Atsuro Saito

Prevention of chemotherapy-induced vomiting in children receiving multiple-day cisplatin chemotherapy: A hospital-based, retrospective cohort study: Kishimoto et al.

Optimal prevention of chemotherapy‐induced vomiting (CIV) has not been established for patients receiving cisplatin in divided doses. The aim of this study was to describe the incidence and risk factors of CIV in children who received multiple‐day cisplatin chemotherapy.

Low-dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high-risk pediatric acute myeloid leukemia

The dismal prognosis of pediatric acute myeloid leukemia (AML) relapsing after hematopoietic stem cell transplantation (HSCT) requires exploration of novel strategies to prevent relapse. Azacitidine (AZA) maintenance therapy could potentially reduce the recurrence rate post HSCT. Here, we presents the cases of three children with high‐risk AML post HSCT who were treated with low‐dose AZA maintenance therapy, demonstrating the feasibility of this therapy. Currently, all three are in complete remission for 13–41 months despite their high‐risk characteristics. Our encouraging data warrant larger prospective studies to assess the efficacy and safety of low‐dose AZA maintenance therapy post HSCT for pediatric patients with high‐risk AML.

Co-occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

We report a case of a neonate with Noonan syndrome presenting with concurrent hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia, which resulted in premature death. Cases with Noonan syndrome diagnosed during the neonatal period might not necessarily show mild clinical course, and premature death is a possible outcome to be considered.

Abstract A11: A pediatric ETV6-ABL1-positive acute lymphoblastic leukemia case with ETV6-ABL1-independent resistance to tyrosine kinase inhibitor

Introduction: ETV6-ABL1 fusion represents a rare subgroup of pediatric acute lymphoblastic leukemia (ALL) with unfavorable outcomes. ETV6-ABL1-positive ALL is recently identified in Philadelphia chromosome (Ph)-like ALL and exhibits a gene expression profile similar to BCR-ABL1-positive ALL. Analogous to BCR-ABL1 fusion, ETV6-ABL1 fusion results in the formation of constitutively active non-receptor tyrosine kinases that can also be targeted by selective ATP-competitive tyrosine kinase inhibitors (TKIs). Since TKIs are currently incorporated into the standard treatment of BCR-ABL1-positive ALL, they will be a promising option also for the treatment ETV6-ABL1-positive ALL. However, TKI resistance becomes a common problem in TKI-treated patients, where it is frequently caused by BCR-ABL1-dependent alterations including mutations, genomic amplification, and enhanced expression of BCR-ABL1-fusion kinase. In addition, BCR-ABL1-independent alterations have also been reported to cause TKI resistance. It includes a variety of activating and/or inactivating alterations in RAS, NF-kB, PI3K-AKT, and JAK-STAT signaling pathways that mediate the oncogenic activity of BCR-ABL1 fusion kinase. In contrast, the molecular mechanisms of TKI resistance have been poorly described in ETV6-ABL1-positive ALL, except for T315I mutation of ETV6-ABL1 fusion gene in a single patient and K89M mutation of GNB1 gene in a cell line model. Patient and Results: A previously healthy 14-year-old girl was admitted to our hospital because of persistent fever. Laboratory data showed white blood cell count of 417,800 /µL and increased LDH level and uric acid level. Bone marrow examination showed nuclear cell count of 855,000 /µL with 90.0% blastic cells of lymphoid morphology. Bone marrow blasts at initial diagnosis were positive for CD10, CD19, CD20, CD34, cyCD79a, cyTdT, HLA-DR, and CD66c; had a karyotype of 45, XX, -7; and were sensitive to TKIs (imatinib and dasatinib) in vitro. A split signal analyzed by ABL1 FISH probe was positive (92.7%), while major and minor BCR-ABL1 fusion transcripts were not detected by RT-qPCR. She was treated with the high-risk protocol based on BFM 95 protocol because of prednisolone poor response. After induction chemotherapy, she achieved complete remission (CR) without ABL1 split signal and IgH gene rearrangement. However, she relapsed 19 months after initial diagnosis, and failed to achieve second CR by alternating administration of dasatinib and antileukemic drugs. Bone marrow blasts at initial diagnosis and after relapse were subjected to whole-transcriptome sequencing. ETV6-ABL1 fusion transcripts were identified in both initial diagnostic and relapsed samples, and their level of expression was not significantly changed. No known alteration in ETV6-ABL1 fusion and GNB1 genes was detected. These results suggested a novel mechanism of TKI resistance in ETV6-ABL1-positive ALL. Conclusion: To our knowledge, this is a first case of ETV6-ABL1-positive ALL who acquired ETV6-ABL1-independent TKI resistance. It will provide a foundation for the treatment of TKI-resistant ETV6-ABL1-positive ALL. Citation Format: Suguru Uemura, Daiichiro Hasegawa, Akemi Shono, Khin Kyae Mon Thwin, Nanako Nino, Satoru Takafuji, Takeshi Mori, Akihiro Tamura, Nobuyuki Yamamoto, Atsuro Saito, Kenji Kishimoto, Toshiaki Ishida, Yoshiyuki Kosaka, Kazumoto Iijima, Noriyuki Nishimura. A pediatric ETV6-ABL1-positive acute lymphoblastic leukemia case with ETV6-ABL1-independent resistance to tyrosine kinase inhibitor [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A11.

Successful Treatment of Transplantation-associated Atypical Hemolytic Uremic Syndrome With Eculizumab

We herein reported a 4-month-old boy with transplantation-associated atypical hemolytic uremic syndrome (TA-aHUS) who was successfully treated with eculizumab. The patient diagnosed with type 3 of familial hemophagocytic lymphohistiocytosis underwent cord blood transplantation. After transplantation, he developed TA-aHUS, but plasma exchanges were unsuccessful. We identified deletions in CFH-related gene 1 (del-CFHR1) by the multiplex ligation-dependent probe amplification testing procedure and CFH autoantibodies. Eculizumab has been administered to the patient, with a marked improvement being achieved in thrombocytopenia. He has been well except for the persistent microhematuria for a year after transplantation. Uncontrolled complement activation might be involved in the pathophysiology of TA-aHUS.

Reemergence of translocation t(11;19)(q23;p13.1) in the absence of clinically overt leukemia

We report the case of a 10-year-old female with acute myeloid leukemia (AML) FAB M0 carrying a novel t(11;19)(q23;p13.1) MLL–ELL variant, in which intron 8 of MLL is fused to exon 6 of ELL. Complete remission, judged by morphology and cytogenetic analysis, was achieved after the conventional chemotherapy. Eight months after completion of therapy, the level of WT-1 in peripheral blood and the number of cells with the MLL–ELL fusion transcript resurged. However, the patient remained overtly healthy and the morphology in the bone-marrow smear was innocuous, with no sign of relapse or secondary leukemia. Without any evidence of relapse, the patient has been closely observed without any therapeutic intervention. For approximately 2 years after the completion of therapy, despite clonal proliferation of pre-leukemic cells with an MLL–ELL fusion gene, she has maintained complete remission. In this case, the rare variant form of MLL–ELL fusion that has been identified may be related to diminished leukemogenic capacity, resulting in the persistence of pre-leukemic status; an additional genetic abnormality may thus be necessary for full transformation of pre-leukemic cells.

Congenital immature pure erythroid leukemia with E-cadherin expression

Congenital pure erythroid leukemia is exceedingly rare and poses a diagnostic challenge. We report an atypical case of congenital pure erythroid leukemia that did not express typical erythroid markers. The patient presented with a high white blood cell count with blastic cells at birth. Although flow cytometric analyses of peripheral blood and bone marrow showed a large CD45-negative cell population, we did not identify any evidence of monoclonality. While the circulating blasts decreased with only supportive care, hepatomegaly with multiple nodules was accompanied by liver failure, disseminated intravascular coagulation, and development of hemophagocytic lymphohistiocytosis. Pathological examination of the liver biopsy specimen revealed a small round cell tumor that was negative for nearly all hematopoietic cell markers, including classical erythroid cell markers, and positive for CD43, CD71, and E-cadherin, an early erythroid marker epithelial calcium-dependent adhesion protein, suggesting that these tumor cells originated from an immature erythroblast. We found high β-catenin and c-Myc protein expression, which were not previously described in pure erythroid leukemia. Cytosine arabinoside temporarily alleviated clinical symptoms; however, the patient died of progressive disease at 8 months of age. This case indicates that E-cadherin is useful for diagnosing pure erythroid leukemia, even in immature cases.

Successful non-myeloablative allogenic bone marrow transplantation in a child with severe congenital neutropenia complicated by chronic pulmonary infection.

We herein describe a 2-year-old boy with severe congenital neutropenia (SCN) who was successfully treated with reduced-intensity bone marrow transplantation (HSCT). He had suffered recurrent episodes of bacterial pneumonia from 12 months of age, and was found to have severe neutropenia with white blood cell counts below 100/μl. The patient harbored a heterozygous missense mutation in ELANE exon 4 (p.Gln134Pro, NM_001972.2: c.401A>C). This was a novel mutation. Due to intractable pneumonia and severe persistent neutropenia, reduced-intensity HSCT was performed from an HLA-matched sibling donor. The preparative regimen consisted of melphalan, fludarabine, and 4 Gy of total body irradiation. Hematopoietic engraftment was rapidly obtained, i.e., by day +14, and complete donor chimerism was subsequently achieved. The lung complications observed pre-transplantation markedly improved after neutrophil recovery, i.e., by day +60. We concluded that HSCT is a useful treatment for SCN patients, especially for those at high risk of leukemic transformation. Fludarabine-based reduced-intensity HSCT may represent a safe and effective therapeutic option for patients with SCN who need HSCT even if they have intractable infectious complications.