded to undergo haploidentical HSCT. After HSCT, he received three doses of BV to prevent an early relapse, and remains in remission 16 months post‐transplantation. Our case suggests the potential use of BV both as a bridging therapy to allogeneic HSCT and as a maintenance therapy post‐transplantation. Pediatr Blood Cancer 2015;62:1063–1065.

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