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.

Pregnancy outcome of Japanese patients with glucokinase-maturity-onset diabetes of the young.

AIMS/INTRODUCTION: Glucokinase-maturity-onset diabetes of the young (GCK-MODY; also known as MODY2) is a benign hyperglycemic condition, which generally does not require medical interventions. The only known exception is increased birthweight and related perinatal complications in unaffected offspring of affected women. As previous data were obtained mostly from white Europeans, the present study analyzed the pregnancy outcomes of Japanese women with GCK-MODY to better formulate the management plan for this population. MATERIALS AND METHODS: The study participants were 34 GCK-MODY families whose members were diagnosed at Osaka City General Hospital during 2010-2017. A total of 53 pregnancies (40 from 23 affected women, 13 from 11 unaffected women) were retrospectively analyzed by chart review. RESULTS: Birthweights of unaffected offspring born to affected women were significantly greater as compared with those of affected offspring (P = 0.003). The risk of >4,000 g birthweight (16%), however, was lower as compared with that previously reported for white Europeans, and none of the offspring had complications related to large birthweight. Insulin treatment of the affected women resulted in a significant reduction in the birthweights of unaffected offspring. Perinatal complications including small-for-gestational age birthweight were found only in affected offspring born to insulin-treated women. CONCLUSIONS: In Japanese GCK-MODY families, unaffected offspring born to affected women were heavier than affected offspring. However, insulin treatment of affected women might not be advisable because of the lower risk of macrosomic birth injury, and an increased risk of perinatal complications in affected offspring.

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.

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.

Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia.

OBJECTIVE: To determine the extent of growth impairment resulting from imatinib treatment in children with chronic myeloid leukemia (CML). STUDY DESIGN: Clinical records of 48 chronic-phase CML children administered imatinib as the first-line therapy between 2001 and 2006 were analyzed retrospectively. Cumulative change in height was assessed using the height height-SDS and converted height data from age- and sex-adjusted Japanese norms. RESULTS: A decrease in height-SDS was observed in 72.9% of children, with a median maximum reduction in height-SDS of 0.61 during imatinib treatment. Median follow-up time was 34 months (range, 10-88 months). Growth impairment was seen predominantly in children who started imatinib at a prepubertal age compared with those who started at pubertal age. Growth velocity tended to recuperate in prepubertal children with growth impairment, as they reached pubertal age, suggesting that imatinib had little impact on growth during puberty. CONCLUSIONS: Growth impairment was a major adverse effect of long-term imatinib treatment in children with CML. We report the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. We should be aware of growth deceleration in children, especially in young children given imatinib before puberty and subjected to prolonged exposure.

Outcome of 125 children with chronic myelogenous leukemia who received transplants from unrelated donors: the Japan Marrow Donor Program.

Because of a small number of patients, only a few studies have addressed the outcome of bone marrow transplantation (BMT) in children with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), who receive graft from a volunteer-unrelated donor (VUD), especially after practical application of imatinib mesylate. The outcomes of BMT from a VUD in 125 children with Ph+ CML were retrospectively reviewed. Patients were identified through the Japan Marrow Donor Program as having undergone BMT between 1993 and 2005 and were aged 1-19 years at the time of transplant (median age, 14 years). The probabilities of 5-year overall survival (OS) and leukemia-free survival (LFS) were 59.3% and 55.5%, respectively. Multivariate analysis identified the following unfavorable survival factors: infused total nucleated cell dose<314 x 10(6) /kg (relative risk [RR]=2.43; 95% confidence interval [CI]=1.33-4.44; P=.004), advanced phase (RR=2.43; 95% CI=1.37-4.31; P=.004), and no major cytogenetic response (MCyR) at the time of BMT (RR=6.55; 95% CI=1.98-21.6; P=.002). Of the 17 patients treated with imatinib, 15 (88%) achieved MCyR at the time of BMT, and this group had an excellent 5-year OS of 81.9%. Disease phase, infused total nucleated cell dose, and cytogenetic response were independent risk factors for survival of unrelated BMT. These findings provide important information for assessing the indications for and improving outcome in unrelated BMT for the treatment of pediatric CML.

Successful outcome of mismatched hematopoietic stem cell transplantation from a related donor in an infant with acute lymphoblastic leukemia and 9;11 translocation: case report and review of the literature.

Although infants with acute lymphoblastic leukemia (ALL) and MLL gene rearrangements have a poor prognosis, those with acute myeloid leukemia (AML) have been shown to have a superior outcome with intensive chemotherapy alone despite the presence of MLL gene rearrangements. We report the case of an ALL infant with t(9;11), a common cytogenetic abnormality in infant AML, who after relapse underwent successful hematopoietic stem cell transplantation (HSCT) from her HLA 2-loci-mismatched mother. Analysis of the outcome among ALL infants with MLL gene rearrangements registered in the Japan Infant Leukemia Study between 1996 and 1999 showed the event-free survival of patients with t(9;11) was not different from that of those with other 11q23 translocations. Most of the patients with t(9;11) described in the reviewed literature also experienced either induction failure or early relapse after achievement of complete remission, but some of them were rescued with subsequent HSCT. These findings suggest that infant ALL with t(9;11) has features distinct from those of infant AML with the same karyotype and that the prognosis among these patients can be improved only with the combination of intensive chemotherapy and HSCT An appropriate strategy for the treatment of ALL infants with different 11q23 translocations must be clarified.

Genetic analysis of Shwachman-Diamond syndrome: phenotypic heterogeneity in patients carrying identical SBDS mutations.

Shwachman-Diamond syndrome (SDS) is a rare hereditary disorder characterized by pancreatic exocrine insufficiency, bone marrow dysfunction and skeletal changes. Recently, the cause of SDS was identified as mutations of Shwachman-Bodian-Diamond syndrome gene (SBDS) and most mutations are caused by gene conversion between SBDS and its highly homologous pseudogene. Clinical variations especially in skeletal and bone marrow abnormalities are well known in this syndrome. To study the relationship between SBDS mutation and its clinical features, we analyzed 9 Japanese patients including one sibling and detected the three different SBDS mutations in 7 patients: a mutation that disrupts the donor splice site of intron 2, deletes 8 bp of the exon 2 and produces premature termination (258+2 T > C), a dinucleotide change that replaces a lysine at 62 nd amino acid to a termination codon (183-184 TA > CT), and a 4-bp deletion that causes premature termination by frameshift (292-295 delAAAG). The 5 patients represent compound heterozygotes of the 258+2 T > C and 183-184 TA > CT mutations. One patient is a compound heterozygote of the 258+2 T > C and 292-295 delAAAG mutations, and in the remaining one case only a 258+2 T > C mutation could be detected. Thus, the 258+2 T > C and 183-184 TA > CT mutations are prevalent among Japanese patients. No mutations were found in two cases, despite the clinical features. Of the 7 patients with SBDS mutations, persistent hematologic abnormalities and skeletal changes were not observed in 3 and 2 patients, respectively. Notably, clinical variations are present even among the patients with the identical genotype: compound heterozygotes of the 258+2 T > C and 183-184 TA > CT mutations. Further study will be required to explain the clinical heterogeneity.