[Adverse effects of high-dose methotrexate therapy].

OBJECTIVE: To investigate the adverse effects of high-dose methotrexate (HDMTX) therapy, and to provide a theoretical basis for optimizing clinical treatment. METHODS: A retrospective analysis was performed for the clinical data of 120 children with acute lymphoblastic leukemia or non-Hodgkin lymphoma who underwent 601 times of HDMTX therapy. The adverse effects of various systems were analyzed according to the WHO criteria for the classification of adverse effects of anticancer drugs. RESULTS: Almost all the children experienced bone marrow suppression, and 93.3% had granulocytopenia. The most common adverse effects in the digestive system and urinary system were elevated glutamic-pyruvic transaminase (60.4%) and proteinuria (9.2%) respectively. For skin symptoms, skin erythema had the highest incidence rate (7.2%). The adverse effects in the nervous system (hyperpathia, numbness of extremities, or headache) were only observed in 7 cases. Serious adverse effects were only seen in the blood system and digestive system. Compared with the 3 g/m2 methotrexate (MTX) group, the 5 g/m2 HDMTX group had a significantly higher 24-hour plasma MTX concentration, significant reductions in hemoglobin and platelet count, and significantly higher incidence rates of oral mucositis, proteinuria, and skin symptoms (P<0.05). CONCLUSIONS: Serious adverse effects of HDMTX therapy mainly involve the blood system and digestive system, and the adverse effects such as bone marrow suppression, oral mucositis, proteinuria, and skin symptoms occur in a dose-dependent manner.

[Autoimmune lymphoproliferative syndrome: a case report and literature review].

We described 1 case of autoimmune lymphoproliferative syndrome (ALPS), first diagnosed in our hospital, and reviewed the recent literature. The 11-month old male patient presented with a history of splenomegaly and hepatomegaly since 1 month after birth. He suffered recurrent infectious diseases including cytomegalovirus infection, parvovirus B19 infection and chronic diarrhea disease. Besides, his symptoms included hemolytic anemia and thrombocytopenia. The laboratory abnormality indicated an expanded population of alpha/beta double-negative T cells (DNTs) (27.18% of lymphocytes, 35.16% of CD3+ T lymphocytes) in peripheral blood, and autoantibodies including antinuclear antibody, double-stranded DNA and rheumatic factor were positive. Hyper gamma globulinemia and positive direct Coombs tests were seen in the patient. His parents were both healthy and denied autoimmune diseases. We identified a heterozygous point mutation in exon 3 of the FAS gene carrying c.309 A>C, resulting in a single base pair substitution in exon 3 of FAS gene which changed the codon of Arg103 to Ser103. Unfortunately, we were unable to obtain the gene results of the child's parents. The patient was treated with glucocorticoids in our hospital and with mycophenolatemofetil in other hospital. And we were informed that his anemia condition relieved through the telephone follow-up, but he still suffered recurrent infections, hepatomegaly and splenomegaly still existed. As we all know ALPS is characterized by defective lymphocyte apoptosis, and thus cause lymphoproliferative disease and autoimmune disease, and increase the risk of lymphoma. It is more likely to be misdiagnosed as other diseases. ALPS should be suspected in the case of chronic lymphadenopathy, splenomegaly and autoimmune features. Flow cytometry approach is helpful for the diagnosis. Immunosuppressive drugs are the necessary treatment.

[Therapeutic strategies for childhood high-risk acute lymphoblastic leukemia].

Contemporary treatments have resulted in 5-year event-free survival rates (EFS) of approximately 75% to 80% for childhood acute lymphoblastic leukemia (ALL). Relapses of ALL in children were more often in HR-ALL but also in very few non-HR-ALL. Thus current clinical study of ALL has focused on improving the outcome of a few subtypes of HR-ALL. Infants with ALL have a particularly high risk of treatment failure. Infant ALL Interfant-99 study found that MLL rearrangement, age younger than 6 months, poor response to a prednisone prophase and high WBC count were strong independent predictive factors for poor prognosis in infants with ALL. Treatments with hybrid protocol, including both lymphoid- and myeloid-directed treatment elements, also contain HD-MTX and high dose Ara-C(HD-Ara-C), will further improve the outcome for infant ALL. Children Philadelphia chromosome positive ALL (Ph+ALL) was associated with a high relapse rate when treated with chemotherapy alone. The Children's Oncology Group (COG) AALL0031 trial showed that the addition of tyrosine kinase inhibitors(TKIs) imatinib to intensive chemotherapy resulted in 3-year EFS more than historical control treated with chemotherapy alone. These findings create a new paradigm for integrating molecularly targeted agents with intensified chemotherapy. Children with T-ALL have had a worse outcome than with the precursor B-cell ALL previously. With more intensified chemotherapy , outcomes for children T-ALL were improved, approaching those for the precursor B-cell ALL. Recently, COG decided to treat children with T-cell ALL with separate protocols different from those for the precursor B-cell ALL, and the protocols of BFM for children with T-ALL have been the same as those of the precursor B-cell ALL. Early precursor T-cell ALL, a novel subtype of T-cell ALL, was identified by gene expression profiling, flow cytometry, and single nucleotide polymorphism array analyses. ETP-ALL, identified in 13% of T-cell ALL cases, is characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and co-expression of stem cell or myeloid markers). A retrospective analysis suggested that ETP-ALL had a poor prognosis. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Ph-like ALL (BCR-ABL1-like ALL) patients lack a previously identified chromosomal rearrangement, but exhibit a gene-expression profile highly similar to that of Ph+ALL, and often have deletion/mutation of IKZF1, CRLF2 rearrangments and JAK1/2sequence mutations which are also common in Ph+ALL. The prognosis of Ph-like ALL is poor. Development of new agents targeted to leukemogenic pathways will promise to further improve the outcome of children ALL.

[Investigation on individualized adjustment of target range of high-dose methotrexate].

OBJECTIVE: To explore the way of individualized adjustment of target range of each high-dose methotrexate (MTX) 24 hours infusion to treat acute lymphoblastic leukemia in children. METHODS: Twenty-four children and 105 infusions were included in the study. According to 1 h and 6 h plasma MTX concentrations after infusion, based on established high-dose MTX population pharmacokinetics model, the course predicted value of drug concentration at steady state (C(SS)) was calculated. MTX infusion rate and dosage was adjusted 8 h after the start according to the predicted value of C(SS). Then MTX concentration at 23 h (actual value of C(SS)) was measured. RESULTS: To achieve the target range of C(SS), adjustments of MTX dosage were required in 17 (71%) patients. Adjustments of MTX dosage were required in 45 (43%) infusions, the dose was increased in 42 infusions and decreased in 3 infusions. There were 29 infusions of high-dose MTX during consolidation therapy (after remission induction therapy). Among them, 16 infusions had increased dosage, and 1 infusion had decreased dosage. There were 76 infusions during maintenance therapy. Among them, 26 infusions increased dosage, and 2 infusions decreased dosage. Overall 95 (90%) infusions achieved the target range of C(SS), while in 8 infusions the doses were lower than the target range in 2 infusions the doses were higher than the target range. If there had been no adjustments, only 74 (70%) infusions could have achieved the target range. Adjustments of MTX dosage, compared with no adjustments, could remarkably enhance the rate of achieving the target range of C(SS) (chi(2) = 13.366, P = 0.000). Among 60 infusions of no adjustments, the actual values of C(SS) were well correlated with the predicted values of C(SS) (r = 0.487, P = 0.000), and the actual values of C(SS) were also correlated with the 6 h plasma MTX concentrations after infusions (r = 0.389, P = 0.002). The actual values of total clearance (CL) of MTX of 105 infusions were 7.01 +/- 2.06 L/(m(2).h). Inter-courses variability in CL was up to 4.4-fold. Intra-patient variability in CL was up to 2.9-fold. Predisposing factors that correlated with decreased CL of MTX were old age, heavy body weight, low blood phosphate, high blood bilirubin and infusions during maintenance therapy (P < 0.05). CONCLUSIONS: High-dose methotrexate chemotherapy needed individualized adjustment, as inter-courses variability of CL was up to 4.4-fold among 105 infusions. According to 1 h and 6 h plasma MTX concentrations after infusion, adjusting MTX infusion rate and dosage, overall 90% infusions achieved the target range of C(SS). High-dose MTX infusions during consolidation therapy needed individualized adjustment of target range more.

[Nonmuscle myosin heavy chain 9 gene mutations related disease: a family report].

OBJECTIVE: To improve the recognition of nonmuscle myosin heavy chain 9 gene (MYH9) mutations related disease. METHODS: Clinical information and laboratory data of a family of MYH9-related disease was reported. Cytomorphology examination of peripheral blood and bone marrow smears were stained with Wright-Giemsa stain. Ultrastructural studies of peripheral blood were carried out. Surface expression of platelet glycoproteins was investigated by flow cytometry. The MYH9 mRNA was isolated from EBV-transformed peripheral blood leukocytes and analyzed by reverse-transcription-polymerase chain reaction (RT-PCR) and direct sequencing. Meanwhile, mutation analysis of the MYH9 gene was performed by PCR and direct sequencing. RESULTS: Both the patient and his father had large platelets, thrombocytopenia and characteristic granulocyte inclusion bodies (Dohle-like bodies). Platelet glycoproteins (GPIb) of the patient and his father were also slightly lower than normal. In the patient, a heterozygous mutation (5797C>T) in the MYH9 gene was detected both at the RNA level and the genomic DNA level. His father carried the same mutation. CONCLUSION: Patient and his father both had giant platelets, thrombocytopenia, leukocyte inclusions and mutation of MYH9. The diagnosis of MYH9-related disease was established.