Takako Miyamura

Activation of Akt is Associated With Poor Prognosis and Chemotherapeutic Resistance in Pediatric B-Precursor Acute Lymphoblastic Leukemia

Activation of the phosphoinositide 3‐kinase (PI3K)/Akt pathway, a pro‐survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B‐precursor acute lymphoblastic leukemia (B‐pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P‐Akt) in pediatric B‐pre ALL.

The Effects of Bone Marrow Transplantation on X-linked Hypophosphatemic Mice

The genes responsible for X‐linked hypophosphatemic (XLH) vitamin D‐resistant rickets and the murine homolog, hypophosphatemic mice (Hyp), were identified as PHEX and Phex (phosphate‐regulating gene with homology to endopeptidases on the X chromosome), respectively. However, the mechanism by which inactivating mutations of PHEX cause XLH remains unknown. We investigated the mechanisms by syngeneic bone marrow transplantation (BMT) from wild mice to Hyp mice. The expression of the Phex gene was detected in mouse BM cells. BMT introduced a chimerism in recipient Hyp mice and a significant increase in the serum phosphorus level. The renal sodium phosphate cotransporter gene expression was significantly increased. The effect of BMT on the serum phosphorus level depended on engraftment efficiencies, which represent the dosage of normal gene. Similarly, the serum alkaline phosphatase (ALP) activity was decreased and bone mineral density was increased. Furthermore, the renal expression of 25‐hydroxyvitamin D3 24‐hydroxylase, which is a key enzyme in the catabolic pathway and is increased in XLH/Hyp, was improved. From these results, we conclude that transplantation of normal BM cells improved abnormal bone mineral metabolism and deranged vitamin D metabolism in Hyp by replacing defective gene product(s) with normal gene product(s). This result may provide strong evidence for clinical application of BMT in metabolic bone disorders.

Early use of allogeneic hematopoietic stem cell transplantation for infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia

Sixty-two infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia (MLL-r ALL) were treated with the MLL03 protocol of the Japanese Pediatric Leukemia/Lymphoma Study Group: short-course intensive chemotherapy followed by early allogeneic hematopoietic stem cell transplantation (HSCT) within 4 months of the initial induction. The 4-year event-free survival and overall survival rates were 43.2% (95% confidence interval (CI)=30.7–55.1%) and 67.2% (53.8–77.4%), respectively. A univariate analysis showed younger age (<90 days at diagnosis), central nervous system disease and poor response to initial prednisolone therapy significantly associated with poor prognosis (P<0.05). In a multivariate analysis, younger age at diagnosis tended to be associated with poor outcome (hazard ratio=1.969; 95% CI=0.903–4.291; P=0.088). Although the strategy of early use of HSCT effectively prevented early relapse and was feasible for infants with MLL-r ALL, the fact that substantial number of patients still relapsed even though transplanted in their first remission indicates the limited efficacy of allogeneic HSCT for infants with MLL-r ALL. Considering the risk of severe late effects, indications for HSCT should be restricted to specific subgroups with poor risk factors. An alternative approach incorporating molecular-targeted drugs should be established.

Outcome of recurrent or refractory acute lymphoblastic leukemia in infants with MLL gene rearrangements: A report from the Japan infant leukemia study group

Despite the poor outcome of recurrent or refractory acute lymphoblastic leukemia (ALL) in infants with MLL gene rearrangement, few studies have focused on this specific group. We conducted a retrospective analysis of infants with recurrent or refractory ALL from two previous consecutive Japanese studies to clarify the characteristics and prognostic factors among these patients

Low Serum Concentrations of Anti-Müllerian Hormone Are Common in 53 Female Childhood Cancer Survivors

Background/Aims: Gonadal dysfunction is one of the major endocrinological late effects among childhood cancer survivors (CCSs). Periodic screening evaluation of gonadotropins and sex steroids has been recommended, although it remains difficult to predict gonadal function and reproductive capacity in childhood. We evaluated the effects of cancer treatments on the ovarian function of Japanese female CCSs by measuring serum levels of anti-Müllerian hormone (AMH) and gonadotropin. Methods: This was a retrospective, cross-sectional study at a single hospital. Results: Among 53 female CCSs, 28 (53%) had a decreased AMH level, while only 16 (30%) had an increased follicle-stimulating hormone (FSH) level. AMH was low in all patients with high FSH, while FSH was not elevated in 43% of patients with a low AMH level. AMH was low in 8 of 9 patients with no breast development, 11 of 14 patients with no spontaneous menstruation, and 3 of 22 patients with regular menstrual cycles. Conclusion: Measurement of AMH concentration is useful as a marker of ovarian reserve in female CCSs for detecting primary gonadal deficiency, particularly among patients without increased gonadotropin levels.

Clinical significance of minimal residual disease in childhood acute myeloid leukemia

Many studies have assessed the clinical significance of the detection of minimal residual disease (MRD) in acute leukemia.Thus far, many studies have suggested that MRD detection to evaluate the response to chemotherapy is useful for predicting the prognosis of childhood acute lymphoblastic leukemia (ALL). However, few studies have reported on the significance of MRD in childhood acute myeloid leukemia (AML), because of small numbers of patients and limited availability of MRD markers.Therefore, we monitored MRD using currently available markers at several points during the treatment for childhood AML and tried to intensify the treatment based on the results of MRD.Thirty-one patients (26 de novo cases and 5 other cases) were examined for MRD between February 1999 and May 2002.After the first consolidation therapy (consolidation 1), the expression of Wilms tumor gene (WT1) and/or leukemia-specific fusion genes such as AML1/MTG8,PML/RAR_, and MYH11/CBF_were analyzed. Patients with positive MRD but in hematological remission at that point were recommended to undergo stem cell transplantation (SCT). Positive WT1 expression (more than 103 copies/_g RNA) was detected in 18 of 31 patients (58.1%) at onset. After consolidation 1 therapy, the WT1 expression became negative in 14 of 18 patients. The AML1/MTG8 fusion gene was expressed in 8 patients,PML/ RAR_was expressed in 3 patients, and MYH11/CBF_ was expressed in 1 patient.Four of the 8 patients withAML1/MTG8 expression and all 3 with PML/RAR_expression also demonstrated positive WT1 expression at onset. Eight (5 de novo cases and 3 other cases) of the 31 patients had no available MRD markers. Four patients who showed persistently high expression of WT1 after consolidation 1 therapy underwent SCT, and only 1 patient remained in complete remission (CR). Among 14 patients who became negative for WT1 expression, 6 patients received SCT for various reasons. Among 8 patients with the AML1/MTG8 fusion gene, 2 became MRD negative and 6 continued to be positive. Four of these 6 patients underwent SCT, and all but one who underwent syngeneic SCT became MRD negative. On the other hand, 1 of the 2 patients who continued on chemotherapy continued to be MRD positive, suggesting a graft-versus-leukemia effect in allogeneic SCT. All patients with the PML/RAR_and MYH11/CBF_ fusion gene continued to be in CR. The 3-year event-free survival in de novo AML was 69.4% _ 9.8% (n = 26), a result that is encouraging and superior to other reported outcomes.Thus, an MRD-based treatment strategy together with conventional risk factors appears to be required for further improving the outcomes of AML.

Two cases of chronic active Epstein-Barr virus infection in which EBV-specific cytotoxic T lymphocyte was induced after allogeneic bone marrow transplantation.

Abstract:  CAEBV is a high mortality and morbidity disease with life‐threatening complications. Nevertheless, the treatment regimens for CAEBV have not yet been established. Although some reports have described CAEBV therapy involving treatments such as antiviral drugs, immunomodulatory agents, and immunochemotherapy, none of these treatments have been demonstrated to be effective. The only treatment reported to be effective is allogeneic SCT. However, the complications of SCT are severe, so treatment results have been poor. Recently, immunotherapy has been devised, but this is still in the developmental stage. In this report, two cases of CAEBV in which allogeneic SCT was performed soon after diagnosis are reported. In both cases, a high EBV genome titer in the peripheral blood was detected at onset. After SCT, the EBV genome titer decreased as CTL activity gradually increased. This fact suggested that not only high‐dose chemotherapy as a preconditioning treatment of SCT but also increased CTL activity which could eliminate virus‐infected cells might be effective, although additional cases should be studied in order to establish effective treatments.

ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases

The tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL), which had showed poor prognosis before the dawn of IM treatment. However, if Ph-ALL patients showed IM resistance due to ABL kinase mutation, second-generation TKI, dasatinib or nilotinib, was recommended. We treated 4 pediatric Ph-ALL patients with both IM and bone marrow transplantation (BMT); however, 3 relapsed. We retrospectively examined the existence of ABL kinase mutation using PCR and direct sequencing methods, but there was no such mutation in all 4 diagnostic samples. Interestingly, two relapsed samples from patients who were not treated with IM before relapse did not show ABL kinase mutation and IM was still effective even after relapse. On the other hand, one patient who showed resistance to 3 TKI acquired dual ABL kinase mutations, F359C at the IM-resistant phase and F317I at the dasatinib-resistant phase, simultaneously. In summary, Ph-ALL patients relapsed with or without ABL kinase mutation. Furthermore, ABL kinase mutation was only found after IM treatment, so an IM-resistant clone might have been selected during the IM treatment and intensive chemotherapy. The appropriate combination of TKI and BMT must be discussed to cure Ph-ALL patients.

Unrelated donor bone marrow transplantation for 100 pediatric patients: a single institute's experience

Summary:In all, 100 unrelated donor bone marrow transplantations (UD-BMT) were performed in our institute between October 1993 and January 2003. Of 93 evaluable patients, 73 patients had hematological malignancy, 13 had nonmalignancy and seven had lymphoproliferative disease. The estimated 9-year event-free survival (EFS) rate was 57.1±5.5% in all patients. In the following analyses of the patients with hematological malignancy, the standard group had significantly better EFS than the high-risk group (61.5±7.0 vs 35.6±9.7%, P=0.02), and the EFS rate of the tacrolimus (FK-506)+methotrexate (MTX)±methylprednisolone prophylactic group for graft-versus-host disease was superior to that of the FK-506 without MTX group (75.7±8.0 vs 55.8±7.6%, P=0.02). When we compared the EFS rates of the FK506+MTX±methylprednisolone (mPSL) group and the HLA-matched related donor BMT group in our institute, these were almost similar (75.7±8.1 vs 68.4±9.3%). Therefore, UD-BMT using FK-506+MTX±mPSL is a safe and useful method for children with hematological malignancy who require allogeneic BMT.

Mycobacterium avium complex-associated peritonitis with CAPD after unrelated bone marrow transplantation

Peritonitis remains an important complication of peritoneal dialysis and is mostly caused by aerobic enteric bacteria. Non‐tuberculous mycobacteria (NTM)‐associated peritonitis is an unusual but serious infection, requiring special culture techniques to avoid delay in diagnosis. We report the case of an 11‐year‐old girl with aplastic anemia on ambulatory peritoneal dialysis who had Mycobacterium avium complex‐associated peritonitis after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). This case emphasizes that we should be constantly cautious about NTM infection in allo‐HSCT recipients, especially when standard cultures are negative and the infection is refractory to empirical antibiotic therapy.