Keiko Okada

Comparison of Intravenous with Oral Busulfan in Allogeneic Hematopoietic Stem Cell Transplantation with Myeloablative Conditioning Regimens for Pediatric Acute Leukemia

Recent reports revealed that intravenous (iv) busulfan (BU) may not only reduce early nonrelapse mortality (NRM) but also improve overall survival (OS) probability in adults. Therefore, we retrospectively compared outcomes for 460 children with acute leukemia who underwent hematopoietic stem cell transplantation with either iv-BU (n = 198) or oral busulfan (oral-BU) (n = 262) myeloablative conditioning. OS at 3 years was 53.4% ± 3.7% with iv-BU and 55.1% ± 3.1% with oral-BU; the difference was not statistically significant (P = .77). OS at 3 years in 241 acute lymphoblastic leukemia and 219 acute myeloid leukemia patients was 56.4% ± 5.5% with iv-BU and 54.6% ± 4.1 with oral-BU (P = .51) and 51.0% ± 5.0% with iv-BU and 55.8% ± 4.8% with oral-BU (P = .83), respectively. Cumulative incidence of relapse at 3 years with iv-BU was similar to that with oral-BU (39.0% ± 3.6% and 36.4% ± 3.1%, respectively; P = .67). Cumulative incidence of NRM at 3 years was 16.6% ± 2.7% with iv-BU and 18.3% ± 2.5% with oral-BU (P = .51). Furthermore, multivariate analysis showed no significant survival advantage with iv-BU. In conclusion, iv-BU failed to show a significant survival advantage in children with acute leukemia.

Outcome of non-T-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation from family donors in children and adolescents.

Non-T-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (SCT) from family members has been reported, but its effectiveness and safety are not fully known. In this study, we examined the outcomes of 83 children and adolescents with nonmalignant (n = 11) or malignant (n = 72) disorders who underwent SCT mismatched at 2 or 3 HLA loci, either from the mother (n = 56), a noninherited maternal antigen (NIMA)-mismatched sibling (n = 14), or the father/a noninherited paternal antigen (NIPA)-mismatched sibling (n = 13). Engraftment was satisfactory. Severe (grade III-IV) acute graft-versus-host disease (GVHD) was noted only in malignant disease, with an incidence of 21 of 64 evaluable patients. GVHD prophylaxis with a combination of tacrolimus and methotrexate was significantly associated with a lower risk of severe acute GVHD, compared with other types of prophylaxis(P = .04). Nine of 11 patients with nonmalignant disease and 29 of 72 patients with malignant disease were alive at a median follow-up of 26 months (range, 4-57 months). Outcomes were not significantly different among the 3 donor groups (mother versus NIMA-mismatched sibling versus father/NIPA-mismatched sibling) for the malignancy disorders. Our results indicate that non-T-cell-depleted HLA-haploidentical SCT may be feasible, with appropriate GVHD prophylaxis, for young recipients who lack immediate access to a conventional stem cell source.

Phase I Study of Bevacizumab Plus Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors

OBJECTIVE Studies have suggested that bevacizumab has shown activity against various pediatric solid tumors. We, therefore, conducted a Phase I study of bevacizumab plus irinotecan in Japanese children with recurrent, progressive or refractory solid tumors. METHODS The starting dose was bevacizumab 10 mg/kg over 60-90 min and irinotecan 125 mg/m(2) over 90 min intravenously on Days 1, 15 and 29. The dose of irinotecan was 340 mg/m(2) for patients receiving enzyme-inducing antiepileptic drugs. Treatment was repeated every 6 weeks for up to three courses in the absence of disease progression or unacceptable toxicity. RESULTS Of 11 patients, 9 (median age, 9 years) were fully assessable for toxicity and received 24 courses. Dose-limiting toxicities were Grade 2 diarrhea and Grade 4 neutropenia/thrombocytopenia in two of the five patients at dose level 1. No dose-limiting toxicities were observed in four patients at dose level -1 at bevacizumab 10 mg/kg and irinotecan 100 mg/m(2) (270 mg/m(2) for patients taking enzyme-inducing antiepileptic drugs). The maximum-tolerated dose was bevacizumab 10 mg/kg and irinotecan 100 mg/m(2). The most frequent non-dose-limiting toxicities were Grade 1 or 2 hypertension, bleeding and hematologic toxicity. One patient with optic nerve glioma had a partial response. Three patients with medulloblastoma, optic nerve glioma and diffuse intrinsic pontine glioma had stable disease. CONCLUSIONS Combination chemotherapy of bevacizumab plus irinotecan was well tolerated in children. We plan Phase II pediatric studies at doses of bevacizumab 10 mg/kg and irinotecan 100 mg/m(2) every 2 weeks (270 mg/m(2) for patients taking enzyme-inducing antiepileptic drugs).

Sorafenib treatment in children with relapsed and refractory neuroblastoma: an experience of four cases.

Metastatic neuroblastoma is an aggressive malignancy with a poor prognosis. Recent findings have shown that sorafenib decreases cell viability and increases apoptosis in human neuroblastoma cell lines. We report an experience of compassionate use of sorafenib in children with treatment‐refractory neuroblastoma. Sorafenib showed transient anti‐tumor activity in all four patients without adverse effects. However, progression was observed after a short stabilization phase. While sorafenib showed minimal anti‐tumor activity in our patients, it might still be effective in patients with neuroblastoma in an earlier stage.

Impact of graft-versus-host disease on relapse and survival after allogeneic stem cell transplantation for pediatric leukemia

Graft-versus-host disease (GVHD) occasionally leads to morbidity and mortality but is thought to reduce the risk of relapses in patients with a hematological malignancy. However, information on the effect of GVHD in pediatric leukemia is limited. Using a nationwide registry, we retrospectively analyzed 1526 children who underwent allogeneic stem cell transplantation for leukemia. Grades 0–I acute GVHD were associated with a higher relapse rate at three years after transplantation, at 25.4 and 24.3%, respectively, than grades II, III, or IV acute GVHD at 18.9%, 21.2%, and 2.6%, respectively. In contrast, the overall survival curve of the grades 0 and I GVHD groups (79.0% and 79.5%, respectively) approximated that of the grade II GVHD group (76.3%), and the probability of survival was worst in the severe GVHD groups (66.9% for grade III and 42.5% for grade IV). Chronic GVHD also reduced the relapse risk but conferred no survival advantage. Acute lymphoblastic leukemia was more sensitive to acute GVHD than acute myeloid leukemia (AML) while AML was more sensitive to chronic GVHD. Our study reproduced the preventive effects of GVHD against pediatric leukemia relapses but failed to demonstrate a significant survival advantage.

Comparison of second transplantation and donor lymphocyte infusion for donor mixed chimerism after allogeneic stem cell transplantation for nonmalignant diseases

Donor mixed chimerism (MC) is an increasing problem after hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases.

Allogeneic hematopoietic stem cell transplantation for children and adolescents with high-risk cytogenetic AML: distinctly poor outcomes of FUS-ERG -positive cases

Allocating patients with acute myeloid leukemia and high-risk cytogenetic abnormalities (HR-AML) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is part of the standard treatment protocol; however, whether allo-HSCT truly improves the outcomes in these patients is debatable. Data on 169 children and adolescents with HR-AML who received their first allo-HSCT in first or second remission between 2000 and 2015 were extracted from a nationwide, Japanese HSCT registry. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 55.2% (95% CI, 46.8–62.9%) and 69.6% (61.4–76.3%), respectively, for all the HR-AML patients. In univariate analysis, the cytogenetic subgroup had a significant impact on both the DFS (P = 0.011) and OS (P < 0.001) rates. In particular, 14 patients with t(16;21) showed an extremely poor outcome. Additionally, older age at allo-HSCT (10–19 years old, P = 0.025), myeloablative conditioning with total-body irradiation (P = 0.019), and grade II–IV acute graft-versus-host disease (GVHD, P = 0.049) were associated with inferior OS. The donor type and occurrence of chronic GVHD did not affect the outcome. Multivariate analysis revealed t(16;21) to be associated with increased overall mortality (hazard ratio = 4.416, P < 0.001). Because the outcome of patients with certain HR-AML subgroups, such as t(16;21)-positive cases, is extremely poor even with allo-HSCT in remission, a novel therapy is urgently required.

Acute Myeloid Leukemia With RBM15-MKL1 Presenting as Severe Hepatic Failure

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