CAR-T cell therapy in paediatric acute lymphoblastic leukaemia - past, present and future.

Over the last decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising treatment modality for relapsed/refractory B-cell malignancies in both children and adults. As an adoptive immune therapy, CAR-T cells have the potential to overcome disease that is resistant to chemo- and radiotherapy as well as represent a viable option for those who have already reached toxicity ceilings with standard therapies. CD19-directed CAR-T cell products have been licensed for use in paediatric B-cell acute lymphoblastic leukaemia that is refractory, in relapse post-transplant or in second or later relapse. Many challenges remain, rightly resulting in a heavily-mined research field. These include mitigating short-term immune-mediated toxicity, maintaining durability of responses, broadening treatment accessibility and extending its applicability to other malignant settings. In this review, dedicated to marking 60 years since the establishment of the British Society for Haematology, we will focus on the contribution of our community towards the success of CD19-directed CAR-T cell therapy in children. We will put current practice in CAR-T cell therapy into the context of future challenges to be addressed in order for it to fulfil its "game-changing" therapeutic potential.

Removal of osteoid osteoma of the tibia using two-portal posterior ankle arthroscopy.

The case of a 30-year-old male with a history of pain in his left ankle is presented. The pain was described as predominantly nocturnal and frequently relieved by the use of nonsteroidal anti-inflammatory drugs. Computed tomography indicated a diagnosis of an osteoid osteoma in the posteromedial portion of the tibia. The patient underwent excision of the tumor using 2-portal posterior ankle arthroscopy. A clearly visualized nidus was removed using a combination of a cochlea and shaver. Histopathologic analysis of the resected tissue confirmed the diagnosis of an osteoid osteoma. The patient reported immediate relief of the pain and was rapidly allowed to bear weight on the foot. During regular follow-up, he had no pain recurrence and his joint mobility was normal. To our knowledge, this is the first report of the removal of an osteoid osteoma of the ankle using 2-portal posterior ankle arthroscopy.

CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study.

Relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may occur in the central nervous system (CNS). Most clinical trials of CAR T-cell therapy excluded patients with active CNS leukemia, partially for concerns of neurotoxicity. Here, we report an international study of fifty-five children and adolescents who received CAR T-cell therapy for relapsed BCP-ALL with CNS involvement at the time of referral. All patients received bridging therapy, 16 still having active CNS disease at the time of lymphodepletion. Twelve patients received CD28-based CAR T-cells, 9 being subsequently treated with allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Forty-three patients received 4-1BB-based CAR T-cells. Cytokine-release syndrome (CRS) and neurotoxicity occurred in 65% and 38% of patients, respectively, more frequently following treatment with CD28-based CARs. Fifty-one of 54 evaluable patients (94%) achieved complete response following this therapy. Relapse occurred in 22 patients: 19/43 following 4-1BB-based CARs (12 CNS relapses), and 3/12 after CD28-based CARs with subsequent HSCT (no CNS relapse). Patients treated with tisagenlecleucel for an isolated CNS relapse had a high incidence of a subsequent CNS relapse (6 of 8). CAR T-cells were found to be effective in this cohort, though the risk of CNS relapse was not completely mitigated by this approach.

Pre-B-cell acute lymphoblastic leukemia with bulk extramedullary disease and chromosome 22 (EWSR1) rearrangement masquerading as Ewing sarcoma.

We report a 2-year-old female with a subcutaneous tumor who was initially misdiagnosed as suffering from Ewing sarcoma with a positive EWSR1 rearrangement and EWS/FLI1 transcript. After finding lymphoblasts in peripheral blood, the diagnosis of acute lymphoblastic leukemia was established. This necessitated further analysis of the subcutaneous tumor. The tissue was positive for immature B-cell markers and an immunoglobulin heavy chain gene rearrangement, which confirmed the final diagnosis of common type acute lymphoblastic leukemia with bulk extramedullary disease. The patient was treated with chemotherapy and was in remission 30 months after the diagnosis.

Juvenile myelomonocytic leukemia with PTPN11 mutation in a 23-month-old girl.

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder affecting young children. The natural course of JMML is rapidly fatal with 80% of patients surviving less than three years. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment of JMML. We report a case of a 23-month-old girl who presented with an upper respiratory tract infection, fever, rash, diarrhea, hepatosplenomegaly and abdominal distention. Severe elevation of white blood cell count with monocytosis and myeloid progenitors in the peripheral blood was also detected. Bone marrow smear showed morphology suggestive of JMML, an unspecific immune phenotype and a normal karyotype. DNA analysis revealed a mutation in the PTPN11 gene. Therefore, the final diagnosis of JMML with somatic PTPN11 mutation was established. Following three months of cytostatic therapy with 6-mercaptopurine and low doses of cytarabine partial remission was achieved and allogeneic HSCT was successfully performed. Six months after the diagnosis, the girl was in a good condition and in a complete remission of JMML. Early diagnosis and allogeneic HSCT were crucial for successful treatment outcome.

Familial hemophagocytic lymphohistiocytosis in a 6-week-old male infant.

Familial hemophagocytic lymphohistiocytosis (FLH) is an autosomal recessively inherited multisystem disease. This defect in cellular cytotoxicity is a life threatening condition characterized by fever, rash, splenomegaly, cytopenias and neurologic manifestations. PRF1, UNC13D and STX11 gene defects underlie in about 40-50% of primary cases. Chemoimmunotherapy followed by hematopoietic stem cell transplantation improved disease outcome. We report a case of a 6-week-old boy who presented with a fever, diffuse rash, disseminated intravascular coagulation, hypofibrinogenemia, hypertrigliceridemia, hepatosplenomegaly, leukocytosis with 90% of lymphocytes, granulocytopenia, anemia, trombocytopenia, hyperferritinemia and pathological findings in cerebrospinal fluid. The patient had decreased frequency of NK cells and low NK cell activity in peripheral blood. Bone marrow aspiration analysis showed degenerative changes of histocyte cells, with preserved cytophages (lymphophages and erythrophages) consistent with hematophagocytic syndrome. Given that the molecular diagnosis of the known mutations in genes PRF1 and UNC13D showed a mutation in UNC13D, the diagnosis of familial hemophagocytic lymphohistiocytosis subtype 3 was established. HLH-2004 chemotherapy protocol was performed and partial remission with residual central nervous system disease was achieved. Hematopoietic stem cell transplantation was successfully performed with an unrelated HLA-matched donor. Familiar HLH is generally a progressive and fatal disease. Early diagnosis with molecular genetic analysis and chemoimmunotherapy followed by hematopoietic stem-cell transplantation is the best approach.

Unrecognized fracture of the posteromedial process of the talus--a case report and review of literature.

In this report, we present a rare case of an initially unrecognized fracture of the posteromedial process of the talus sustained in a seldom reported position of dorsiflexion and supination of the foot. Fractures of the posteromedial process of the talus are very rare and represent an important diagnostic problem. Difficult x-ray visualization makes these fractures often misdiagnosed as ankle sprains. Complications due to this kind of fractures can include serious consequences such as avascular osteonecrosis, tarsal tunnel syndrome, post-traumatic osteoarthritis, or chronic pain. Timely diagnosis represents an important factor in the development of these conditions. A heightened awareness in examining ankle traumas with specific patient history details is of great importance. The most common mechanism of injury includes dorsiflexion and pronation of the foot. However, in an increasing number of cases alternative mechanisms have been described, all including high-energy impacts. Our patient sustained a fracture of the posteromedial process of the talus in dorsiflexion and supination with high-energy impact due to a 3-m fall. The patient was treated with excision of the fragment six months after the injury, and 18 months after the surgery the patient returned to his normal daily activities with significantly less pain in the posteromedial part of the ankle.