ALBERT

Description: Introduction: Anthracyclines (Atc) are the key drugs in the treatment of acute promyelocytic leukemia (APL) combined with all-trans retinoic acid (ATRA), however, dose-dependent risk of long-term cardiac toxicity is sometimes problematic especially in pediatric patients. To evaluate efficacy of the treatment with reduced cumulative doses of Atc in childhood APL, we conducted a nationwide non-randomized prospective study, AML-P05, in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). Patients & Methods: Between April 2006 and March 2011, forty-six children with newly diagnosed APL were enrolled in this study. All patients received at least 3-day precedence of ATRA monotherapy (45mg/m2/d for 35 days in total), followed by chemotherapeutic agents consisted of cytarabine (200mg/m2/d for 7 days) and daunorubicin (DNR, 45mg/m2/d for 3 days) as the first induction therapy. The second induction therapy and subsequent 3 courses of consolidation therapy consisted of ATRA, either high- or intermediate-dose of cytarabine, triple intrathecal injection, and single dose of Atc; 10mg/m2 of mitoxantrone (MIT) in the first 2 courses and 45mg/m2 of pirarubicin (THP) in the last 2 courses. Finally, patients received one-year maintenance therapy with ATRA for 15 days every 3 months. Results: Among the 46 patients registered in this study, 3 were excluded because of PML/RARA negativity, and the remaining 43 patients including 2 with molecular variants were evaluated. The median age at diagnosis was 9 years (range, 11 months to 15 years old). The median follow up period was 4.47 years (0.00-7.45 years). FLT3-ITD was positive in 6 out of 40 patients examined. Two patients died during induction therapies; one of coagulopathy in first course and the other of infection in second course. Two patients developed differentiation syndrome but resolved with temporary cessation of ATRA and supportive therapies. Three patients did not achieve complete remission (CR) after 2 courses of induction therapy, and overall CR rate was 85.7% (36/42, 95%CI: 71.5-94.6%). Neither cardiac adverse events nor treatment-related death were observed during consolidation and maintenance therapies. Three patients exhibited relapse during or after maintenance therapy, and another one developed secondary acute myeloid leukemia. Consequently, the 3-year event-free (EFS) and overall survival rate were 83.6% (95%CI: 68.6-91.8%) and 90.7% (95%CI: 77.1-96.4%), respectively. Age less than 4 years old at diagnosis and non-M1 marrow after first induction therapy were associated with lower EFS. High WBC count (〉10,000/μL), low platelet count (

Description: Although tyrosine kinase inhibitor (TKI) is popular in controlling chronic myeloid leukemia in the chronic phase (CML-CP), its long-term adverse effects in children are an issue of concern. One such concern is the negative impact on growth in these children. We previously demonstrated that growth impairment was a major adverse effect in imatinib-treated CML children. However, severity of impairment was not completely elucidated because of the short follow-up period. The Japanese Pediatric Leukemia/Lymphoma Study Group CML committee reviewed the clinical records of 107 Japanese children diagnosed with CML-CP (1 SD in 21 children (27.2%). Decrease in height-SDS was more severe in prepubertal children than in pubertal children (0.85 vs. 0.36, p〈 0.01). However, in prepubertal children median annual change in height-SDS significantly decreased 2 years after TKI initiation, and was

Description: Background Response to induction chemotherapy is one of the most important predictors of outcome in acute myeloid leukemia (AML) as well as cytogenetics and molecular genetics. Measurement of minimal residual disease (MRD) by flow cytometry is an informative method for assessment of initial treatment response, but the heterogeneity of leukemia-associated antigens and antigen shifts during treatment limit its sensitivity and specificity. We prospectively evaluated the prognostic prevalence of MRD monitoring using multi-color flow cytometry in children with AML treated on the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 trial. Patients and methods From January 2007 to October 2010, 34 children with newly diagnosed de novo AML were enrolled on the AML-MRD study conducted by the Tokyo Children's Cancer Study Group. The median age at the diagnosis was 8 years (1 month- 15 years), and 17 patients were boys and 17 were girls. They were all treated with the JPLSG AML-05 trial. In AML-05, enrolled patients received two induction courses and those achieving a complete remission (CR) were treated according to risk classification at which all the core binding factor-AML cases and good initial response based on morphology after induction 1 were assigned to low risk (LR) group, cases presented with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), unfavorable cytogenetics including monosomy7, 5q-,t(16;21), and with poor initial response were assigned to high risk (HR) group, the others were assigned to intermediate risk (IR) group. Allogeneic hematopoietic stem cell transplantation (HSCT) was indicated for the HR patients after the third or later treatment courses. Among the 34 patients enrolled on the AML-MRD study, 8 presented with LR, 22 with IR, and 4 with HR regarding the cytogenetics and FLT3-ITD status. MRD of 63 bone marrow samples were analyzed after induction 1 (BMA-2) and induction 2 (BMA-3) by four-color flow cytometry using 9 AML-associated antigens. A threshold level for MRD-positivity was set at the point of 0.1%. Results Sixty-two (98.4%) of 63 bone marrow samples were evaluable for MRD. Thirteen (39.4%) of 33 samples and 8 (27.6%) of 29 showed MRD-positivity at BMA-2 and BMA-3 respectively. Among the patients with MRD-positivity, 12 at BMA-2 and 7 at BMA-3 were diagnosed as achieving CR by morphology. MRD was associated neither specific FAB subtype nor white blood cell count at diagnosis, but all 3 patients with FLT3-ITD showed the MRD-positivity at BMA-2. Although 3-year probability of event free survival (3-yr EFS) at BMA-2 or BMA-3 was similar between patients with and without MRD; 53.8% (n= 13) vs 70.0% (n= 20) (p=0.30) and 50.0% (n= 8)vs 62.0%(n= 21) (p=0.36), respectively, 3-yr EFS of those with MRD at BMA-2 or BMA-3 was significantly worse compared to those without MRD; 33.3% (n= 9) vs 83.3% (n= 12) (p=0.02) and 20.0%(n= 5) vs 76.9% (n= 13) (p=0.04), respectively, in the group of the IR cytogenetics and negative FLT3-ITD. Multivariate analysis indicated that the MRD detected by multi-color flow cytometry was solely associated with worse outcome in this group. Conclusion Highly sensitive detection of MRD by multi-color flow cytometry was possible in children with AML. The present study suggests that MRD monitoring may have a prognostic relevance in childhood AML with the IR cytogenetics and negative FLT3-ITD. Disclosures: No relevant conflicts of interest to declare.

Description: [Background] Acute promyelocytic leukemia (APL) cells induce dysregulation of coagulation and fibrinolysis, and most of the cases are complicated with disseminated intravascular coagulopathy (DIC) at the time of diagnosis. Administration of all-trans retinoic acid (ATRA) rapidly corrects dysregulation and improves DIC. But in some cases, management of DIC with ATRA alone is very difficult because addition of chemotherapeutic agents may reactivate fibrinolytic state. Thus the control of DIC is still an issue for the initial management of APL even in the ATRA era. Recombinant thrombomodulin (rTM) improves DIC by inhibiting excessive coagulation through the activation of protein C cascade (Saito H, et al. J Thromb Haemost 2007), and was approved in Japan for the treatment of DIC induced by severe infection or hematological malignancy in 2008. However, because activated protein C also facilitate fibrinolytic pathway by inhibiting plasminogen activator inhibitor-I, administration of rTM may lead to severe hemorrhage complication in patients with APL. Therefore, we retrospectively analyzed its efficacy and safety in pediatric APL. [Object & Methods] This study included 45 cases; 42 who registered to the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-P05 study (UMIN Clinical Trials Registry, # UMIN000000645) and responded to the questionnaire and 3 cases outside the study. Questionnaire regarding the use of rTM and efficacy and safety issues, such as “Worst DIC score according to the diagnostic criteria of the Japanese Ministry of Health and Welfare (worst DIC score)” and “Days until resolution of DIC score from diagnosis of DIC (DIC duration)” were investigated. [Results] Among 45 cases analyzed, 38 (84%) were diagnosed to complicate with DIC, and 9 (24%) among them used rTM by physician’s decision. In these 9 cases (rTM+ group), mean duration of rTM administration was 13.8 days (7–24 days). WBC count and FDP level at diagnosis of APL were not different between rTM+ group and rTM-NOT used group (rTM- group). In rTM+ group, mean value of “Worst DIC score” was 5.8 and mean “DIC duration” from diagnosis was 16.8 days, both of them were not statistically significant with those in rTM- group (5.4 and 13.0 days, respectively). However, median “DIC duration” from commencement of rTM (11.5 days) seems shorter than “DIC duration” from diagnosis of DIC in rTM- group (13.0 days), although the difference was not statistically significant. Regarding safety issues, there was no death or severe hemorrhage in rTM+ group, while 3 cases (10%) of severe hemorrhage due to uncontrolled DIC were reported in rTM- group, with fatal brain hemorrhage in 1 case (3%) among them. There was no significant difference of induction rate between rTM+ group (1 case, 11%) and rTM- group (3 cases, 10%), although 2 cases of ATRA-refractory APL in rTM+ group who were additionally treated with arsenic trioxide. [Conclusions] In this retrospective analysis investigating efficacy and safety of rTM in the management of pediatric APL-related DIC, there were no significant differences regarding the efficacy of rTM because of the limited cases of rTM+ group. However, it is notable that there was no severe hemorrhage or death in rTM+ group. rTM seems to be safely used for the management of pediatric APL-related DIC. Disclosures No relevant conflicts of interest to declare.