Masahiro Sekimizu

Chromosome abnormalities in advanced stage T-cell lymphoblastic lymphoma of children and adolescents: a report from Japanese Paediatric Leukaemia/Lymphoma Study Group (JPLSG) and review of the literature

T‐cell acute lymphoblastic leukaemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL) are combined into one category as T lymphoblastic leukaemia/lymphoma in the current World Health Organization (WHO) classification. However, there is still ongoing discussion on whether T‐ALL and T‐LBL are two separate entities or represent two variant phenotypes of the same disease. Cytogenetic analysis has been used to identify the molecular background of haematological malignancies. To compare the distribution of chromosomal abnormalities of T‐ALL and T‐LBL, large series of cytogenetic data are required, but are absent in T‐LBL in contrast to the abundant data in T‐ALL. Among 111 T‐LBL cases in our clinical trial, we obtained complete cytogenetic data from 56 patients. The comparison between our cytogenetic findings and those from three published T‐LBL studies revealed no significant difference. However, meta‐analysis showed that translocations involving chromosome region 9q34 were significantly more common in T‐LBL than in T‐ALL. In particular, four out of the 92 T‐LBL cases, but none of the 523 paediatric T‐ALL cases, showed translocation t(9;17)(q34;q22–23) (P = 0·0004). Further studies are needed for the possible linkage between abnormal expression of genes located at 9q34 and/or 17q22–23 and the unique ‘lymphoma phenotype’ of T‐LBL.

A case of NUT midline carcinoma with complete response to gemcitabine following cisplatin and docetaxel.

Background: NUT midline carcinoma (NMC) is recognized as a very rare tumor that most often occurs around the midline and shows NUT rearrangement. This tumor affects children and younger adults, progresses rapidly, and shows an extremely poor prognosis, even with intensive chemotherapy. Very few reports have described effective treatment for this tumor. Methods: A 12-year-old girl with NMC was treated using cisplatin (CDDP), docetaxel, gemcitabine, pemetrexed, and vinorelbine. Results: Imaging showed partial response with CDDP and docetaxel, and complete response with gemcitabine. After reexacerbation of the tumor, although partial response was achieved with vinorelbine, the patient died 89 weeks after onset because of reexacerbation. Conclusions: NMC is a very rare disease with poor prognosis. This study is the first to report response of NMC to gemcitabine and vinorelbine. The findings suggest that combination chemotherapies including CDDP, docetaxel, gemcitabine, and vinorelbine may be a choice in the treatment for NMC.

Prognostic Impact of Intensified Maintenance Therapy on Children With Advanced Lymphoblastic Lymphoma: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study.

Childhood advanced lymphoblastic lymphoma (LBL) has a favorable outcome with an event‐free survival (EFS) rate of over 80% in response to treatment strategies for acute lymphoblastic leukemia (ALL). However, no progress has been made in this outcome over the past 10 years.

Osteosarcoma After Bone Marrow Transplantation

Three children treated with bone marrow transplantation for acute lymphoblastic leukemia, Diamond-Blackfan anemia, and congenital amegakaryocytic thrombocytopenia developed secondary osteosarcoma in the left tibia at the age of 13, 13, and 9 years, respectively, at 51, 117, and 106 months after transplantation, respectively. Through treatment with chemotherapy and surgery, all 3 patients are alive without disease. We surveyed the literature and reviewed 10 cases of osteosarcoma after hematopoietic stem cell transplantation (SCT), including our 3 cases. Eight of the patients had received myeloablative total body irradiation before SCT. The mean interval from SCT to the onset of osteosarcoma was 6 years and 4 months, and the mean age at the onset of osteosarcoma was 14 years and 5 months. The primary site of the post-SCT osteosarcoma was the tibia in 6 of 10 cases, in contrast to de novo osteosarcoma, in which the most common site is the femur. At least 7 of the 10 patients are alive without disease. Osteosarcoma should be one of the items for surveillance in the follow-up of patients who undergo SCT.

Prognostic impact of cytogenetic abnormalities in children and adolescents with mature B-cell non-Hodgkin lymphoma: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

Little information is available on cytogenetic abnormalities and their prognostic importance in childhood mature B‐cell non‐Hodgkin lymphoma (B‐NHL). We performed a review of 79 abnormal karyotypes in childhood B‐NHL treated by a uniform protocol. Del(17p) was independently associated with significantly inferior event‐free survival in Burkitt or Burkitt‐like lymphoma. The adverse prognosis of MYC/8q24 rearrangement, +7q or del(13q), was not observed, which had been suggested as risk factors in FAB/LMB96. Our results imply the possible existence of a biological difference among ethnicities and should be useful to narrow down the gene causing poor prognosis in childhood B‐NHL. Pediatr Blood Cancer 2015;62:1294–1296.

Randomized study of granulocyte colony stimulating factor for childhood B-cell non-Hodgkin lymphoma: a report from the Japanese pediatric leukemia/lymphoma study group B-NHL03 study

Abstract The objective of this study was to assess the impact of the primary prophylaxis of granulocyte colony-stimulating factor (G-CSF) in the management of childhood B-cell non-Hodgkin lymphoma (B-NHL). Patients with advanced-stage mature B-NHL were randomized to receive prophylactic G-CSF (G-CSF+) or not receive G-CSF (G-CSF−) based on protocols of the B-NHL03 study. The G-CSF group received 5 μg/kg/d Lenograstim from day 2 after each course of six chemotherapy courses. Fifty-eight patients were assessable, 29 G-CSF + and 29 G-CSF−. G-CSF + patients showed a positive impact on the meantime to neutrophil recovery and hospital stay. On the other hand, they had no impact in the incidences of febrile neutropenia, serious infections, stomatitis and total cost. Our study showed that administration of prophylactic G-CSF through all six chemotherapy courses for childhood B-NHL showed no clinical and economic benefits for the management of childhood B-NHL treatment.

Treatment of pediatric lymphoma in Japan: Current status and plans for the future

Results of pediatric lymphoma treatment have improved markedly over the past 30 years. In Hodgkins lymphoma, the 5 year event‐free survival (EFS) was 81.5% in a retrospective study. In the ALB‐NHL03 study, the 5 year EFS according to clinical stage in patients with lymphoblastic T‐cell lymphoma (T‐LBL) was 70.6% for stage III and 88.9% for stage IV. In mature B‐cell lymphoma, the B‐NHL03 study indicated that the 4 year EFS according to treatment group was 94% for group 1, 98% for group 2, 84% for group 3, and 78% for group 4. Moreover, the 2 year EFS rate was 81% in Japanese advanced stage patients based on the international ALCL99 study. Thus, EFS >80% was achieved in any subtype of pediatric lymphoma. With regard to refractory or recurrent lymphoma, however, treatment methods for improvement of the survival rate in these patients still need to be developed. Also the difference between child, and adolescent and young adult patients still needs to be clarified, and treatment protocols developed. Although lymphoma treatment does not greatly change according to country, it does differ between other countries and Japan for some subtypes of lymphoma. In particular, the results of treatment of stage III T‐LBL in Japan are worse than those in the USA and Europe. The priority in future studies will be to collect data on these differences, and the reasons for these differences.

Phase II trial of CH5424802 (alectinib hydrochloride) for recurrent or refractory ALK-positive anaplastic large cell lymphoma : study protocol for a non-randomized non-controlled trial

ABSTRACT Currently, a standard therapy has not been established for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. While there are many treatment options, such as hematopoietic stem cell transplantation, patients with resistant disease to conventional chemotherapies have particularly poor prognosis. There is urgent need to develop new drugs because of the lack of a standard therapy and poor prognoses. This phase II trial is designed for evaluating the efficacy and safety of alectinib hydrochloride for patients with recurrent or refractory anaplastic lymphoma kinase -positive anaplastic large cell lymphoma. The primary endpoint is the response rate according to the Revised Response Criteria for Malignant Lymphoma. The secondary endpoints are pharmacokinetics, safety in children, complete response rate, response duration, progression-free survival, event-free survival, overall survival, and adverse events. The results of this trial will be the pivotal data for the drug approval of alectinib hydrochloride for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.

Efficacy and safety of administering pediatric treatment to adolescent patients with mature B-cell non-Hodgkin lymphoma within the Japanese Pediatric Leukemia/Lymphoma Study Group clinical trial

Currently, there is no standardized treatment for adolescents, aged 15 years or older, with mature B‐cell non‐Hodgkin lymphoma (B‐NHL), although this age group has been reported to have a poorer prognosis than younger patients.

Clinical Features and Prognosis According to Immunophenotypic Subtypes Including the Early T-Cell Precursor Subtype of T-Lymphoblastic Lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study

We reviewed the immunophenotypic subtypes of pediatric T-cell lymphoblastic lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 study. Of the 104 patients, 40 patients each had sufficient data to evaluate the immunophenotypes and early T-cell precursor (ETP) subtype. Pro-T, pre-T, intermediate T, and mature T cells were observed in 1, 9, 21, and 9 cases, respectively. The 3-year event-free survival (EFS) rates of those with pro-T/pre-T, intermediate T, and mature T cells were 80.0±12.6%, 71.4±9.9%, and 88.9±10.5%, respectively (P=0.546). There were 8 and 32 cases of ETP and non-ETP subtypes, with 3-year EFS rates of 75.0±15.3% and 71.9±8.0%, respectively (P=0.828), indicating that the immunophenotypic subtype was not predictive of EFS in this study.