Fumio Bessho

Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study.

The treatment outcome of multifocal childhood Langerhans cell histiocytosis (LCH) has not been satisfactory and has resulted in poor therapeutic responses with high mortality and a high incidence of reactivation with late sequelae. To overcome these issues, the Japan LCH Study Group‐96 (JLSG‐96) protocol was conducted prospectively from 1996 to 2001 in Japan.

Long-term follow-up of childhood acute lymphoblastic leukemia in Tokyo Children's Cancer Study Group 1981-1995.

The objectives were as follows: Firstly, to estimate the overall probability of event-free survival (EFS) and isolated CNS relapse in the studies for children with acute lymphoblastic leukemia (ALL) during the 1980s and 1990s. Secondly, to report the EFS according to presenting features and lineage. Thirdly, to evaluate the treatment results re-classified by the risks of NCI criteria. Four consecutive protocol studies were performed in the Tokyo Childrens Cancer Study Group: L81–10 protocol (1981–1984, 189 patients), L84–11 (1984–1989, 484 patents), L89–12 (1989–1992, 418 patients) and L92–13 (1992–1995, 347 patients). Overall EFS at 5 years in each protocol was 56.5 ± 3.8(1 s.e.)%, 71.0 ± 2.1%, 67.8 ± 2.3%, and 63.4 ± 2.7%, respectively. The cumulative isolated CNS relapse rate at 5 years was 8.1 ± 2.1%, 3.5 ± 0.9%, 3.6 ± 1.0%, 1.0 ± 0.6. The EFS in SR/HR (standard risk/high risk) according to the NCI criteria in B-precursor ALL at 5 years was 61.9 ± 4.3%/41.4 ± 7.4% (lineage was not confirmed.), 72.5 ± 2.6%/63.4 ± 5.0%, 77.4 ± 2.7%/56.3 ± 4.7%, and 67.8 ± 3.4%/56.7 ± 5.4% in each protocol. Also EFSs according to NCI SR/HR at 5 years of T-ALL in protocols L84–11, L89–12 and L92–13 were 55.6 ± 16.6%/60.9 ± 10.1%, 72.7 ± 13.4%/51.6 ± 9.1%, and 77.1 ± 14.4%/53.6/10.1%, respectively. The truncation of maintenance therapy to 6 months resulted in a decreased EFS in L92–13, particularly due to an increase of bone marrow relapse after cessation of therapy in SR and HR. The NCI risk criteria work properly even in the patients treated by different intensities, so that it makes the comparison possible among the patients in various groups. The overall EFSs in childhood ALL improved in 1980s, but it seemed stable or decreased in 1990s. The short maintenance therapy resulted in poor outcome in SR on the L92–13 protocol. Many of these late relapsers were effectively rescued and overall survival remained at a high level. The proportion of patients who received cranial irradiation reduced without any increase of the CNS events.

High serum values of soluble CD154, IL‐2 receptor, RANKL and osteoprotegerin in Langerhans cell histiocytosis

To determine useful biochemical markers in Langerhans cell histiocytosis (LCH), we analyzed the serum levels of soluble CD154 (sCD154), IL2 receptor (sIL2‐R), receptor activator of NF‐κB ligand (sRANKL), and osteoprotegerin (OPG).

Mosaic Down syndrome-associated acute myeloid leukemia does not require high-dose cytarabine treatment for induction and consolidation therapy

The present study aimed to identify optimal treatment intensity in children with mosaic Down syndrome (DS) and acute megakaryoblastic leukemia (AMKL). A retrospective review of AMKL patients was undertaken to identify mosaic DS children. Between November 1992 and November 2007, seven children were diagnosed as mosaic DS and AMKL. The median age at diagnosis was 29xa0months (range 4–34xa0months). Three patients had a past history of transient abnormal myelopoiesis. UPN1–4 were treated with intermediate-dose cytarabine and UPN4 received additional one course of high-dose cytarabine. All of these patients were remained in first CR. UPN5–7 were treated with high-dose cytarabine according to the AML99 protocol. UPN5 with GATA1 mutation suffered from acute pneumonia and pancreatitis and discontinued chemotherapy. UPN7 relapsed after cessation of chemotherapy and was rescued with allo-PBSCT. The cumulative doses of cytarabine were 3.5–10.65xa0g/m2 in the UPN1–4 and 40.4–78.4xa0g/m2 in the UPN5–7. The 8-year overall survival was 100% and the 8-year event-free survival 85.7%, respectively. Our retrospective study reveals that patients with mosaic DS and AMKL have a good prognosis. Reduction in intensity may work in patients with mosaic DS as well as with AML-DS.

Intensified and prolonged therapy comprising cytarabine, vincristine and prednisolone improves outcome in patients with multisystem Langerhans cell histiocytosis: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study.

The JLSG-96 study reported very low mortality rates for children newly diagnosed with multifocal Langerhans cell histiocytosis (LCH). The JLSG-02 study was performed to further improve the prognosis from 2002 to 2009. The present study compared the therapeutic results of these two studies in terms of multisystem disease. All patients were treated with 6xa0weeks of the Induction A regimen, comprising cytarabine, vincristine and prednisolone, followed by maintenance therapy. Poor responders to Induction A were switched to Induction B. JLSG-02 has been revised from JLSG-96 in the following respects: prednisolone dosage during Induction A increased; duration of maintenance therapy extended from 24 to 48xa0weeks; cyclosporine introduced to Induction B for progressive disease. One hundred forty-seven children with multisystem LCH were evaluated. Of these, 84 were positive for risk of organ involvement (RO) and 63 were RO-negative. At the 6-week point, 76.2xa0% of RO+ and 93.7xa0% of RO− patients responded to Induction A. Five-year event-free survival (EFS) was 46.2xa0% [95xa0% confidence (CI), 35.5–56.9] for RO+ and 69.7xa0% (58.4–81.1) for RO−, which was significantly superior to that in JLSG-96 [26.8xa0% (13.3–40.4) and 38.9xa0% (16.4–61.4), respectively]. The intensified induction and prolonged maintenance regimens in JLSG-02 improved EFS in patients with multisystem LCH.

Impact of reactivation on the sequelae of multi-system Langerhans cell histiocytosis patients.

To the Editor: We read with interest the article by Pollono et al., which reported the incidences of reactivation and sequelae in pediatric Langerhans cell histiocytosis (LCH) patients [1]. High incidence of sequelae remains a major challenge with the treatment of LCH, particularly in patients with multi-system LCH [2]. When comparing their therapeutic results with ours, we noted contradictory data in the reactivation and sequelae for patients in mutisystem LCH. Fifty-nine Japanese children less than 15 years of age (median age: 10 months), who were newly diagnosed as multi-system LCH, were treated with the JLSG-96 protocol [3] between 1996 and 2001. With a median follow-up of 6.8 years, 43 of the 59 (72.9%) patients had no evidence of active LCH lesions (NAD) after initial treatment. Of these 43 patients, 23 (53.5%) experienced reactivation(s) at least once (n1⁄4 1 in 10, n1⁄4 2 in 12, and n1⁄4 3 in 1 case); first reactivation was observed within 2 years in 18 and between 2 and 3 years in five patients. Incidence of reactivation did not differ significantly between the Pollono et al. study and ours. However, the incidence of sequelae was significantly different; 18.6 versus 66.2% (Table I). The impact of reactivation on sequelae was significant (P< 0.001) in our study, but not in the Pollono et al. study.Moreover, sequelae in the risk organ (RO) siteswere significantly lower in our series than in the Pollono et al. study (lungs; 2.3 vs. 10.8%and liver; 0.0 vs. 7.7%). We did not have any therapy-related sequelae. In our study, at the last follow-up of entire 59 patients, three patients (5.1%) had died of progressive disease, four patients (6.8%) had active disease and the remaining 52 patients (88.1%) were in NAD.A total of 14 patients (23.7%) had sequelae including diabetes insipidus (n1⁄4 8) and degenerative CNS disease (n1⁄4 3). Sequelaefree NAD status was observed in 40 patients (67.8% of total, 75.9% of patients less than 12 months old at diagnosis, 63.4% of patients with risk organ involvement, 57.1% of poor responders to the induction, and 52.2% of reactivated patients), and again, reactivation alone did significantly affect the long-term outcome (P1⁄4 0.04). The lower incidence of sequelae in our study could potentially be explained from rare or no sequelae in the RO sites aswell as in the high proportion of no reactivation group.We think that the intensive therapy leading to prompt treatment of LCH lesions is the most probable cause of few sequelae and it also negated poor prognostic factors such as onset age, RO involvement, and induction response in our study [3].

A complex t(1;22;11)(q44;q13;q23) translocation causing MLL-p300 fusion gene in therapy-related acute myeloid leukemia

The p300 protein shows a striking homology with cyclic‐AMP‐response‐element‐binding‐protein binding protein (CBP) and both proteins form a family of DNA‐binding transcriptional coactivators/histone acetyltransferases. The authors, herein, report a therapy‐related acute myeloid leukemia with MLL‐p300 fusion gene. Spectral karyotyping clarified that chromosome 11 is involved in complex t(1;22;11)(q44;q13;q23), and is fused to the chromosome 22, and direct sequencing revealed the fusion of exon 8 of MLL and exon 15 of p300 in this case. This is only the second reported case of leukemia with an MLL‐p300 fusion gene, and the other case with MLL‐p300 was also a therapy‐related leukemia. Considering that the MLL‐CBP fusion gene is also found almost exclusively in therapy‐related leukemia, the association of MLL‐p300 and MLL‐CBP with therapy‐related leukemia rather than de novo leukemia is thereby suggested.

Long-term follow-up of children with refractory immune thrombocytopenia treated with rituximab

Data on long-term outcomes of children with refractory immune thrombocytopenia (ITP) treated with rituximab are limited. We retrospectively analyzed the long-term effect of rituximab on 22 pediatric ITP patients (11 boys and 11 girls). Compete response (CR) (platelet count ≥100xa0×xa0109/L) and partial response (PR) (platelet count 30–99xa0×xa0109/L) were achieved in nine (41xa0%) and two (9xa0%) patients, respectively. Of the 11 responders, eight subsequently relapsed 2–26xa0months after initial rituximab treatment. The 5-year relapse-free rate was 14xa0% (3/22, 95xa0% confidence interval: 0–27xa0%) with a median follow-up period of 6.4xa0years. Five initial responders with subsequent relapse and one non-responder received multiple rituximab treatments of nine courses; all patients responded to the second rituximab therapy without any significant toxicity. All eight patients who relapsed after an initial response and six of 11 non-responders achieved CR or PR with subsequent treatment, including repeated courses of rituximab, splenectomy, steroids, and other immunomodulating agents. Our findings indicated that the sustained effect of rituximab on children with refractory ITP is low, but that the long-term outcome of ITP itself is not poor. Furthermore, repeated rituximab administration may be a promising therapy for those who relapse after an initial response.

In vitro drug resistance to imatinib and mutation of ABL gene in childhood Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia.

Imatinib, the ABL kinase inhibitor, is used not only for Philadelphia chromosome-positive (Phu200a+u200a) chronic myelogenous leukemia, but also for Phu200a+ acute lymphoblastic leukemia (ALL), although resistance to the drug tends to develop in an early stage of the clinical course. We describe a childhood refractory Phu200a+ ALL patient in whom progressive resistance to imatinib was correlated with the appearance of a mutation in the BCR-ABL kinase domain and in vitro drug resistance to imatinib as determined by the methyl-thiazol-tetrazolium (MTT) assay. A missense mutation of T to C (Y253H) of the ABL gene was identified in the resistant clone, suggesting that this mutation may play an etiological role in the rapid loss of drug sensitivity.

FAGGOT FORMATION IN MATURE NEUTROPHILS AND METAMYELOCYTES IN ACUTE MYELOID LEUKEMIA WITHOUT MATURATION

The authors report a rare case of acute myeloid leukemia (AML) M1 with faggot formation in mature neutrophils and metamyelocytes. Although Auer rods in mature neutrophils are occasionally experienced, they are usually found in AML M2, M3, or M4 cases, but not in M1 cases. In addition, faggot formation in mature neutrophils, as seen in this case, is considered to be particularly unusual because most previously reported cases tended to show simple Auer rods except for AML M3 cases. This case also showed trisomy 4 in its karyotype, although its relationship with faggot formation remains unclear.