Refractory Burkitt Lymphoma With False-positive and False-negative Mass Detected on Positron Emission Tomography-computed Tomography After Chemotherapy.

A 4-year-old boy with an abdominal mass extending from the spleen to the lower umbilicus was diagnosed with Burkitt lymphoma stage III. Because the fluorodeoxyglucose uptake on positron emission tomography (PET)-computed tomography of the residual splenic tumor remained elevated, splenectomy was performed. The PET-positive area was composed of inflammatory infiltrates, whereas the PET-negative area was composed of a viable tumor surrounded by necrotic or dying tumor cells. The residual tumor may have been false-negative for PET because of its poor proliferative potential. In this case, the comparison of PET-computed tomography and pathologic findings demonstrates the simultaneous presence of a false-positive inflammatory lesion and a false-negative residual tumor.

Discontinuation of tyrosine kinase inhibitors in pediatric chronic myeloid leukemia.

BACKGROUND: The feasibility of tyrosine kinase inhibitor (TKI) discontinuation in pediatric chronic myeloid leukemia (CML) remains to be fully elucidated. PROCEDURES: TKI was prospectively discontinued in patients who were diagnosed with CML at <20 years of age, treated with TKI for ≥3 years, and sustained molecular response 4.0 (MR4.0) for ≥2 years. Molecular relapse was defined as a single loss of major molecular response (MMR) (BCR-ABL1IS >0.1%). Relapsed patients resumed the same TKI therapy administered before discontinuation. RESULTS: Twenty-two patients with chronic-phase CML were enrolled, and the median ages at diagnosis and at TKI discontinuation were 9 (range: 1-14) years and 16 (5-26) years, respectively. The median follow-up time after TKI discontinuation was 37 months (range: 24-41 months). The median duration of TKI treatment before discontinuation was 100 (42-178) months, and that of MR4.0 was 53.5 (25-148) months. The treatment-free remission (TFR) rate at 12 months was 50.0% (90% confidence interval: 31.7%-65.8%). Eleven patients experienced loss of MMR within 4 months after TKI discontinuation and resumed TKI as originally prescribed. No progression was observed, and all 11 patients regained MR4.0 after TKI resumption. No patient had a withdrawal syndrome. The quality-of-life analysis suggested that successful TFR may improve academic performance in some patients. In patients who discontinued TKI therapy before puberty, the possibility of improvement in growth velocity upon TKI discontinuation was observed. CONCLUSIONS: TKI could be discontinued safely in patients with pediatric CML showing a sustained deep MR.

A case of primary CNS embryonal rhabdomyosarcoma with PAX3-NCOA2 fusion and systematic meta-review.

PURPOSE: Primary central nervous system (CNS) rhabdomyosarcoma is a rare mesenchymal tumor predominantly seen in children and associated with a poor outcome. We report a case of primary CNS rhabdomyosarcoma with PAX3-NCOA2 fusion and present a systematic meta-review of primary CNS rhabdomyosarcoma to characterize this rare tumor. METHODS: We present the case of a 6-year-old boy with primary CNS rhabdomyosarcoma in the posterior fossa. In a systematic meta-review, we compare the demographic data of primary CNS rhabdomyosarcoma with data of rhabdomyosarcoma at all sites from the SEER database and analyze clinical factors associated with survival outcome. RESULTS: Our patient underwent gross total resection and received vincristine, actinomycin-D, cyclophosphamide with early introduction of concurrent focal radiation and remained alive with no evidence of disease for 2 years after the end of therapy. Histopathological review revealed embryonal-type rhabdomyosarcoma, and whole-transcriptome analysis revealed PAX3 (EX6)-NCOA2 (EX12) fusion. In all, 77 cases of primary CNS rhabdomyosarcoma were identified through the meta-review. The demographic data of primary CNS rhabdomyosarcoma were similar to data of rhabdomyosarcoma at all sites. Overall and event-free survival outcomes were available for 64 and 56 patients, respectively, with a 3-year OS of 29.0% and a 3-year EFS of 25.7%. The group that received trimodal treatment exhibited better survival outcomes, with a 3-year OS of 57.4% and a 3-year EFS of 46.3%. CONCLUSIONS: Primary CNS rhabdomyosarcoma shares common histological, molecular, and demographic features with non-CNS rhabdomyosarcoma. A trimodal treatment approach with early introduction of radiation therapy may result in favorable survival outcomes.

Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells.

Eradication of chemotherapy-resistant leukemia stem cells is expected to improve treatment outcomes in patients with acute myelogenous leukemia (AML). In a mouse model of AML expressing the MOZ-TIF2 fusion, we found that Ring1A and Ring1B, components of Polycomb repressive complex 1, play crucial roles in maintaining AML stem cells. Deletion of Ring1A and Ring1B (Ring1A/B) from MOZ-TIF2 AML cells diminished self-renewal capacity and induced the expression of numerous genes, including Glis2 Overexpression of Glis2 caused MOZ-TIF2 AML cells to differentiate into mature cells, whereas Glis2 knockdown in Ring1A/B-deficient MOZ-TIF2 cells inhibited differentiation. Thus, Ring1A/B regulate and maintain AML stem cells in part by repressing Glis2 expression, which promotes their differentiation. These findings provide new insights into the mechanism of AML stem cell homeostasis and reveal novel targets for cancer stem cell therapy.

A Case of Pulmonary Veno-occlusive Disease Following Hepatic Veno-occlusive Disease After Autologous Hematopoietic Stem Cell Transplantation for Neuroblastoma.

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension that is usually difficult to diagnose and is refractory to conservative treatment. PVOD can occur in connection with high-dose chemotherapy or hematopoietic stem cell transplantation, similar to hepatic veno-occlusive disease (HVOD). Here, we present a case of neuroblastoma with PVOD following HVOD after high-dose chemotherapy that was resolved with conservative treatment. Respiratory symptoms or edema after HVOD may suggest PVOD, and prompt diagnosis on high-resolution computed tomography will result in a favorable prognosis.

Haploidentical stem cell transplantation with posttransplant cyclophosphamide for refractory systemic juvenile xanthogranuloma.

Juvenile xanthogranuloma (JXG) is a generally benign, self-limited histiocytic disorder, which belongs to non-Langerhans cell histiocytoses (non-LCH). However, systemic JXG can be fatal in rare cases. We present the case of an 11-year-old female with systemic JXG, who experienced repeated vertebral compression fractures and did not fully respond to systemic chemotherapy. Based on its reported efficacy in LCH, the patient underwent human leukocyte antigen-haploidentical hematopoietic stem cell transplantation (HSCT) with posttransplant cyclophosphamide. The patient did not suffer major complications and has not experienced relapse for 13 months since HSCT. HSCT may be a potential treatment option for patients with refractory non-LCH.

Sequential use of second-generation tyrosine kinase inhibitors following imatinib therapy in pediatric chronic myeloid leukemia: A report from the Japanese Pediatric Leukemia/Lymphoma Study Group.

BACKGROUND: The details of the sequential use of imatinib for first-line treatment followed by second-generation tyrosine kinase inhibitors (2G-TKIs) for pediatric chronic myeloid leukemia (CML) are still unknown. This study analyzed clinical responses and adverse effects of the use of 2G-TKIs following imatinib in pediatric chronic phase (CP)-CML. PROCEDURES: The Japanese Pediatric Leukemia/Lymphoma Study Group conducted a retrospective study of patients with newly diagnosed CML from 1996 to 2011. A total of 152 cases that received imatinib as first-line therapy were analyzed. RESULTS: Excluding 46 cases treated with hematopoietic stem cell transplantation before nilotinib and dasatinib became available, 31 of 106 patients changed to 2G-TKIs. The primary reason for changing from imatinib was poor response, followed by intolerance, with the main reason for the latter being musculoskeletal events. Switches from imatinib to 2G-TKIs with intolerance occurred significantly earlier than switches with poor response. Sixteen and 15 patients were treated with nilotinib and dasatinib, respectively, following imatinib therapy. After switching to 2G-TKIs, the response status improved in 63% of evaluable patients. The adverse effect profiles of nilotinib and dasatinib tended to be different, with hyperbilirubinemia observed in 33% of nilotinib-treated patients, but in none of the cases with dasatinib. CONCLUSION: This retrospective study represents the first series of children and adolescents in whom sequential use of imatinib followed by 2G-TKIs was reported. These data provide useful insights into the selection of 2G-TKIs as first-line treatment for children and adolescents with CP-CML.

Nodular Lymphocyte-predominant Hodgkin Lymphoma in a 15-Year-Old Boy With Li-Fraumeni Syndrome Having a Germline TP53 D49H Mutation.

Germline mutations in TP53 are the primary cause of Li-Fraumeni syndrome (LFS). Most mutations are reported within the DNA-binding domain. We report a case of a 15-year-old boy with LFS who developed early-stage nodular lymphocyte-predominant Hodgkin lymphoma, a rare subtype of Hodgkin lymphomas. His sister was diagnosed with embryonal rhabdomyosarcoma at the age of 1.5 years. Sequence analysis revealed a germline mutation in the transactivation domain of TP53, c.145G>C (p.D49H), in the patient, his sister, and father. One family with LFS with a germline TP53 D49H mutation has previously been reported. This report supports the pathogenicity of this mutation.

Flow cytometric analysis as an additional predictive tool of treatment response in children with chronic-phase chronic myeloid leukemia treated with imatinib.

Bone marrow samples of newly diagnosed children with chronic-phase chronic myeloid leukemia (CML) were obtained at diagnosis and after imatinib initiation and stained with anti-human CD34, CD38, CD123, CD45RA, cMpl, and lineage antibodies. Flow cytometric analysis revealed that granulocyte macrophage progenitor predominance in CML progenitors at diagnosis and elevated cMpl expression in bone marrow progenitors at 3 months may predict poor outcome in children with chronic-phase CML treated with imatinib. We recommend flow cytometric analysis of bone marrow in the early phase of treatment, as it is a convenient tool that may predict treatment response and guide CML management.

Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group.

BACKGROUND: The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML. PROCEDURE: A total of 256 cases from a retrospective study of patients with CML conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group from 1996 to 2011 were analyzed, and of these, 238 cases were evaluated in this study. RESULTS: Leukostasis was diagnosed in 23 patients (9.7%). The median leukocyte count and spleen size below the left costal margin in cases with leukostasis were significantly higher and larger when compared to those in cases without leukostasis (458.5 × 10(9) /l vs. 151.8 × 10(9) /l (P < 0.01), and 13 vs. 5 cm (P < 0.01), respectively). Leukostasis occurred with ocular symptoms in 14 cases, priapism in four cases, and dyspnea, syncope, headache, knee pain, difficulty hearing, and aseptic necrosis of the femoral head in one case each. One case had two leukostasis symptoms simultaneously. Three cases were diagnosed before imatinib became available. Five cases received special treatment, and in the remaining 15 cases, all of these symptoms resolved after treatment with imatinib. CONCLUSIONS: This retrospective study represents the largest series of children and adolescents in which leukostasis of CML has been reported. Our data provide useful insight into the characteristics of leukostasis in recent cases of children and adolescents with CML.

Recent progress in the management of pediatric chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a rare myeloproliferative disease in children. The primary cause of CML is the chimeric BCR::ABL1 gene in hematopoietic stem cells, which leads to leukocytosis, platelet proliferation, and splenomegaly. Lately, tyrosine kinase inhibitors (TKIs) have replaced hematopoietic cell transplantation, which was previously considered the only curative therapy, as the first-line treatment for chronic-phase CML. However, the clinical efficacy of TKIs, including those effective in adult CML, has not been well-investigated in pediatric CML. This review describes the recommended TKI-based management strategies for pediatric CML according to the literature and guidelines. Furthermore, we discuss the prospects for TKI discontinuation to avoid important adverse events, such as growth impairment, in children.

Pneumocystis jirovecii pneumonia after CD4+ T-cell recovery subsequent to CD19-targeted chimeric antigen receptor T-cell therapy: A case report and brief review of literature.

BACKGROUND: CD19-targeted chimeric antigen receptor (CAR)-T cell therapy involves administration of patient-derived T cells that target B cells, resulting in B-cell depletion and aplasia. In immunity against Pneumocystis jirovecii (Pj), CD4+ T cells and, more recently, B cells, are generally considered important. Antigen presentation by B cells to CD4+ T cells is particularly important. Trimethoprim-sulfamethoxazole (TMP/SMX) for Pj pneumonia (PJP) prophylaxis is generally discontinued when the CD4+ T-cell count is >200/µL. Here we report the first case, to our knowledge, of PJP in a patient with a CD4+ T cell count of >200/µL after CAR-T cell therapy. CASE: A 14-year-old girl developed hemophagocytic lymphohistiocytosis (HLH) after cord blood transplantation (CBT) for relapsed precursor B-cell acute lymphoblastic leukemia (B-ALL). Twenty-one months after CBT, she was diagnosed with combined second relapse in the bone marrow and central nervous system. The patient was treated with CD19-targeted CAR-T cell therapy for the relapse. After CAR-T cell therapy, the patient remained in remission and continued to receive TMP/SMX for PJP prophylaxis. Seven months after CAR-T cell therapy, CD4+ T cells recovered and TMP/SMX was discontinued. The B-cell aplasia persisted. Ten months after CAR-T cell therapy, the patient developed PJP. The patient was also considered to have macrophage hyperactivation at the onset of PJP. Treatment with immunoglobulin, TMP/SMX, and prednisolone was initiated, and the patient's symptoms rapidly ameliorated. CONCLUSION: The patient in the present case developed PJP despite a CD4+ T-cell count of >200/µL after CAR-T cell therapy, probably because of inadequate CD4+ T-cell activation caused by B-cell depletion after CAR-T cell therapy and repeated abnormal macrophage immune responses after CBT. It is important to determine the duration of TMP/SMX for prophylaxis after CAR-T cell therapy according to each case, as well as the CD4+ T-cell count.

A 15-Year-Old Boy with Primary Maxillary Bone Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma Relapsed with Rib Metastasis after Spontaneous Remission of a Maxillary Bone Lesion: A Case Report and Literature Review.

Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin's lymphoma (NHL) in children, accounting for 10-15% of all NHL cases. ALCL is currently classified as follows: systemic anaplastic lymphoma kinase (ALK)-positive, systemic ALK-negative, primary cutaneous, and breast implant-associated ALCL. In children, systemic ALK-positive ALCL is the most common, and patients often present with extranodal involvement. We report a rare case of systemic ALK-positive ALCL with primary bone involvement in a 15-year-old male patient. Primary bone lymphoma is most commonly observed in diffuse large B-cell lymphoma and is extremely rare in systemic ALCL. Therefore, the clinical features and prognosis of primary bone ALCL remain unclear. Our patient had spontaneous remission of primary maxillary bone ALCL after gingival scraping but relapsed 12 months later with rib metastasis. Spontaneous remission of ALCL has been reported frequently in primary cutaneous ALCL and rarely in systemic ALCL. Our case demonstrates for the first time that systemic ALCL can also present as solitary bone involvement that can spontaneously remit. Because systemic ALCL is aggressive and has a risk of relapse, as in our case, it is important to consider ALCL in the differential diagnosis of primary bone lesions and to make a precise pathological diagnosis.

Cervical Edema Extending to the Larynx as Local Cytokine Release Syndrome Following Chimeric Antigen Receptor T-Cell Therapy in a Boy with Refractory Acute Lymphoblastic Leukemia.

Cytokine release syndrome (CRS) is one of the major acute complications caused by massive cytokine release after chimeric antigen receptor (CAR) T-cell therapy. Patients with tumor masses were considered at high risk of local CRS induced by the expansion of CAR T cells in the tumor masses. However, even patients without any tumor burden around the neck are at risk of developing cervical edema as local CRS, which can lead to life-threatening airway obstruction. Here, we present the case of a 15-year-old boy who developed cervical edema as a local CRS after CAR T-cell therapy for refractory acute lymphoblastic leukemia. Despite administration of tocilizumab and methylprednisolone for persistent fever as a symptom of systemic CRS after CAR T-cell therapy, cervical edema occurred and extended to the larynx, resulting in dysphagia and hoarseness. Dexamethasone was remarkably effective, and the laryngeal symptoms resolved within a few hours. Local cytokine syndrome showed exacerbation with tocilizumab but exhibited considerable improvement with dexamethasone administration.

Severe bloody diarrhea due to cytokine release syndrome after chimeric antigen receptor T cell therapy for refractory acute lymphoblastic leukemia.

Cytokine release syndrome (CRS), which may be associated with fever, hypotension, hypoxia, and organ damage, is caused by a massive cytokine release after chimeric antigen receptor (CAR)-T cell therapy. We present the case of a patient who developed severe bloody diarrhea due to CRS after CAR-T cell infusion. A 10-year-old boy presented with a second relapse of B-cell precursor acute lymphoblastic leukemia 6 months after hematopoietic stem cell transplantation from an unrelated donor. CAR-T cells (tisagenlecleucel) were infused at the third complete remission after salvage chemotherapy. While fever >39°C was sustained from day 4, circulatory and respiratory status remained stable. However, he experienced severe bloody diarrhea. There was no evidence of infection; lower gastrointestinal (GI) endoscopy revealed extensive edema with erosion and ulceration, suggestive of non-specific intestinal inflammation. Thus, we considered CRS-associated grade 3 GI damage and administered a single dose of tocilizumab for grade 2 CRS, followed by 4 days of corticosteroids. Afterwards, no fever or GI bleeding was observed. Biopsy of the intestinal mucosa revealed ulcerative change with a lack of epithelial cells, which may correspond to histologic grade 4 graft versus host disease (GVHD). However, diarrhea corresponded to stage 1 GVHD, and the GVHD risk after CAR-T cell infusion has been reported to be rare in clinical practice. Although severe GI symptoms associated with CRS after CAR-T therapy are rare, early tocilizumab use is recommended for non-infectious severe GI symptoms to avoid long-term corticosteroid use, which may reduce CAR-T cell efficacy.