Sixty-two infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia (MLL-r ALL) were treated with the MLL03 protocol of the Japanese Pediatric Leukemia/Lymphoma Study Group: short-course intensive chemotherapy followed by early allogeneic hematopoietic stem cell transplantation (HSCT) within 4 months of the initial induction. The 4-year event-free survival and overall survival rates were 43.2% (95% confidence interval (CI)=30.7-55.1%) and 67.2% (53.8-77.4%), respectively. A univariate analysis showed younger age (<90 days at diagnosis), central nervous system disease and poor response to initial prednisolone therapy significantly associated with poor prognosis (P<0.05). In a multivariate analysis, younger age at diagnosis tended to be associated with poor outcome (hazard ratio=1.969; 95% CI=0.903-4.291; P=0.088). Although the strategy of early use of HSCT effectively prevented early relapse and was feasible for infants with MLL-r ALL, the fact that substantial number of patients still relapsed even though transplanted in their first remission indicates the limited efficacy of allogeneic HSCT for infants with MLL-r ALL. Considering the risk of severe late effects, indications for HSCT should be restricted to specific subgroups with poor risk factors. An alternative approach incorporating molecular-targeted drugs should be established.

Recent findings indicate that Epstein-Barr virus (EBV)-infected T-/natural killer (NK) cells play an important role in the pathogenesis of mosquito allergy, and most patients with mosquito allergy die early in life if not properly treated. Over the last 7 years, we have been using combination chemotherapy and allogeneic stem cell transplantation for the treatment of EBV-associated T-/NK cell lymphoproliferative disease (LPD) in which chronic active EBV infection and mosquito allergy were included. As of this writing, we have successfully treated 2 patients with mosquito allergy with chemotherapy in which EBV-infected T-/NK cells were eradicated. The findings suggest the possible role of chemotherapy in the treatment of EBV-associated T-/NK cell LPD.

The pathogenesis of sinusoidal obstruction syndrome (SOS) and thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) is poorly understood, and limited information is available on global hemostatic function in HSCT. We assessed changes in coagulation and fibrinolysis using a simultaneous thrombin and plasmin generation assay (T/P-GA) during HSCT. Measurements of endogenous thrombin potential (T-EP) and plasmin peak height (P-Peak) using T/P-GA in six pediatric acute leukemia patients treated with HSCT were compared to normal plasma. In the SOS case, the ratios of T-EP and P-Peak to normal were simultaneously decreased at four weeks post-HSCT (Pre; ~1.1/1.1-1.4, Week+4; 0.14/0.0084, respectively). Similarly, in the TMA patient, both ratios were decreased at 3 weeks and recovered after 8 weeks (Pre; 1.2/~0.95, Week+3; 0.59/0.22, Week+8; 1.2/0.64-0.85). In the other patients, when SOS/TMA was not evident, the T/P-GA data remained within normal limits. These findings suggest that the simultaneous reduction of coagulation and fibrinolytic function in patients developing SOS/TMA can lead to a life-threatening coagulopathy. Further research is warranted to clarify global hemostatic function after HSCT to establish optimal supportive therapy for these critical clinical disorders of hemostasis.

SummaryAllogeneic haematopoietic stem cell transplantation (HSCT) is still considered to play an important role as a consolidation therapy for high-risk infants with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed outcomes of HSCT in infants with ALL based on nationwide registry data of the Japan Society for Haematopoietic Cell Transplantation. A total of 132 allogeneic HSCT for infant ALL with KMT2A (MLL) gene rearrangements, which were performed in first complete remission (CR1), were analysed. The 5-year overall survival rate after transplantation was 67Á4 AE 4Á5%). Although recent HSCT (after 2004) had a trend toward better survival, no statistical correlation was observed between outcomes and each factor, including age at diagnosis, initial leucocyte count, cytogenetics, donor types or conditioning of HSCT. Myeloablative conditioning with total body irradiation did not provide a better survival (60Á7 AE 9Á2%) over that with busulfan (BU; 67Á8 AE 5Á7%). Two of the 28 patients treated with irradiation, but none of the 90 BU-treated patients, developed a secondary malignant neoplasm. In conclusion, allogeneic HSCT using BU was a valuable option for infant ALL with KMT2A rearrangements in CR1.

Background Thrombosis and hemorrhage are serious complications of pediatric solid tumor, and enhanced fibrinolysis associated with disseminated intravascular coagulation (DIC) is often observed. Fibrinolytic enzymes also play an important role in metastasis. Limited information is available, however, on the assessment of overall hemostatic function in children with malignant solid tumor. Methods We have investigated the comprehensive hemostatic potential in these circumstances using simultaneous thrombin/plasmin generation assay (T/P‐GA). Endogenous thrombin potential (T‐EP) and plasmin peak height (P‐Peak) were measured using T/P‐GA in six children newly diagnosed with solid tumor at regular intervals during chemotherapy at the present hospital from 2013 to 2016. Four patients with metastasis were defined as the advanced group, and the other patients were defined as the non‐advanced group. Results In the advanced group, the ratio of P‐Peak to normal was higher than the slightly increased ratio of T‐EP to normal (range, 1.2–2.1 vs 1.1–1.5, respectively). In the non‐advanced group, however, the P‐Peak ratio was relatively lower than the slightly increased T‐EP ratio (range, 1.0–1.5 vs 1.1–1.5, respectively). Fibrin–fibrinogen degradation product was elevated in all patients except in one non‐advanced brain tumor patient during this induction therapy (maximum, 11.6–161 μg/mL). Conclusions Uncontrolled fibrinolysis together with an imbalance between coagulation and fibrinolytic potential might lead to DIC. Further research is warranted to clarify comprehensive hemostatic function in pediatric patients with solid tumors to establish optimal supportive therapy, and possibly limit tumor progression in these critical disorders.