BACKGROUND: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a subset of ALL with poor prognosis. Here, we analyzed the outcomes and prognostic factors of children with Ph+ ALL who received imatinib and chemotherapy followed by allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR). METHODS: Thirty-one Ph+ ALL patients (female 10) diagnosed from January 2005 to December 2016 were included in the study. All patients were treated with imatinib and chemotherapy before HCT. Bone marrow (BM) evaluations included real-time quantitative polymerase chain reaction (RQ-PCR) study of the BCR-ABL1 fusion transcript. All patients received HCT with total body irradiation (TBI)-based conditioning at a median of 6.4 (range, 4.2–47.1) months from diagnosis. RESULTS: Compared to values at diagnosis, the median decrement of RQ-PCR value post-consolidation, and prior to HCT was −3.7 Log and −4.8 Log, respectively. The 5-year event-free survival (EFS) and overall survival of the patients were 64.5±9.4% (20/31) and 75.0±8.3% (23/31) respectively. Events included relapse (N=5) and death in CR post-HCT (N=6). The 5-year incidence of molecular relapse was 30.9±9.1% (9/31). An RQ-PCR decrement of at least −4 Log post-consolidation significantly predicted lower incidence of molecular relapse: 7.7±7.7% for ≥−4 Log decrement, 50.0±13.8% for <−4 Log decrement (P=0.027). CONCLUSION: Decrement in RQ-PCR for the BCR-ABL1 transcript that was determined after consolidation was the only significant prognostic factor for incidence of molecular relapse. In the post-induction TKI initiation setting, steadfast imatinib treatment during consolidation may allow for optimum post-HCT outcomes.
Bone Marrow ; Cell Transplantation ; Child ; Diagnosis ; Disease-Free Survival ; Drug Therapy ; Humans ; Imatinib Mesylate ; Incidence ; Philadelphia Chromosome ; Polymerase Chain Reaction ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; Recurrence ; Transplants ; Whole-Body Irradiation

PURPOSE: This study aimed to investigate the effects of PIK3CA on the sensitivity of acute B lymphocytic leukemia cells (Nalm-6 cells) to chemotherapy drugs. MATERIALS AND METHODS: Children's normal B lymphocytes and Nalm-6 cells were cultured. Nalm-6 cells were transfected with PIK3CA siRNA (siPIK3CA group) or its negative control (PIK3CA-Control group). Normal Nalm-6 cells were named Mock group. Nalm-6 cells transfected by PIK3CA siRNA were treated with Akt inhibitor (siPIK3CA+Akti-1/2 group). mRNA and protein expression was detected by qRT-PCR and Western blot. Proliferation and sensitivity to chemotherapeutic drugs was detected by MTT assay. Cell cycle and apoptosis was explored by low cytometry. Transwell assay was performed to test invasion. RESULTS: PIK3CA mRNA (p=0.008) and protein (p=0.006) expression was higher in Nalm-6 cells than that in normal B lymphocytes. Compared with the Mock group and PIK3CA-Control group, Nalm-6 cells of the siPIK3CA group had lower OD495 values (all p < 0.05) and invasion cell numbers (p=0.03 and p=0.025), as well as a higher proportion of G0/G1 phase cells (p=0.020 and p=0.022), percentage of apoptosis (p=0.016 and p=0.022), and inhibition rate (all p < 0.05). pAkt expression in the siPIK3CA group (p=0.026 and p=0.031) and siPIK3CA+Akti-1/2 group (p=0.019 and p=0.023) was lower than that in the Mock group. CONCLUSION: PIK3CA silencing inhibited Nalm-6 cell proliferation and invasion, and promoted their apoptosis and sensitivity to chemotherapeutic drugs, potentially through regulation of the PI3K/AKT signaling pathway.
Apoptosis ; B-Lymphocytes ; Blotting, Western ; Cell Count ; Cell Cycle ; Cell Proliferation ; Drug Therapy ; Leukemia ; Leukemia, B-Cell ; Phosphorylation ; RNA, Messenger ; RNA, Small Interfering

BACKGROUND: High doses of methotrexate (MTX) are often used in various chemotherapy protocols to treat acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) in children, but its delayed elimination increases the occurrence of adverse events, such as bone marrow suppression. The aim of this study was to investigate the elimination of MTX at 24 and 48 hours. METHODS: We retrospectively analyzed electronic medical records of ALL or NHL pediatric patients who received 5 g/m² MTX infusion over 24 hours (between June, 2012 and July, 2018) at the Yonsei University Health System, Korea. The delayed elimination of MTX concentrations was assessed with 100 or 150 µM MTX at 24 hours, and 2 or 5 µM at 48 hours. RESULTS: Among the 85 MTX cycles administered, 23 cycles were classified in delayed elimination group, and 62 cycles showed normal elimination. At 24 hours, the delayed elimination group with MTX concentration > 100 µM showed higher percentage than group with MTX concentration < 100 µM (45.8% vs. 19.7%, p = 0.015). However, no differences were observed at 150 µM MTX (p = 0.66). At 48 hours, the delayed elimination was higher than the normal elimination at both concentration baselines (p < 0.001 at 2 µM, p = 0.024 at 5 µM). CONCLUSIONS: MTX concentrations greater than 100 µM show high probability of delayed elimination at 24 hours. When MTX levels are above normal, leucovorin and hydration regimens should be continued to prevent delayed elimination.
Bone Marrow ; Child ; Drug Therapy ; Electronic Health Records ; Humans ; Korea ; Leucovorin ; Lymphoma ; Lymphoma, Non-Hodgkin ; Methotrexate ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Retrospective Studies

No abstract available.
Dasatinib ; Drug Therapy ; Humans ; Hypopigmentation ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Protein-Tyrosine Kinases

BackgroundStudies of haploidentical-related donor (HRD) stem cell transplantation using a combination of peripheral blood stem cells (PBSCs) and bone marrow as the graft have reported encouraging results for patients with hematological diseases. However, few studies specifically reported transplantation of only PBSCs from HRDs among patients with relapsed or refractory acute myeloid leukemia (AML). Here, the long-term outcomes and side effects of unmanipulated HRD PBSC transplantation (HRD-PBSCT) for relapsed/refractory AML were analyzed.

MethodsWe performed a retrospective analysis of the outcomes in relapsed/refractory AML patients who underwent PBSCT from HRDs (n = 36).

ResultsThirty-one (86.1%) patients in the HRD-PBSCT group achieved platelet recovery. The cumulative incidence of acute graft-versus-host disease (aGVHD) in the HRD-PBSCT group was 40.00%, and the cumulative incidence of grades 2-4 aGVHD in this group was 13.33%. A total of 13 patients in the HRD-PBSCT group had recurrent disease at a median of 183 days after transplantation (range: 10-1700 days), reaching cumulative incidences of relapse of 50.28% at 5 years. On multivariate analysis, donor age and patient age >40 years were independent risk factors for inferior disease-free survival or overall survival (P < 0.05). The results of the present study demonstrate rapid and complete neutrophil engraftment, a low incidence of grade 2-4 aGVHD, and promising survival rates in patients after HRD-PBSCT. Thus, granulocyte colony-stimulating factor-primed PBSCs may be a reliable graft source in unmanipulated HRD-HSCT under myeloablative conditioning when no matched sibling donor is available.

ConclusionsOur results support the feasibility, effectiveness, and tolerability of PBSCs as a graft source in unmanipulated HRD transplantation under myeloablative conditioning in patients with leukemia.

Adult ; Female ; Graft Survival ; Graft vs Host Disease ; Granulocyte Colony-Stimulating Factor ; metabolism ; Humans ; Incidence ; Leukemia, Myeloid, Acute ; therapy ; Male ; Multivariate Analysis ; Peripheral Blood Stem Cell Transplantation ; adverse effects ; methods ; Retrospective Studies

OBJECTIVETo study the effects of minimal residual disease (MRD) level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia (B-ALL).

METHODSA total of 152 children with newly-diagnosed B-ALL who had complete remission after the first cycle of the chemotherapy and had complete follow-up information were enrolled in this study. According to the MRD detection by flow cytometry on day 33 of remission induction, they were divided into three groups: standard-risk (SR) group (MRD <10; n=60), intermediate-risk (IR) group (10≤ MRD <10; n=55), and high-risk (HR) group (MRD ≥10; n=37). Nested RT-PCR was used to determine the IKZF1 genotype of all children before chemotherapy. The effects of MRD level on day 33 of remission induction and IKZF1 genotype on the recurrence-free survival (RFS) of children with B-ALL were analyzed.

RESULTSThere were 7 common IKZF1 subtypes in all the 152 children with B-ALL: IK1, IK2/3, IK4, IK6, IK8, IK9, and IK10. Of the 152 children, 130 had functional subtypes of IKZF1 and 22 had non-functional subtypes of IKZF1. During the follow-up period, relapse occurred in 26 (17%) children, and the recurrence rate was highest in the HR group (P<0.05). However, there was no significant difference in the recurrence rate between the SR group and the IR group (P>0.05). The cumulative recurrence rate of the children with non-functional subtypes of IKZF1 was significantly higher than that of those with functional types of IKZF1 (P<0.01). The predicted 5-year RFS rates in the SR, IR, and HR groups were (94.2±2.9)%, (86.7±3.8)%, and (56.2±4.5)% respectively (P<0.05). The 5-year RFS rate of the children with functional subtypes of IKZF1 was significantly higher than that of those with non-functional subtypes of IKZF1 (P<0.01). There was no significant difference in the predicted 5-year RFS rate between the children with functional subtypes of IKZF1 and those with non-functional subtypes of IKZF1 in the SR group (P>0.05). However, the predicted 5-year RFS rate of the children with functional subtypes of IKZF1 was significantly higher than that of those with non-functional subtypes of IKZF1 in the IR group and the HR group (P<0.05).

CONCLUSIONSB-ALL children with non-functional subtypes of IKZF1 have a high recurrence rate, and the recurrence rate will be even higher in B-ALL children with non-functional subtypes of IKZF1 and MRD ≥10 on day 33 of chemotherapy.

Antineoplastic Combined Chemotherapy Protocols ; Child ; Child, Preschool ; Female ; Genotype ; Humans ; Ikaros Transcription Factor ; genetics ; Male ; Neoplasm, Residual ; genetics ; mortality ; therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; mortality ; therapy ; Prognosis ; Recurrence ; Remission Induction ; Survival

In recent years, great progress has been made in the treatment outcome of childhood acute leukemia with the improvement of chemotherapy regimens and the introduction of risk-stratified therapy; however, minimal residual disease (MRD) is still a difficult problem which affects the prognosis of acute leukemia. MRD influences the selection of chemotherapy regimens and recurrence risk stratification, and meanwhile, it can be used for prognostic prediction. At present, flow cytometry and polymerase chain reaction are mainly used for MRD detection. The next-generation sequencing also plays an important role in MRD detection, especially in MRD detection after stem cell transplantation. This article reviews the methodology and significance of MRD detection in childhood acute leukemia.
Hematopoietic Stem Cell Transplantation ; High-Throughput Nucleotide Sequencing ; Humans ; Leukemia, Myeloid, Acute ; diagnosis ; therapy ; Neoplasm, Residual ; diagnosis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; therapy ; Prognosis

Various endocrine dysfunctions occur during chemotherapy, including hypoglycemia. However, reports of hypoglycemia associated with 6-mercaptopurine (6-MP) are rare. Herein, we report an 8-year-old boy with severe symptomatic hypoglycemia likely due to 6-MP during chemotherapy. He had been diagnosed with acute lymphoblastic leukemia 3 years previously and was in the maintenance chemotherapy period. Treatment included oral dexamethasone, methotrexate, and 6-MP, of which only 6-MP was administered daily. Hypoglycemic symptoms appeared mainly at dawn, and his serum glucose dropped to a minimum of 37 mg/dL. Laboratory findings showed nothing specific other than increased serum cortisol, free fatty acids, ketone, alanine aminotransferase, and aspartate aminotransferase. Under the hypothesis of hypoglycemia due to chemotherapy drugs, we changed the time of 6-MP from evening to morning and recommended him to ingest carbohydrate-rich foods before bedtime. Hypoglycemia improved dramatically, and there was no further episode during the remaining maintenance chemotherapy period. To the best of our knowledge, this is the first report of this type of hypoglycemia occurring in an Asian child including Korean.
6-Mercaptopurine* ; Alanine Transaminase ; Asian Continental Ancestry Group ; Aspartate Aminotransferases ; Blood Glucose ; Child* ; Dexamethasone ; Drug Therapy* ; Fatty Acids, Nonesterified ; Humans ; Hydrocortisone ; Hypoglycemia* ; Maintenance Chemotherapy ; Male ; Methotrexate ; Precursor Cell Lymphoblastic Leukemia-Lymphoma*

OBJECTIVE: To investigate the effect of a rehabilitation program in terms of De Morton Mobility Index (DEMMI) score, in hematologic cancer patients after chemotherapy. METHODS: Hematologic cancer patients admitted for chemotherapy were reviewed. They received a rehabilitation program during their hospital stay. DEMMI score measurement was performed, before and after rehabilitation. Demographics, diagnosis, chemotherapy information, rehabilitation program duration, mortality, body mass index (BMI), and laboratory test results were collected. For analysis, patients were classified according to diagnosis (multiple myeloma, leukemia, and others), mortality, and additional chemotherapy. RESULTS: There was statistically significant improvement in DEMMI score of 10.1 points (95% confidence interval, 5.9–14.3) after rehabilitation. It was more evident in the multiple myeloma group, and they revealed less mortality. When patients were divided according to mortality, survivors received the program earlier, and in a shorter period than in mortality cases. Although survivors revealed higher initial DEMMI score, improvement after rehabilitation did not differ significantly. CONCLUSION: In hematologic cancer patients, rehabilitation program was effective for recovery from deconditioning, revealing significant increase in DEMMI score. Multiple myeloma patients may be good candidates for rehabilitation. Rehabilitation could be sustained during chemotherapy and for high-risk patients.
Body Mass Index ; Demography ; Diagnosis ; Drug Therapy* ; Hematology ; Humans ; Inpatients* ; Length of Stay ; Leukemia ; Mortality ; Multiple Myeloma ; Rehabilitation* ; Survivors

Hairy cell leukemia (HCL) is a rare chronic B cell leukemia morphologically characterized by cells with an abundant cytoplasm and hair-like projections that can be found in the peripheral blood and bone marrow. The treatment for HCL is splenectomy or chemotherapy with the purine analogs pentostatin and cladribine. However, patients continue to relapse. Retreatment with the same or alternate purine analogs produces lower response rates and a shorter duration of response. Fludarabine is another purine analog widely used in treating indolent lymphoid cancers, often in combination with rituximab. Here, we report a case of HCL variant in a 60-year-old man who experienced multiple relapses after splenectomy and retreatment with cladribine. The patient was then treated with fludarabine and rituximab combination chemotherapy. After the treatment, he achieved complete remission that continued for 35 months.
Bone Marrow ; Cladribine ; Cytoplasm ; Drug Therapy ; Drug Therapy, Combination ; Humans ; Leukemia, B-Cell ; Leukemia, Hairy Cell ; Middle Aged ; Pentostatin ; Recurrence ; Retreatment ; Rituximab ; Splenectomy