[The Effect and Safety of Flumatinib in Patients with Chronic Myelogenous Leukemia Failed First-and Second-line Treatment].

OBJECTIVE: To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment. METHODS: The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed. RESULTS: At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group (P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant (P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant (P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients (P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant (P =0.317). CONCLUSION: The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

[Clinical Efficacy and Safety of Ixazomib-Containing Regimens in the Treatment of Patients with Multiple Myeloma].

OBJECTIVE: To investigate the clinical efficacy and safety of ixazomib-containing regimens in the treatment of patients with multiple myeloma (MM). METHODS: A retrospective analysis was performed on the clinical efficacy and adverse reactions of 32 MM patients treated with a combined regimen containing ixazomib in the Hematology Department of the First People's Hospital of Lianyungang from January 2020 to February 2022. Among the 32 patients, 15 patients were relapsed and refractory multiple myeloma (R/RMM) (R/RMM group), 17 patients who responded to bortezomib induction therapy but converted to ixazomib-containing regimen due to adverse events (AE) or other reasons (conversion treatment group). The treatment included IPD regimen (ixazomib+pomalidomide+dexamethasone), IRD regimen (ixazomib+lenalidomide+dexamethasone), ICD regimen (ixazomib+cyclophosphamide+dexamethasone), ID regimen (ixazomib+dexamethasone). RESULTS: Of 15 R/RMM patients, overall response rate (ORR) was 53.3%(8/15), among them, 1 achieved complete response (CR), 2 achieved very good partial response (VGPR) and 5 achieved partial response (PR). The ORR of the IPD, IRD, ICD and ID regimen group were 100%（3/3）, 42.9%（3/7）, 33.3%（1/3）, 50%（1/2）， respectively， there was no statistically significant difference in ORR between four groups (χ 2=3.375, P =0.452). The ORR of patients was 50% after first-line therapy, 42.9% after second line therapy, 60% after third line therapy or more, with no statistically significant difference among them (χ2=2.164, P =0.730). In conversion treatment group, ORR was 88.2%(15/17), among them, 6 patients achieved CR, 5 patients achieved VGPR and 4 patients achieved PR. There was no statistically significant difference in ORR between the IPD（100%， 3/3）, IRD（100%， 6/6）, ICD（100%， 3/3） and ID（60%， 3/5） regimen groups (χ2=3.737，P =0.184). The median progression-free survival (PFS) time of R/RMM patients was 9 months (95% CI : 6.6-11.4 months), the median overall survival (OS) time was 18 months (95% CI : 11.8-24.4 months). The median PFS time of conversion treatment group was 15 months (95% CI : 7.3-22.7 months), the median OS time not reached. A total of 10 patients suffered grade 3- 4 adverse event (AE). The common hematological toxicities were leukocytopenia, anemia, thrombocytopenia. The common non-hematological toxicities were gastrointestinal symptoms (diarrhea, nausea and vomit), peripheral neuropathy, fatigue and infections. Grade 1-2 peripheral neurotoxicity occurred in 7 patients. CONCLUSION: The ixazomib-based chemotherapy regimens are safe and effective in R/RMM therapy, particularly for conversion patients who are effective for bortezomib therapy. The AE was manageable and safe.

[Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome].

OBJECTIVE: To investigate the efficacy, prognosis and safety of decitabine combined with modified EIAG regimen in the treatment of patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). METHODS: The clinical data of 44 patients with relapsed/refractory AML and high-risk MDS admitted to our hospital from January 2017 to December 2020 were analyzed retrospectively. The patients were equally divided into D-EIAG group (decitabine combined with EIAG regimen) and D-CAG group (decitabine combined with CAG regimen) according to clinical treatment regimen. The complete response (CR), CR with incomplete hematologic recover (CRi), morphologic leukemia-free state (MLFS), partial response (PR), overall response rate (ORR), modified composite complete response (mCRc), overall survival (OS) time, 1-year OS rate, myelosuppression and adverse reactions between the two groups were compared. RESULTS: In D-EIAG group, 16 patients (72.7%) achieved mCRc (CR+CRi+MLFS), 3 patients (13.6%) achieved PR, and ORR (mCRc+PR) was 86.4%. In D-CAG group, 9 patients (40.9%) achieved mCRc, 6 patients (27.3%) achieved PR, and ORR was 68.2%. Difference was observed in mCRc rate between the two groups (P=0.035), but not in ORR (P>0.05). The median OS time of D-EIAG group and D-CAG group was 20 (2-38) months and 16 (3-32) months, and 1-year OS rate was 72.7% and 59.1%, respectively. There was no significant difference in 1-year OS rate between the two groups (P>0.05). After induction chemotherapy, the median time for absolute neutrophil count recovery to 0.5×109/L in D-EIAG group and D-CAG group was 14 (10-27) d and 12 (10-26) d, for platelet count recovery to 20×109/L was 15 (11-28) d and 14 (11-24)d, the median red blood cell suspension transfusion volume was 8 (6-12) U and 6 (6-12) U, and the median apheresis platelet transfusion volume was 4 (2-8) U and 3 (2-6) U, respectively. There were no statistically significant differences in comparison of the above indicators between the two groups (P>0.05). The hematological adverse reactions of patients were mainly myelosuppression. Grade III-IV hematological adverse events occurred in both groups (100%), with no increase in the incidence of non-hematological toxicities such as gastrointestinal reactions or liver function damage. CONCLUSION: Decitabine combined with EIAG regimen in the treatment of relapsed/refractory AML and high-risk MDS can improve remission rate, provide an opportunity for subsequent therapies, and have no increase in adverse reactions compared with D-CAG regimen.

[Clinical Significance of RAS Gene Mutations in Patients with Acute Myeloid Leukemia].

OBJECTIVE: To investigate the clinical characteristics of RAS gene mutations in patients with acute myeloid leukemia (AML). METHODS: 43 myeloid gene mutations were detected using next-generation sequencing (NGS) in 180 patients with AML who were first diagnosed between May 2011 and February 2021. The molecular and clinical features of RAS gene mutations and their effects on efficacy and survival of patients were retrospectively analyzed. RESULTS: Among 180 AML patients, the proportion of mutations in RAS pathway-related genes were NRAS (14.4%), KRAS (2.2%), FLT3-ITD (13.8%), PTPN11 (7.7%), KIT (5.0%), FLT3-TKD (3.8%) and CBL (2.7%). Seventy-three (40.6%) AML patients had gene mutations associated with the RAS pathway.The number of peripheral blood white blood cells and the proportion of bone marrow primitive juvenile cells in patients with NRAS/KRAS gene mutation were higher than those of patient with RAS wild-type, the difference was statistically significant (P<0.05). NRAS/KRAS gene mutations were significantly associated with the CBL gene mutation(r=0.287). In young AML patients (age <60 years), there were no significant differences in complete response rate (CR), progression-free survival (PFS), and overall survival (OS) between patients with RAS gene mutation and those with wild-type(P>0.05). In elderly AML patients (age≥60 years), PFS and OS in RAS mutants were significantly lower than those in wild-type patients(P<0.05). CONCLUSION: In AML patients, RAS gene mutation is relatively common, and RAS gene mutation is associated with clinical characteristics and efficacy of patients, and may be a molecular marker of poor prognosis for elderly AML.

Electro-optical equivalent calibration technology for high-energy laser energy meters.

Electro-optical equivalent calibration with high calibration power and high equivalence is particularly well-suited to the calibration of high-energy laser energy meters. A large amount of energy is reserved during this process, however, which continues to radiate after power-off. This study measured the radiation efficiency of a halogen tungsten lamp during power-on and after power-off in order to calculate the total energy irradiated by a lamp until the high-energy laser energy meter reaches thermal equilibrium. A calibration system was designed based on the measurement results, and the calibration equivalence of the system was analyzed in detail. Results show that measurement precision is significantly affected by the absorption factor of the absorption chamber and by heat loss in the energy meter. Calibration precision is successfully improved by enhancing the equivalent power and reducing power-on time. The electro-optical equivalent calibration system, measurement uncertainty of which was evaluated as 2.4% (k = 2), was used to calibrate a graphite-cone-absorption-cavity absolute energy meter, yielding a calibration coefficient of 1.009 and measurement uncertainty of 3.5% (k = 2). A water-absorption-type high-energy laser energy meter with measurement uncertainty of 4.8% (k = 2) was considered the reference standard, and compared to the energy meter calibrated in this study, yielded a correction factor of 0.995 (standard deviation of 1.4%).

[IDH1 Gene Mutation and Its Clinical Significance in patients with Acute Myeloid Leukemia].

OBJECTIVE: To evaluate the incidence rate of IDH1 in acute myeloid leukemia and analyze its effect on clinical characteristics and prognosis. METHODS: Mononuclear cells in bone marrow samples were collected from 192 adult patients with newly diagnosed AML. Polymerase chain reaction (PCR) and direct sequencing were used to amplify exon 4 of IDH1 gene, the gene sequencing was used to analyze the gene mutations, at same time, the detection of NPM1, FLT3-TKD, FLT3-ITD, C-KIT, CEPBA, TET2 and JAK2V617F and MLL mutations were carried out, the follow-up was used to determine its therapeutic efficacy and outcomes of patients. The clinical and laboratory data of these cases were collected, and their clinical characteristics and prognosis were then analyzed. RESULTS: Among the 192 AML patients, 13 cases were detected with IDH1 gene mutation, the mutation rate was 6.77% [95% CI (5.70%-13.38%)]. The sequencing chart of IDH1 gene showed double peaks, the mutations were heterozygous, out of them c.G395A (p.R132H) was found in 8 cases, c.C394T was found in 4 cases (p.R132C), c.C394A (p.R132S) was found in 1 cases, R132H and R132C are common, 13 cases showed missense mutation. The median age in mutation group was 52 years old, the median age in unnutration group was 40 years, there was significant difference between them (P = 0.010). Mutation rate of IDH1 gene in M1 and M2 was significantly higher than that in other FAB subtypes. There were no significant difference in sex, newly diagnosed peripheral white blood cell count, hemoglobin, platelet count, peripheral blood and bone marrow original cell proportion of primitive cells between them. Mutation of IDH1 gene had certain correlation with NPM1 gene mutation, but no correlation with FLT3-TKD, FLT3-ITD, C-KIT, TET2 and JAK2V617F and MLL natations was found. In addition, the IDH1 mutation easily occurred in patients with normal karyotype or in patients with middle prognostic risk karyotype, IDH1 mutation occurred in 11 cases with normal karyotype, the mutation rate was 10.28%, IDH1 mutation were observed in 2 cases with abnormal karyotype, the mutation rate was 3.50%, there was significant difference. In AML patients with middle prognostic risk karyotype. The complete remission (CR) and the 3 year survival (OS) rate of IDH1 mut patients were less than that in IDH1 wt, there was significant difference (P < 0.05). CONCLUSIONS: The IDH1 mutation more easily occurr in older AML patients and mutations effect of IDH1 on clinical characteristics may represent a molecular marker for poor prognosis in AML.

Technology for radiation efficiency measurement of high-power halogen tungsten lamp used in calibration of high-energy laser energy meter.

The calibration method using a high-power halogen tungsten lamp as a calibration source has many advantages such as strong equivalence and high power, so it is very fit for the calibration of high-energy laser energy meters. However, high-power halogen tungsten lamps after power-off still reserve much residual energy and continually radiate energy, which is difficult to be measured. Two measuring systems were found to solve the problems. One system is composed of an integrating sphere and two optical spectrometers, which can accurately characterize the radiative spectra and power-time variation of the halogen tungsten lamp. This measuring system was then calibrated using a normal halogen tungsten lamp made of the same material as the high-power halogen tungsten lamp. In this way, the radiation efficiency of the halogen tungsten lamp after power-off can be quantitatively measured. In the other measuring system, a wide-spectrum power meter was installed far away from the halogen tungsten lamp; thus, the lamp can be regarded as a point light source. The radiation efficiency of residual energy from the halogen tungsten lamp was computed on the basis of geometrical relations. The results show that the halogen tungsten lamp's radiation efficiency was improved with power-on time but did not change under constant power-on time/energy. All the tested halogen tungsten lamps reached 89.3% of radiation efficiency at 50 s after power-on. After power-off, the residual energy in the halogen tungsten lamp gradually dropped to less than 10% of the initial radiation power, and the radiation efficiency changed with time. The final total radiation energy was decided by the halogen tungsten lamp's radiation efficiency, the radiation efficiency of residual energy, and the total power consumption. The measuring uncertainty of total radiation energy was 2.4% (here, the confidence factor is two).

Research on temperature measurement technology for graphite-cone-absorption-cavity absolute calorimeter.

The nonlinear effect of materials and sensors in high-energy laser calorimeters is especially obvious-due to the steep temperature gradients of their absorbers. Significant measurement errors occur when traditional integral temperature sensors and methods are utilized. In an effort to remedy this, a method is proposed in this paper in which an absorption cavity is divided into many parts and multiple discrete thermocouple sensors are used to measure the temperature rise of the absorbers. The temperature distribution in the absorbers is theoretically analyzed, numerically simulated, and verified through experimentation. Energy measurement results are compared according to the temperature distribution for different layouts of thermocouples. A high-accuracy calorimeter is developed by setting and optimizing thermocouple layout, as well as correcting various elements such as the specific heat of graphite and responsivity of thermocouples. The calorimeter employing this measurement method is calibrated against a standard energy meter, resulting in correction coefficient of 1.027 and relative standard deviation of the correction coefficient of only 0.8%. Theoretical analysis, numerical simulation, and experimental verification all prove that the proposed method successfully improves measurement accuracy.

[The incidence of TET2 gene mutation and its clinical significance in acute myeloid leukemia patients].

OBJECTIVE: To evaluate the prevalence of TET2 gene mutation in acute myeloid leukemia (AML) patients, and analyze their clinical characteristics and prognosis. METHODS: Polymerase chain reaction (PCR) and direct sequencing were used to sequence exon 3 to 11 of TET2 gene. RESULTS: Among 96 AML patients, TET2 gene mutation was detected in 13 (13.54%) patients (95%CI 6.70% - 20.38%). The median age was 54 years in mutated group and 41 years in unmutated group (P = 0.010). Mutated and unmutated patients did not significantly differ in gender, white blood cells (WBC) count at diagnosis, platelet count, PB and BM blast percentage and chromosome karyotype, excepting for hemoglobin level 84 (70 - 108) g/L in mutated group versus 70 (55 - 87) g/L in unmutated group (P = 0.032). TET2 gene mutation had no significant correlation with C-KIT, FLT3, JAK2V617F mutations, but did with NPM1 mutation. TET2 mutated patients had lower CR1 rate and 2-year overall survival than unmutated in non-M(3) patients (P < 0.05). CONCLUSIONS: TET2 gene mutation is more prevalent in older AML patients and has a certain correlation with clinical characteristics and outcome. It may be a molecular marker for poor prognosis in AML.