Chimeric antigen receptor (CAR)-transduced T (CAR-T) cell therapy is an emerging cancer immunotherapy and has made remarkable progress in recent years. CAR-T cell therapy targeting CD19 (tisagenlecleucel) has shown remarkable efficacy in the treatment of recurrent and refractory B-cell leukemia and lymphoma and has been covered by the national health insurance in Japan since 2019. However, an effective CAR-T cell therapy against acute myeloid leukemia (AML) and solid tumors has not yet been established. One of the major issues is the difficulty in identifying appropriate antigens that are expressed specifically in tumors and can be attacked by CAR-T cells. Conventional CARs recognize antigens on the surface of target cells using single-chain variable fragments derived from monoclonal antibodies. On the other hand, the physiological binding of natural receptors to their ligands is also available for the antigen recognition of CAR. Natural killer (NK) cells are effector lymphocytes of the innate immune system, which can mediate spontaneous cytotoxicity against transformed cells. Various CARs utilizing the binding capability of activating receptors expressed by NK cells to ligands expressed on tumor cell surface have been reported. Among them, CAR-T cells endowed with the antigen recognition capability of natural killer group 2 member D (NKG2D) have been most actively developed, and several clinical trials for AML and solid tumors are underway. In this article, we will review the basics of CARs, followed by detailed explanation of CARs utilizing the activating receptors expressed by NK cells.

The prognosis of relapsed/refractory acute lymphoblastic leukemia remains poor. Recently developed CAR-T cell therapy is one of the promising new therapies because it provides a high response rate in patients with this leukemia. However, unique side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can happen and become potentially very severe. Massive cytokine production by activated CAR-T cells is postulated to be the cause, but this needs more research to better cope with it. On the basis of our experience in the ELIANA trial, we discuss the flow of CAR-T therapy, the main clinical course, and the management of CRS.

Reirradiation to the brain has traditionally been considered contraindicated, but in recent years, it has become relatively accepted owing to the progress of radiotherapy modalities and their techniques. Because of the risk of radiation necrosis, the indication for reirradiation should be carefully decided depending on the type of disease and the condition of patients. Since there is no other efficacious treatment for diffuse intrinsic pontine glioma (DIPG) after its progression, reirradiation should be considered because of its high efficacy. However, further investigation is required for the optimum timing and dosage of reirradiation. For ependymoma, the effectiveness of reirradiation, including craniospinal irradiation (CSI) after the first recurrence, has been reported in recent years. However, the late effect should be fully taken into consideration when reirradiation is planned, since ependymoma patients are expected to have a relatively long-term survival even after recurrence. In the setting of local reirradiation for ependymoma, a strict irradiation plan that fully considers the previous irradiation plan is required because of the extremely high cumulative dosage. Reirradiation for relapsed medulloblastoma potentially has a relatively high risk of radiation necrosis because standard therapy for medulloblastoma includes CSI. Nevertheless, reirradiation has been shown to prolong overall survival after medulloblastoma relapse. Note that the dose and fields of reirradiation differ depending on the previous irradiation plan and/or the site of relapse. Bevacizumab is an effective treatment for radiation necrosis, and its efficacy in children has recently been shown.

Wilms tumor 1 (WT1) was considered as a high-priority antigen target for cancer immunotherapy because of its high immunogenicity and oncogenicity, as well as its expression in the majority of pediatric hematologic malignancies and solid tumors. We reported previously the cases of recurrent rhabdomyosarcoma patients. A female patient received WT1 peptide vaccination after radiation therapy and became well after the WT1 peptide vaccine treatment. We reported previously on a male pediatric patient with relapsed diffuse midline glioma, whose H3.3K27M mutation was demonstrated by immunohistochemistry. He exhibited an encouraging clinical evolution during WT1 peptide vaccination as manifested by a stable disease, improved clinical manifestations, steroid dose reductions, a WT1-specific immune response, and a good safety profile. In pediatric refractory patients with leukemia, we performed a phase II clinical study of immunotherapy targeting the WT1 protein. We were able to show that WT1 vaccination is safe and can induce a WT1-specific immune response. Therefore, this immunotherapy is a potentially promising therapeutic modality for refractory pediatric cancer. We created a novel oral cancer vaccine using a recombinant Bifidobacterium longum displaying the WT1 protein. Orally administered B. longum significantly inhibited WT1-expressing tumor growth and led to protracted survival in mice. We have clarified the mechanism of efficacy of this oral vaccine, which is expected to be effective without severe adverse events and pain for pediatric patients.

The Children’s Oncology Group Neuroblastoma Pathology Reference Laboratory is a part of the Neuroblastoma Biology Study and plays a critical role in the front–end central pathology review of cases at the time of study enrollment for patient stratification and protocol assignment. The Laboratory has been participating in establishing and running a biorepository that is supported by grant funding from the National Institutes of Health (NIH) and providing researchers with high-quality biology samples for years. To promote the central pathology review system by expert pediatric pathologists, it is very important to (1) clearly define the role of the central pathology review of study cases with appropriate funding in the system of the Japanese Children’s Cancer Group and (2) compensate expert pathologists with an appropriate consultation fee for their review of non-study cases.

Accurate and immediate pathological diagnosis often cannot be made for rare cancers including bone and soft tissue tumors and pediatric cancers. If general pathologists encounter a rare cancer, they have no choice but to consult with experts. In Europe, a centralized system for the pathological diagnosis of soft tissue sarcoma has been established. In Japan, such a system is impractical. As an alternative, it has been proposed that general pathologists consult with experts on unusual cases or cases with challenging diagnosis. In addition, a project to train general pathologists in the diagnosis of rare cancers is underway, and a system for succession planning should be developed.

The quality of life of hemophilia patients has considerably been improved because unexpected bleeding has become preventable by prophylactic treatments with coagulation factor concentrates. The frequency of injections has decreased along with the development of extended half-life coagulation products and biphasic antibody preparations. However, pain and mental burden for regular replacement therapy remain as problems. The progress of gene and cell therapies is remarkable for many intractable diseases. In gene therapy for hemophilia, worldwide competition in research and development of new therapies has led to clinical trials in Japan. Adenovirus-associated viral vectors are intravenously injected to hemophilia patients. Single administration of the vectors with high transfer efficiency into hepatocytes achieves the production of coagulation factors over a long time. Development of gene and cell therapies for pediatric diseases is being aspired for; however, the therapies are still in developmental stages. We need new evaluation methods for safety and efficacy that are different from those for conventional medicines. For example, viral preparations necessitate a special implementation system at hospitals in accordance with the Cartagena Act. Moreover, when using viral preparations for treatment, it is necessary to establish a special implementation system in medical facilities in accordance with the Cartagena Act. Considering these requirements, we launched the Gene Cell Therapy Promotion Center in 2019 to provide a concrete basis of clinical trials and long-term follow-up. The Center aims at supporting companies and academia to prepare clinical trial protocols and education/training. In this paper, we outline the current status of gene therapy for hemophilia and its conformity with the Cartagena Act.

The supplementation therapy with factor (F)VIII or FIX products for hemophilia patients has resulted in the prevention of the progression of arthropathy and the great improvement of their quality of life (QOL). There have been serious issues, however, associated with this therapy, such as the requirement of frequent intravenous infusion, anti-FVIII or FIX alloantibody (inhibitor) development, and difficulty of hemostatic treatment for patients with inhibitor development. To solve these unmet needs, some extended-half-life FVIII or FIX products and non-clotting factor products have been developed. An anti-FIX/FX bispecific antibody, emicizumab, having the features of long half-life and subcutaneous administration, has resulted in the marked prevention of bleeding in severe hemophilia A patients, irrespective of the presence of the inhibitor. Furthermore, clinical trials using novel products that suppress the anti-coagulation function, which are based on the concept of rebalancing coagulation, are now ongoing. These new therapeutic approaches for hemophilia, which shift the paradigm of hemophilia treatment, could provide further improvement of the QOL of pediatric patients.

Immune thrombocytopenia (ITP) is an autoimmune disease that causes thrombocytopenia due to platelet destruction and impaired platelet production. Pathological triggers such as viral infections induce the presentation of cryptic peptides derived from platelet antigens from antigen-presenting cells to CD4⁺ T cells, resulting in anti-platelet autoantibody production in B cells. There are five established treatment options for childhood ITP: high-dose gamma globulin therapy, corticosteroids, thrombopoietin receptor agonists, rituximab, and splenectomy. The underlying pathophysiology of ITP helps in elucidating the site of action of each drug. Many children with ITP undergo remission spontaneously. However, the following issues arise: (1) selection criteria for patients to be treated, (2) selection of initial treatment, (3) treatment of refractory patients, (4) treatment selection considering patient/family health-related quality of life (HRQoL), and (5) clinical positioning of splenectomy after introduction of new drugs. In Europe and the United States, treatment is selected on the basis of the severity of bleeding symptoms regardless of the platelet count. Buchanan’s bleeding grade is often used to assess the severity of bleeding. Conventionally, patients with the Buchanan classification Grades 0 to 2 are carefully monitored, whereas those with and Grades 4 and 5 should be treated. Whether or not to treat patients with Grade 3 classification is an issue for consideration. We are in an era where treatments that improve the patient’s HRQoL can be selected instead of patients adjusting their lifestyle on the basis of their platelet count. In this paper, an overview of the pathophysiology of childhood ITP, clinical issues, the American Society of Hematology (ASH) 2019 ITP guidelines, and treatment of chronic ITP are presented.

Autoimmune hemolytic anemia (AIHA) is the most common type of acquired hemolytic anemia. Moreover, AIHA is an autoimmune disease in which the autoantibodies produced react with antigens on the erythrocyte surface membrane. The antigen–antibody reaction causes hemolysis, resulting in a markedly shortened erythrocyte lifespan and consequently, anemia. Primary immunodeficiency is a general term for diseases caused by congenital abnormalities of immunocompetent cells or immunocompetent molecules in the immune system, and it includes more than 430 individual diseases. Most of the diseases are caused by a single genetic abnormality. These diseases have been termed as inborn errors of immunity (IEI) in recent years. Interestingly, AIHA has been noted as the first IEI symptom. The representative IEIs that complicate AIHA are cytotoxic T lymphocyte antigen-4 (CTLA-4) deficiency and lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency. Thus, in this paper, we review the IEIs associated with AIHA, focusing on the CTLA-4 and LRBA deficiencies.

A multidisciplinary approach is mandatory in the treatment of refractory pediatric solid tumor patients. To determine the postoperative strategy of chemotherapy or radiotherapy, an accurate evaluation of surgical treatment results is necessary. Although the surgeon who performed the operation write operative notes according to his or her subjective views, are they enough for the accurate evaluation of surgical treatment results? Is it possible to make an objective evaluation of surgical treatment results by postoperative radiological examination? What is the appropriate timing for postoperative radiological evaluation? How should we use the pathological evaluation results? Evaluation methods and results could be variables for a particular disease. This session was conducted to solve these clinical questions. For this reason, we selected the speakers who are not only surgeons but also radiologists and pathologists. We regret that brain tumor, renal tumor, extracranial germ cell tumor and non-rhabdomyosarcoma soft-tissue sarcoma could not be discussed in this session because of limited time. We selected speakers from only the JCCG (Japan Children’s Cancer Group) committees of neuroblastoma, rhabdomyosarcoma and hepatoblastoma. Hopefully, this session could serve as a platform for discussion on the evaluation of surgical treatment results as part of the multidisciplinary approach to the treatment of pediatric solid tumors and could provide a direction for the accurate evaluation. We also hope that this session may improve the quality of clinical studies on pediatric oncology.

Although the outcome of rhabdomyosarcoma has improved, about one-third of localized rhabdomyosarcoma patients and more than two-thirds of metastatic rhabdomyosarcoma patients still suffer a relapse. In general, the prognosis of recurrent rhabdomyosarcoma is poor and no standard treatment has been established. When deciding on a treatment plan for a recurrent disease, it is important to evaluate the patient with risk factors in mind. The stage and group (primary site, regional lymph node metastasis, tumor size, and distant metastasis) at the time of the first occurrence, the details of the treatment history (chemotherapy, surgery and its curative effect, and radiation dose), and the time of recurrence (during treatment, within 18 months after the start of treatment, or after more than 18 months) should be confirmed. Accurate evaluation of the mode of recurrence (local recurrence, regional recurrence, or metastatic (disseminated) recurrence) is very important, and multiple imaging studies should be performed. Biopsy should be performed aggressively when there are atypical findings of imaging or when a second cancer is suspected. If the recurrent disease is localized, whether it is local or metastatic, an aggressive and multifaceted approach to local therapy should be taken to ensure long-term survival. In contrast, long-term survival in cases of disseminated or multiple recurrence is extremely rare. Chemotherapy is usually administered, but oncogene panel testing and participation in early phase trials may be considered. Minimally invasive treatment and palliative treatment to improve QOL should be considered.

Congenital thrombocytopenia is a group of heterogeneous disorders caused by mutations in responsible genes that have indispensable roles in normal differentiation from hematopoietic stem cells to megakaryocytes and in platelet production. Differential diagnosis of congenital thrombocytopenia is clinically required for distinguishing it from immune thrombocytopenia and selecting appropriate therapeutic options. On the basis of recent advances made by our AMED research group, we developed systems for patient registration, protein assays of platelets, and a biobank. The number of responsible genes reached up to 56, and targeted sequencing and subsequent exome sequencing analysis are available in Japan. For making differential diagnosis and selecting appropriate therapeutic options, we report a diagnostic guide for congenital thrombocytopenia. This guide is composed of the disease outline, diagnostic flowchart according to platelet size, brief description of each disease, consultation system, list of responsible genes, and therapeutic and long-term follow-up options.

Background: Although a subset of pediatric cancer patients require intensive care (IC), detailed information about these patients has not been well evaluated. The purpose of this study is to clarify whether IC affects the prognosis of pediatric cancer patients.

Methods: We retrospectively analyzed pediatric cancer patients who were admitted to our hospital between November 2003 and December 2017. IC was defined as requiring at least one of the following modalities: mechanical ventilation, inotropic support or renal replacement therapy.

Results: Among 312 pediatric cancer patients, 40 patients (13%) required IC. The IC group frequently received hematopoietic cell transplantation prior to IC (p<0.01) and suffered a relapse (p<0.01) compared with patients who did not require IC (non-IC group). The overall survival (OS) one year after diagnosis was significantly lower in the IC group than in the non-IC group (68% vs. 97%, p<0.01). The main cause of death was disease progression. The prognosis was worse in patients requiring both mechanical ventilation and inotropic support than in patients who required only one of them. In multivariate analysis, IC had an adverse impact on the survival rate of pediatric cancer patients one year after the diagnosis (p<0.01).

Conclusion: The prognosis for pediatric cancer patients requiring IC was poor. Although the main cause of death was disease progression, results suggest that the condition requiring IC adversely affected the prognosis of pediatric cancer patients.

BACKGROUND: Although therapy-related second malignant neoplasms (SMNs) have been elucidated, their course and prognoses remain unknown. METHODS: We retrospectively investigated 603 cases of children who were treated at our hospital between 1980 and 2010. RESULTS: Eighteen patients developed SMNs. The most common primary malignant neoplasm (PMN) was acute leukemia (n=11). SMNs were hematopoietic tumors (n=5), thyroid cancer (n=3), breast cancer (n=3), digestive cancer (n=3), bone and soft tissue tumors (n=2), renal cancer (n=1), and pleural tumor (n=1). The median time from diagnosis of PMNs to diagnosis of treatment-related hematopoietic tumor was 6.5 years (range, 3.25–15.3 years), and that to diagnosis of treatment-related solid tumor was 13.9 years (range, 4.3–26.6 years). SMNs were detected during routine medical examination (n=9), from subjective symptoms (n=8), and by autopsy (n=1). Four of the patients with treatment-related hematopoietic tumors received hematopoietic cell transplantation, and twelve of the patients with treatment-related solid tumors received standard treatment. Two patients died before a definitive diagnosis was made. Five patients died of causes, namely, treatment-related hematopoietic tumor (n=2), treatment-related solid tumor (n=2), and recurrence of the PMN (n=1). Despite early detection and standard treatment, one patient with breast cancer developed brain metastasis two years later. CONCLUSIONS: Although early detection is necessary to improve the prognoses of SMNs, it is not enough. Further elucidation of SMN etiology, development of new treatments for SMNs, and development of PMN treatments with reduced risk of SMNs are necessary.

The purpose of this study was to clarify information sources and participants’ satisfaction with them, information needs, and information sources needs regarding sexuality and reproduction among childhood, adolescent and young adult (AYA) cancer survivors. We conducted a cross-sectional, self-administered online survey among adult survivors who had been diagnosed with cancer at 0–29 years of age. Questionnaire items included information sources and participants’ satisfaction with them, information needs, and information sources needs regarding sexuality and reproduction. We used data from 107 participants (mean age of 31.2 years old). Their most common information sources were friends, school, and the Internet (74–81%). Less common sources were doctors (34%) and nurses (17%). The top information needs were as follows: effects of diseases and treatments on their ability to reproduce and how to deal with them; illness disclosure to partners and their families; and other survivors’ stories about romantic relationships and having children. The information sources needs were the Internet, booklets (about 50%), same type cancer survivors, and doctors (around 40%). The information needs included not only reproductive information but also illness disclosure and survivors’ stories. Results show that it is necessary to provide information that meets survivors’ needs. Survivors want more information than ever about reproduction from medical professionals, who must make efforts to establish an information provision system. In the future, further studies are necessary to investigate whether survivors’ information needs are being met and to provide information that improves their quality of life.

A three-year-old boy was diagnosed as having B-cell precursor acute lymphoblastic leukemia (BCP-ALL). He was treated using the JPLSG ALL-B12 protocol and underwent allogeneic hematopoietic cell transplantation (HCT) during his first complete remission (CR1) because of a near-haploid karyotype (29 chromosomes). CR1 status was confirmed after induction therapy. The minimal residual disease (MRD) test showed a negative result after early intensive therapy. Moreover, he underwent bone marrow transplantation from his HLA 8/8 allele-matched father as the donor, with a reduced-intensity conditioning (RIC) regimen, consisting of 100 mg/m² fludarabine, 8000 mg/m² cytarabine, 180 mg/m² melphalan, and 3 Gy total body irradiation. He achieved neutrophil count recovery on day 18 and was discharged 80 days after HCT without severe adverse events. He is alive and disease-free 5.5 years after HCT. Although near-haploid BCP-ALL has a poor prognosis, patients with an MRD-negative status can survive with a good quality of life through HCT with RIC in CR1.

The case of a seven-year-old girl with Fanconi anemia (FA) and acute lymphoblastic leukemia (ALL) that was progressing from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML) is presented. The patient was examined with a chief complaint of melena, and FA was suspected from specific facial features and cytopenia. FA was diagnosed on the basis of chromosome breakage test results, and preparations for hematopoietic stem cell transplantation were made due to progression to RAEB-2. Fever and increased number of blast cells were observed, and ALL (L1) was diagnosed on the basis of bone marrow examination results. Remission was induced with intrathecal injection of methotrexate, cytarabine (Ara-C), and prednisolone (PSL) and three drugs (PSL, vincristine, and L-asparaginase). Although remission was achieved, the condition changed to AML. Transplantation of 5/6 HLA-matched umbilical cord blood was carried out following pretreatment with fludarabine, cyclophosphamide, Ara-C, and total body irradiation, and remission was again achieved. On the basis of bone marrow chromosome analysis results, it was conjectured that ALL is a clone that differs from MDS and AML.

Spinal cord compression occurs in 4–5% of pediatric cancers, and spinal cord tumors are often diagnosed on the basis of spinal cord compression symptoms. Spinal cord tumors often present as an oncologic emergency, and the severity of neurological deficits before treatment is an important factor in predicting neurological prognosis. We encountered four pediatric neoplastic disease patients diagnosed with spinal cord compression symptoms. The interval between symptom onset and tumor diagnosis was 3 to 36 days. The patients were histopathologically diagnosed as having Ewing’s sarcoma, malignant rhabdoid tumor, and acute myeloid leukemia. Neurological deficits were assessed using the Frankel classification. One patient with complete paralysis (Frankel grade A) at the time of diagnosis did not recover. Three patients whose motor or sensory function is incomplete loss at the time of diagnosis recovered after the treatment (Frankel grades B and C improved to grade D). Early treatments before complete paralysis might improve neurological prognosis.

A 10-year-old girl with lumber pain and right leg pain persisting for six months gradually became unable to walk and visited our hospital. X-ray examination showed a permeative lytic lesion with periosteal reaction in the right iliac bone. On MRI, the large right iliac bone mass invaded the retroperitoneal cavity, gluteus muscles, and sacrum. The mass was diagnosed as Ewing sarcoma family of tumors on the basis of biopsy findings. Surgical resection with a safety margin was difficult owing to the extensive invasion of the mass. She was treated with five cycles of chemotherapy with vincristine, pirarubicin, cyclophosphamide, etoposide, and ifosfamide, high-dose chemotherapy with melphalan, etoposide, and carboplatin, followed by autologous peripheral blood stem cell transplantation and local radiotherapy without resection, and she achieved complete remission. Endocrine and growth disorders were observed as late complications; however, the sarcoma did not relapse seven years after treatment. If surgical resection is difficult to perform, high-dose chemotherapy can be effective for Ewing sarcoma treatment.

A nine-month-old female infant with a left adrenal gland tumor was referred to our hospital. She was diagnosed as having an intermediate-risk neuroblastoma as per the Children’s Oncology Group risk classification. After five courses of multidrug chemotherapy, the primary tumor was excised and the metastatic liver tumors were biopsied. Although residual histopathological neuroblastoma cells were confirmed in both the primary tumors and liver metastases, treatment was terminated after one additional course of chemotherapy. After the treatment, magnetic resonance imaging and metaiodobenzylguanidine scintigraphy findings revealed liver metastases. The treatment ended two years and one month ago, but no recurrence has been detected since then. In the case of a neuroblastoma with favorable biological factors, it may be advisable to forgo additional treatment for residual tumor after induction therapy even when histopathological neuroblastoma cells remain.

The patient was an 8-year-old girl. About half a year ago, cough appeared and she was treated by a home doctor but her wheezing gradually worsened. Computed tomography showed a solid mass with a contrast effect on the ventral side of the tracheal lumen, which occupied about 80% of the trachea, so she was referred to our department. Since the symptoms worsened over time, semi-urgent surgery was performed. Tracheal wedge resection was performed and the tumor was removed. The pathological result was low-grade tracheal mucoepidermoid carcinoma. Five years have passed since the operation, and no recurrence findings have been found by bronchoscopy. Even nonspecific airway symptoms such as cough should be examined for tracheal tumors if they are accompanied by worsening airway obstruction symptoms. In addition, tracheal mucoepidermoid carcinoma has a good prognosis if completely resected; thus, tracheal wedge resection was an effective method.

Intensive multimodality therapy has led to a marked improvement in the clinical outcome of patients with nongerminomatous germ cell tumor (NGGCT). However, there have only been a limited number of studies on therapy-related secondary tumors. A 14-year-old woman was diagnosed as having high-risk intracranial NGGCT, and she received a combination of chemotherapy and radiotherapy (craniospinal irradiation of 22.4 Gy in 14 fractions and boost irradiation of 27.2 Gy to the primary tumor in 17 fractions), leading to long-term disease-free survival. At the age of 25, a pelvic MRI scan revealed an enhanced mass in the spinal cord of the fifth lumber vertebra. She underwent total resection of the tumor and was histopathologically diagnosed as having schwannoma. A shorter latency period was found between the treatment for the primary tumor and the onset of secondary schwannoma in this case than in previously reported cases (10.3 vs. 24.6 years). Intense treatment with a combination of chemotherapy and radiotherapy or genetic predisposition might be associated with early-onset schwannoma.

In a pediatric terminal cases, siblings’ hospital visitation strengthens family ties and helps them remember the moment when the hospitalized children are at home. However, it is also very stressful for bereaved siblings to experience a loss and to observe their sick sibling’s physical changes over the course of an illness. We have experienced a case in which we needed to make a controversial decision about siblings’ hospital visitation. The patient was a six-year-old girl who died due to acute myeloid leukemia. Through her treatment, her appearance changed considerably since the last time her siblings met her. Therefore, we were concerned that hospital visitation might lead to secondary PTSD and other psychological problems in the siblings in the future. Utilizing this case as a lesson, we reconsidered how our grief care should work and reformulated the guidelines about siblings’ hospital visitation.

[Introduction] We report a case of twins with juvenile myelomonocytic leukemia (JMML), who underwent physical therapy during chemotherapy and hematopoietic stem cell transplantation.

[Cases] Case A (first-born boy) was diagnosed as having JMML at the age of 6 months. He was treated by unrelated bone marrow transplantation at the age of 18 months. Case B (second-born boy) was diagnosed as having JMML when he was 5 months old, and unrelated umbilical cord blood transplantation was performed at the age of 7 months. Both twins were trained to walk, and they could walk independently at the ages of 22 and 18 months, respectively.

[Discussion] Various physical therapy programs based on developmental risk factors were provided to each twin. The causes of retarded development were different, but an extended period was required to enable both toddlers to walk without aids. It is important to carry out a thorough evaluation of each patient and provide rehabilitation tailored to each condition.