Makiko Mori

Addition of High-Dose Cytarabine to Fludarabine-Based Conditioning for Hematopoietic Stem Cell Transplantation for Treating Fanconi Anemia Patients with Advanced Myeloid Malignancy: A Single-Center Experience and Literature Review

The complication of Fanconi anemia (FA) with acute leukemia is rare and challenging to treat because of high relapse rates, despite the improved outcome of hematopoietic stem cell transplantation with fludarabine-based conditioning for treating FA patients with hematological abnormalities. We added high-dose cytarabine to fludarabine-based conditioning to promote an enhanced antitumor effect and successfully subjected 4 patients with FA, including 3 with acute leukemia, to hematopoietic stem cell transplantation. All patients remain alive without treatment-related mortality or evidence of disease. Adding high-dose cytarabine to fludarabine-based conditioning may be tolerable and effective for treating FA patients with acute leukemia.

Association between Chiari malformation and bone marrow failure/myelodysplastic syndrome.

An article in the Images in Haematology section of this journal reported an association between Chiari malformation and Fanconi anaemia (Deepak Amalnath et al, 2012). The authors reported that the detection of Chiari malformation was incidental, but we have encountered four patients (three male, one female) who had Chiari malformation and haematopoietic disorders (Table I). One patient had acute myeloid leukaemia resulting from Fanconi anaemia, and the other three patients had refractory cytopenia of childhood (RCC). Chromosomal breakage analysis with mitomycin C was performed for all four patients, and an increased chromosomal breakage was observed only in the Fanconi anaemia patient. Median age at diagnosis of haematopoietic disease and detection of Chiari malformation was 5 5 and 8 5 years, respectively. They had no family history of neurological or haematological disease. All of them had normal results on neurological examination, and no developmental delay was suspected. Chiari malformation was detected using magnetic resonance imaging at the screening examination before haematopoietic stem cell transplantation (HSCT; Fig 1). All patients underwent HSCT with a reduced intensity conditioning regimen that included low-dose total body irradiation (TBI), and did not experience any neurological adverse

Successful switching from eltrombopag to romiplostim in a pediatric patient with refractory chronic ITP.

Herein, we report a successful treatment experience with romiplostim in a child with immune thrombocytopenia (ITP) refractory to eltrombopag. A 9-year-old female developed chronic ITP, which was refractory to standard treatments, including intravenous immunoglobulin, cepharanthine and splenectomy, and she thus became dependent on prednisolone (PSL). At age 12 years, eltrombopag was started, but failed to increase her platelet count. Another thrombopoietin receptor agonist (TPO-RA), romiplostim, possibly having a different mechanism of action, was then administered. Platelet counts increased and PSL could thus be terminated. Our case suggests TPO-RA alteration to potentially be effective for chronic refractory ITP.

Hypoxic adaptation of leukemic cells infiltrating the CNS affords a therapeutic strategy targeting VEGFA

To the editor: The central nervous system (CNS) is a key site of extramedullary disease in pediatric acute lymphoblastic leukemia (ALL),[1][1] and prior to the development of contemporary risk-adapted treatment strategies, CNS involvement was inevitable in most cases.[1][1] However, the biology of

A pediatric case of acute megakaryocytic leukemia with double chimeric transcripts of CBFA2T3-GLIS2 and DHH-RHEBL1

Approximately 20% of the pediatric acute myeloid leukemia (AML) cases show normal karyotypes without any recognizable cytogenetic alteration on conventional cytogenetic analysis. Recent state-of-the-art techniques have unveiled several previously undetected chimera transcripts in these cytogenetically normal leukemias. One of those chimeric genes, CBFA2T3-GLIS2, formed by the fusion of CBFA2T3, a member of the ETO family of nuclear corepressors, and GLIS2, a member of the GLI family of transcription factors, has been detected in non-Down syndrome acute megakaryocytic leukemia (AMkL), as well as in some other non-megakaryoblastic AML subtypes (FAB-M0, M1, M2, M4, M5, M5a) [1,2]. Multiple chimeric CBFA2T3-GLIS2 transcripts have been reported: CBFA2T3ex10/GLIS2-ex3 [1], CBFA2T3-ex10/GLIS2-ex2, and CBFA2T3-ex11/GLIS2-ex3 [2]. Although patients with CBFA2T3-GLIS2-positive AMkL have a very poor prognosis, the pathogenesis of this disease largely remains unknown. Desert Hedgehog-Ras Homologue Enriched in Brain Like 1 (DHH-RHEBL1) is another cryptic chimera transcript involving DHH, a member of Hedgehog family, and RHEBL1, a small GTPase of the Ras family. This chimeric transcript is found exclusively in CBFA2T3-GLIS2-positive leukemic cells, and the eight-year overall survival rates of patients positive for both these pathological transcripts were found to be worse than those of CBFA2T3-GLIS2rearranged patients not harboring the DHH-RHEBL1 chimera [3]. The biological mechanism and clinical significance of this second chimera remain unknown. A previously healthy one-year-old girl without Down syndrome was admitted for low-grade fever, facial nerve palsy, and solid tumor in her left thigh. The fever and palsy had manifested three days prior to admission, and the patient’s parents had recognized the tumor one month prior to admission. Positron emission tomography – computed tomography revealed multiple tumors in the left mastoid antrum and intracranial epidural space, as well as in the intramuscular space of the left thigh. Bone marrow (BM) aspiration revealed myeloperoxidase-negative blast cells, which constituted 76.4% of all nucleated cells. The blast cells were morphologically distinct in that they had blebs on their surface. Flow cytometry analysis of the leukemic cells revealed that they were positive for CD19, CD33, CD34, CD41, CD61, and CD56. Karyotype analysis showed complex karyotypes (Supplementary Table). The leukemic cells were positive for both CBFA2T3-GLIS2 (CBFA2T3-ex11/GLIS2-ex3) and DHH-RHEBL1 (DHH-ex2/RHEBL1-ex2) chimeric transcripts; RNA sequencing or conventional Sanger sequencing revealed no other chimeric mRNAs, including RBM15-MKL1 (OTT-MAL) and NUP98-JARID1A. The absence of an MLL split signal in a fluorescent in situ hybridization assay indicated no involvement of MLL. The histologic findings of a tumor biopsy from the mastoid lesion were consistent with the diagnosis of myeloid sarcoma (MS), and both CBFA2T3GLIS2 and identical DHH-RHEBL1 transcripts were detected in this biopsy specimen. On the basis of these findings, we arrived at a final diagnosis of AMkL with MS. We initiated treatment with the AML99 protocol, which is characterized by continuous 12-day-long cytarabine-based induction therapy and by augmented usage of cytarabine [4]. Complete remission including reduction of MSs was achieved after induction therapy. Although MS lesions were well controlled, leukemic blast cells were again observed in the BM after the first course of consolidation, resulting in a diagnosis of first relapse. A cord blood transplant (CBT) was performed in non-remission status with M3 marrow and MS recurrence (Figure 1, Supplementary Table). Although the clinical course of the CBT was largely uneventful, MS was identified in the intramuscular space of the left thigh on day 64 after CBT, resulting in a diagnosis of second relapse of AMkL.

Clinical and molecular characteristics of MEF2D fusion-positive precursor B-cell acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion

Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic μ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients. Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.

Reversible Cerebral Vasoconstriction Syndrome during Chemotherapy for Acute Lymphoblastic Leukemia

A previously healthy 7-year-old boy, who was diagnosed with B-cell precursor acute lymphoblastic leukemia without central nervous system infiltration,was being treated with the standard risk protocol of the Japanese Pediatric Leukemia/Lymphoma Study Group B12. He had already completed induction therapy, early intensification, and intensification without any severe adverse effects, and had just started the first reinduction therapy.After he had received oral dexamethasone10mg/mdaily fromday1,vincristine1.5 mg/m and pirarubicin 25 mg/m on day 1, and L-asparaginase 10 000 U/m on days 1 and 4, thunderclap headaches developed on days 6 and 7 without high blood pressure or abnormal electrolytes. Although the headaches improved with loperamide, cerebral magnetic resonance angiography on day 7 revealed vasoconstriction (Figure, A). Cerebrospinal fluid examination on the following day was normal. He continued with chemotherapy along with nifedipine and did not develop aheadacheuntil after finishing the entire chemotherapy regimen. Antithrombin III was replacedwhen its activity was <70%.The irregular narrowing arteries disappeared in 5months without any parenchymal abnormalities (Figure, B), and we diagnosed it as reversible cerebral vasoconstriction syndrome (RCVS). RCVS is characterized by thunderclap headaches with or without additional neurologic symptoms and vasoconstriction of the cerebral arteries. It spontaneously resolves in 1-3months. Although anticancer drugs are not generally considered to be putative precipitants, a few cases of RCVS complicated with cerebral infarction in pediatric patients with leukemia have been recently reported. Tibussek et al suspected that intrathecal cytarabine was associated with the vasoconstriction. However, our patient had not received intrathecal cytarabine for >3 weeks; the other drugs could have induced the condition. L-asparaginase is well known to cause thrombosis during chemotherapy induction, but that disorder is venous in general and does not appear similar to the arterial findings in our patient. As cerebral infarction usually occurs after the first thunderclap headache, appropriate intervention in RCVS may prevent the complications, such as infarction and hemorrhage. Nimodipine is usually given for the treatment and prevention of RCVS. ■

Excellent prognosis of patients with intermediate-risk neuroblastoma and residual tumor postchemotherapy

BACKGROUND/PURPOSE The prognosis of patients with intermediate-risk neuroblastoma is favorable; therefore, a reduction therapy is desired. However, the long-term prognosis of those with residual tumor is unclear. The aim of this study was to clarify the necessity of residual tumor resection. METHODS We retrospectively reviewed the records of patients diagnosed with intermediate-risk neuroblastoma who either were treated by chemotherapy only (nonresection group; n=16), or received postchemotherapy tumor resection (resection group; n=9). RESULTS In the nonresection group, tumor size decreased in 14 patients; 5 had no detectable local tumor at the end of the follow-up period. Tumor size increased in 2 patients 1.5-2.5years postchemotherapy. Both patients received additional treatment and survived. All patients survived during the median follow-up time of 127months. In the resection group, 5 patients received complete resections and 4 patients received nearly complete resections. All patients survived during the median follow-up time of 84months. In 8 out of 9 resected tumors, regression or maturation was pathologically induced by chemotherapy-only treatment. CONCLUSION Patients with intermediate-risk neuroblastoma with or without postchemotherapy residual tumor resection had an excellent long-term outcome. The tumor pathology with intermediate-risk neuroblastoma might be susceptible to change to regression or maturation by chemotherapy. LEVEL OF EVIDENCE IV.

Contraindications and image-defined risk factors in laparoscopic resection of abdominal neuroblastoma

PurposeMinimally invasive surgery (MIS) has become widely accepted as a technique for abdominal neuroblastoma resection. However, the indications for MIS are still controversial. The aim of this study was to evaluate image-defined risk factors (IDRFs), complications, and oncologic outcomes in patients with abdominal neuroblastomas treated with MIS.MethodsBetween August 1998 and February 2016, MIS was planned for 20 children with abdominal neuroblastomas. Clinical data were retrospectively reviewed and compared between the IDRF-negative and IDRF-positive patients.ResultsOn the basis of the latest IDRF guidelines, five patients were classified as IDRF-positive and four of them had operative complications; namely, partial infarction of the ipsilateral kidney or open conversion. Concerning the two patients who needed open conversion, the primary reason for open conversion was difficulty in dissection of the tumor from the vena cava. Preoperative images of these cases showed either deformation or subtotal encasement of the vena cava. Relapse occurred in three high-risk patients and in none of the low/intermediate-risk patients. No complication occurred in the IDRF-negative cases.ConclusionsIDRF-negative might be a good indication for MIS for abdominal neuroblastoma. However, deformation or subtotal encasement of the vena cava should be considered as IDRF-positive for MIS.