ALBERT

Description: Background: Chronic myeloid leukemia (CML) is a rare disease in children and accounts for approximately 2% to 3% of all childhood leukemia. Despite of introduction of tyrosine kinase inhibitors, allogeneic hematopoietic stem cell transplantation is still the only proven curative treatment for patients with CML. Few studies have specifically addressed transplantation outcomes in childhood CML. Patients and Methods: We analyzed the clinical data of 125 children (81 boys and 44 girls) with CML undergoing unrelated bone marrow transplantation (UBMT) through the Japan Marrow Donor Program (JMDP) between 1993 and 2006 (median observation period, 95 months). The recipients’ median age at transplantation was 14 years (range, 1 – 19 years). The disease phases at conditioning were chronic phase (CP) 1 (n=88), CP2 (n=12), CP3 (n=1), accelerated phase (n=11) and blastic crisis (n=13). The median interval from diagnosis to BMT was 14 months (range, 2 – 111 months). 95 (76%) patients received interferon-alpha (IFN-alpha), and 17 (14%) received imatinib mesylate (IM) before BMT. 96 (77%) patients received total body irradiation (TBI) containing a conditioning regimen, and 29 (23%) received a non-TBI regimen. Cyclosporine A (CSA)-based graft-versushost disease (GVHD) prophylaxis was used for 81 (65%) patients, and tacrolimus based prophylaxis was used for 43 (34%) patients. One patient received methotrexate only for GVHD prophylaxis. HLA matching data based on high-resolution DNA typing for HLA-A, -B, -Cw, -DRB1 and -DQB1 alleles were available in 99 (79%) patients; 41 of 99 (41%) patients were “fully matched (10/10)”. The median infused cell number was 314×106/kg (range, 27 – 880×106/kg). Results: Five-year overall survival (OS) and leukemia-free survival probabilities were 59.3% ± 4.5% and 55.5% ± 4.5%, respectively. Grade II to IV acute GVHD occurred in 50 (40%) patients, and chronic GVHD occurred in 51 (41%) patients. Six (5%) patients did not achieve engraftment. In multivariate models for OS, disease phase (advanced phase/CP1) (p=0.008, RR 2.431 (1.261–4.689)), infused cell number (

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: Abstract 2277 Imatinib is now widely used for treating chronic-phase chronic myeloid leukemia (CML) in children as well as in adults, and long-term adverse effects of imatinib therapy in children are now gaining attention. One of its adverse effects is the negative impact on growth in children, suggested by 3 recently published case reports. However, the incidence or prospect of growth impairment resulting from imatinib treatment has not been fully elucidated. In this study, we retrospectively analyzed the clinical records of 48 children with chronic-phase CML who were treated with imatinib as a first-line therapy between 2001 and 2006. The median age at diagnosis was 9 years (2 to 15 years). Cumulative change in height while on imatinib was assessed using the height standard deviations score (height-SDS), the converted height data from age- and sex-adjusted Japanese norms. Our data indicated that growth impairment (decrease in height-SDS) was observed in 72.9% of the patients, with median maximum reduction in height-SDS of 0.61 during imatinib treatment. Growth impairment was noticeable in children who were prepubertal at the commencement of imatinib treatment, while only mild or no growth impairment (with no decrease of height-SDS) was observed in most patients who were pubertal at the commencement of imatinib treatment. Furthermore, in prepubertal children with growth impairment, growth velocity tended to recuperate concomitant with pubertal maturation, suggesting that imatinib has little impact on growth during puberty. To our knowledge, this is the first report to describe and compare the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. Although the introduction of imatinib was a breakthrough in CML therapy, the possibility of continuous remission after discontinuation of imatinib remains uncertain. Thus, the possibility of adverse effects of long-term exposure to imatinib has become a huge issue, especially when treating children. We consider that it is important to promote awareness of growth deceleration in children, especially in young children who started imatinib treatment before puberty and are inevitably going to be subject to prolonged exposure. Disclosures: No relevant conflicts of interest to declare.

Description: X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is a developmental and immunologic disorder caused by hypomorphic mutations in the nuclear factor-κB essential modulator (NEMO) gene. NEMO is the regulatory subunit of the IκB kinase (IKK) complex, which phosphorylates and degrades NF-κB inhibitor α (IκBα), causing NF-κB activation. Following the identification of amorphic NEMO mutations causing familial incontinentia pigmenti (IP), hypomorphic mutations in NEMO have been identified in XL-EDA-ID patients. Affected boys are susceptible to infections with various microorganisms, mostly pyogenic bacteria and mycobacteria. Stem cell transplantation (SCT) is thought to be the only curative treatment, but successful SCT has not yet been reported. We here report the first successful treatment of the disorder by SCT. The patient was a 3-year-old boy. His mother and maternal grandmother had been diagnosed with IP. He had frequent episodes of enterocolitis, and Enterobacter aerogenes sepsis. Mutation analysis revealed NEMO mutation (1167 insC) in both the patient and his mother. Flow cytometry analysis showed lower NEMO expression in each PBMC lineage, and CD40L induced less up-regulation of CD23, CD54, CD86, and CD95 in the patient’s cells. The patient did not have an HLA-matched related or unrelated bone marrow donor. At 3 years of age, an unrelated UCSCT was performed after written consent was obtained from his parents. Pretransplant conditioning consisted of fludarabin (30 mg/m2/d) from day -7 to day -3, melpharan (70 mg/m2/d) from day -6 to day -5, and rabbit anti-T-lymphocyte globulin (ATG) (2.5 mg/kg/d) from day -5 to day -1. The patient received 4.6 × 107 total nucleated cells/kg from a male donor. The recipient and donor were one antigen mismatched by serology and four loci mismatched by DNA typing. Following uneventful engraftment, NEMO protein expression was normalized and cytokine response was significantly improved. Lineage-specific genetic analysis confirmed full donor chimerism. Six months after UCSCT, the patient is in perfect performance status. This outcome shows that correction of immunodeficiency associated with NEMO mutation is possible by SCT, and UCSCT with a reduced-intensity regimen can be a suitable therapy for affected patients.

Description: Background: The Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) CML-08 prospective study was designed to determine the efficacy and tolerability of tyrosine kinase inhibitor (TKI) in children and adolescents with newly diagnosed CML in chronic phase (CP). Methods: Monitoring of response to TKI and the treatment were conducted according to the modified ELN-2009 guidelines. Results: From October 2009 until September 2014, 78 patients (49 males and 29 females) from age 1 to 17 years (median: 11 years) were enrolled in 45 hospitals in Japan. As of May 2015, the median observation period was 31 months (662 months). Median WBC, Hb and platelet counts were 275x109/L (8 to 765), 9.6g/dL (5.8 to 14.6) and 560x109/L (110 to 2875), respectively. Splenomegaly was found in 76%. High scores of Sokal, Hasford and EUTOS were observed in 21, 13 and 27%, respectively. Clonal chromosome abnormalities in Ph-positive cells occurred in 3 patients at diagnosis. Imatinib, dasatinib and nilotinib were used as a first-line treatment in 69 (88%), 7 (9%) and 2 (3%) patients, respectively. The median initial dose of imatinib, dasatinib and nilotinib was 276, 63 and 262mg/m2, respectively. Of 69 patients with a first-line imatinib, 30 (43%) have been continued imatinib treatment, and the others were switched to second TKI (dasatinib or nilotinib) or hematopoietic stem cell transplantation (HSCT) due to poor response or intolerance to imatinib. The most common cause of intolerance to imatinib was musculoskeletal events. At the last observation, HSCT had been conducted in 8 patients (10%). 4y-PFS and 4y-OS was 97.1% (95%CI, 88.7 to 99.3%) and 97.8% (95%CI, 85.3 to 99.7%), respectively. One patient was dead because of blast crisis followed by transplant-related complications. CHR was achieved in 96.2% at 3 months, CCyR in 76.8% at 12 months, MMR in 40.8% at 18 months, and CMR4.0 in 22.4% at 24 months. Cumulative incidence of CMR4.0 by 24 months was 27.8% and 7.5% in patients with BCR-ABL (IS) of ≤ 10% and 〉 10% at 3 months with a first-line imatinib, respectively (P=0.0435). In patients with a first-line imatinib, age and WBC count at diagnosis were found to be potential prognostic factors for cumulative incidence of molecular response. Patients with a first-line second TKI had a higher 12-months cumulative incidence of MMR (60.0% vs 21.7%, P = 0.0460) and CMR4.0 (35.1% vs 6.3%, P = 0.0061) than patients with a first-line imatinib. There were no significant differences between their clinical characteristics including sex, WBC count, Hb, platelet count, Sokal score, Hasford score, and EUTOS score, except for age. Second TKI was used as a first-line treatment only for patients ≥ 9 years of age. In this study, the follow-up is planned to continue until 2019. Conclusion: A first-line second TKI was more effective than imatinib for inducing molecular responses also in pediatric CML-CP, as reported in adult CML-CP. Discontinuation of TKI after achieving CMR is a desirable strategy especially for children and adolescents. Thus, considering prognosis factors including age and WBC count, pediatric CML patients with unfavorable prognosis should be treated by second TKI rather than imatinib as a first-line treatment. Disclosures No relevant conflicts of interest to declare.