BACKGROUND: Azathioprine (AZA) is a widely used immunosuppressant drug. Leukopenia is a serious adverse effect of the drug which often necessitates dose reduction or drug withdrawal. Predictors of leukopenia include genetic and nongenetic factors. Genetic polymorphism of AZA-metabolizing enzyme, thiopurine S-methyltransferase (TPMT) is well established. There is inconclusive evidence about the role of Nudix hydrolase (NUDT15) gene polymorphism. This case-control study assessed the association of genetic polymorphisms of NUDT15 and TPMT with leukopenia induced by AZA.
METHODS: Cases were patients on AZA who developed leukopenia (white blood cell count <4000/μl) within 1 year of treatment initiation that necessitated dose reduction or drug withdrawal. Age and gender-matched patients without leukopenia within 1 year of treatment with AZA served as controls. TPMT (3 loci: c238G to C, c460G to A, c719A to G) and NUDT15 (c 415C to T, rs116855232) genotyping were done using TPMT strip assay and polymerase chain reaction-restriction fragment length polymorphism, respectively. Genotype frequencies were noted, and the odds ratio was calculated to determine the association between genotypes and leukopenia.
RESULTS: Twenty-nine subjects (15 cases and 14 controls) were enrolled. Statistically significant differences were not observed in the TPMT genotype (*1/*1 and *1/*3C) (P = 0.23) between cases and controls. NUDT15 genotypes (*1/*1 and *1/*3) (P = 0.65) also showed no statistically significant difference between cases and controls.
CONCLUSIONS: The above genotypes do not appear to be associated with AZA-induced leukopenia in an eastern Indian population.

OBJECTIVE: To compare the clinical effect of intradermal needling and acupuncture in prevention and treatment of leukopenia after chemotherapy with spleen-kidney deficiency.
METHODS: A total of 90 patients with malignant tumor who received chemotherapy were randomly divided into a intradermal needling group (30 cases, 1 case dropped out), an acupuncture group (30 cases, 2 cases dropped out, 1 case was eliminated) and a control group (30 cases). The control group received conventional symptomatic treatment after chemotherapy. On the basis of the treatment in the control group, the intradermal needling group received intradermal needling at Guanyuan (CV 4), Dazhui (GV 14) and bilateral Geshu (BL 17), Zusanli (ST 36)，Shenshu (BL 23), the needles were retained for 48 h, once every other day. On the basis of the treatment in the control group, the acupuncture group received conventional acupuncture at the same acupoints as the intradermal needling group, once every other day. The treatment started from the first day of chemotherapy, for a total of 2 weeks in the three groups. The white blood cell count, neutrophil count, hemoglobin content, platelet count and Karnofsky performance status (KPS) score before treatment and on 3rd, 7th, 14th, and 21st days after treatment were compared among the three groups. The incidence and grading of leukopenia and the usage of leukocyte-boosting drug during chemotherapy cycle was recorded.
RESULTS: On 7th day after treatment, the white blood cell count in the intradermal needling group and the acupuncture group was higher than that in the control group (P<0.01, P<0.05). On the 14th day after treatment, the hemoglobin content in the intradermal needling group and the acupuncture group was higher than that in the control group (P<0.01). On the 7th, 14th, and 21st days after treatment, the platelet count in the acupuncture group was higher than that in the control group (P<0.01), on the 14th and 21st days after treatment, the platelet count in the intradermal needling group was higher than that in the control group (P<0.01). There was no statistically significant difference among the three groups after treatment in terms of neutrophil count, KPS score, incidence and grading of leukopenia, and the usage of leukocyte-boosting drug (P>0.05).
CONCLUSIONS: Both intradermal needling and acupuncture can effectively increase peripheral blood white blood cell count, hemoglobin content and platelet count during chemotherapy cycle, reduce the toxicity of chemotherapy drug to bone marrow hematopoietic function, and alleviate bone marrow suppression after chemotherapy. The two treatments are equally effective.
目的：比较揿针和针刺防治脾肾两虚型化疗后白细胞减少症的临床疗效。方法：将90例接受化疗的恶性肿瘤患者随机分为揿针组（30例，脱落1例）、针刺组（30例，脱落2例，剔除1例）和对照组（30例）。对照组在化疗的基础上予常规对症治疗；在对照组治疗基础上，揿针组于关元、大椎及双侧膈俞、足三里、肾俞行揿针治疗，留针48 h，隔日1次；在对照组治疗基础上，针刺组于揿针组相同穴位行常规针刺治疗，隔日1次。均从化疗第1天开始，共治疗2周。比较各组患者治疗前及治疗第3、7、14、21天白细胞计数、中性粒细胞计数、血红蛋白含量、血小板计数、Karnofsky功能状态（KPS）评分；于治疗第21天评定白细胞减少症的分度、发生率，记录化疗周期中升白细胞药物使用情况。结果：治疗第7天，揿针组和针刺组白细胞计数高于对照组（P<0.01，P<0.05）。治疗第14天，揿针组和针刺组血红蛋白含量高于对照组（P<0.01）。治疗第7、14、21天，针刺组血小板计数高于对照组（P<0.01），治疗第14、21天，揿针组血小板计数高于对照组（P<0.01）。各组治疗后各时间点中性粒细胞计数、KPS评分及白细胞减少症分度、白细胞减少症发生率、升白细胞药物使用情况比较，差异无统计学意义（P>0.05）。结论：揿针和常规针刺在化疗周期中均可升高外周血白细胞计数、血红蛋白含量、血小板计数，减少化疗药物对骨髓造血功能的影响，减轻化疗后骨髓抑制，两种治疗方法疗效相当。.

BACKGROUND: The current prediction models for the risk of infection during immunosuppressive treatment for lupus nephritis (LN) lack a prediction time window and have poor pertinence. This study aimed to develop a risk stratification to predict infection during immunosuppressive therapy in patients with LN.
METHODS: This retrospective nested case-control study collected patients with LN treated with immunosuppressive therapy between 2014 and 2022 in the Nephrology ward in Huashan Hospital affiliated to Fudan University and Huashan Hospital Baoshan Branch. Cases were defined as patients who experienced infection during the follow-up period; patients were eligible as controls if they did not have infection during the follow-up period.
RESULTS: There were 53 patients with infection by CTCAE V5.0 grade ≥2. According to the 1:3 nested matching, the 53 patients with infection were matched with 159 controls. In the multivariable logistic regression model, the change rate of fibrinogen (OR = 0.97, 95% CI: 0.94-0.99, p = 0.008), leukopenia (OR = 8.68, 95% CI: 1.16-301.72, p = 0.039), and reduced albumin (OR = 6.25, 95% CI: 1.38-28.24, p = 0.017) were independently associated with infection. The AUC of the ROC curve in the validation set of the multivariable logistic regression model in the internal random sampling was 0.864. The scores range from -2 to 10. The infection risk stratification ranges from 2.8% at score -2 to 97.5% at score 10.
CONCLUSIONS: A risk stratification was built to predict the risk of infection in patients with LN undergoing immunosuppressive therapy.

OBJECTIVE: To evaluate effects of bone marrow sparing (BMS) radiotherapy on decreasing the incidence of acute hematologic toxicity (HT) for locoregionally advanced cervical cancer (LACC) patients treated by pelvic irradiation.
METHODS: LACC patients were recruited prospectively from May 2021 to May 2022 at a single center and were evenly randomized into the BMS group and the control group. All patients received pelvic irradiation with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy and BM V40 < 25% in the BMS group was additionally prescribed. Acute HT was assessed weekly. Binary logistic regression model and receiver operating characteristic (ROC) curve were used for predictive value analysis. The trial was registered with Chinese clinical trial registry (ChiCTR2200066485).
RESULTS: A total of 242 patients were included in the analysis. Baseline demographic, disease and treatment characteristics were balanced between the two groups. In the intention-to-treat population, BMS was associated with a lower incidence of grade ≥ 2 and grade ≥ 3 acute HT, leukopenia and neutropenia s(72.70% v 90.90%, P < 0.001*; 16.50% vs. 65.30%, P < 0.001*; 66.10% vs. 85.10%, P = 0.001*; 13.20% vs. 54.50%, P < 0.001*; 37.20% vs. 66.10%, P < 0.001*; 10.70% vs. 43.80%, P < 0.001*). BMS also resulted in decreased dose delivered to the organs at risk (OARs) including rectum, bladder and left and right femoral head. Univariate and multivariate analyses showed that BM V40 was an independent risk factor for grade ≥ 3 acute HT (odds ratio [OR] = 2.734, 95% confidence interval [CI] = 1.959-3.815, P < 0.001*). Cutoff value was 25.036% and area under the curve (AUC) was 0.786. The nomogram was constructed, which was rigorously evaluated and internally cross-validated, showing good predictive performance.
CONCLUSIONS: Receiving BMS pelvic irradiation could reduce the incidence of acute HT in LACC patients, and BM V40 < 25% may be a significant factor in reducing the risks of acute HT.

BACKGROUND: Leukopenia could be induced by chemotherapy, which leads to bone marrow suppression and even affects the therapeutic progression of cancer. Qijiao Shengbai Capsule (QSC) has been used for the treatment of leukopenia in clinic, but its bioactive components and mechanisms have not yet been elucidated clearly.
OBJECTIVE: This study aimed to elucidate the molecular mechanisms of QSC in treating leukopenia.
METHODS: Serum pharmacochemistry, multi-omics, network pharmacology, and validation experiment were combined to study the effect of QSC in murine leukopenia model.
METHODS: First, UPLC-QTOF-MS was used to clarify the absorbed components of QSC. Then, cyclophosphamide (CTX) was used to induce mice model with leukopenia, and the therapeutic efficacy of QSC was assessed by an integrative approach of multi-omics and network pharmacology strategy. Finally, molecular mechanisms and potential therapeutic targets were identified by validated experiments.
RESULTS: 121 compounds absorbed in vivo were identified. QSC significantly increase the count of white blood cells (WBCs) in peripheral blood of leukopenia mice with 15 days treatment. Multi-omics and network pharmacology revealed that leukotriene pathway and MAPK signaling pathway played crucial roles during the treatment of leukopenia with QSC. Six targets (ALOX5, LTB4R, CYSLTR1, FOS, JUN, IL-1β) and 13 prototype compounds were supposed to be the key targets and potential active components, respectively. The validation experiment further confirmed that QSC could effectively inhibit the inflammatory response induced by leukopenia. The inhibitors of ALOX5 activity can significantly increase the number of WBCs in leukopenia mice. Molecular docking of ALOX5 suggested that calycosin, daidzein, and medicarpin were the potentially active compounds of QSC.
CONCLUSIONS: Leukotriene pathway was found for the first time to be a key role in the development of leukopenia, and ALOX5 was conformed as the potential target. QSC may inhibit the inflammatory response and interfere the leukotriene pathway, it is able to improve hematopoiesis and achieve therapeutic effects in the mice with leukopenia.

BACKGROUND: The outcome of relapsed/refractory (R/R) acute myeloid leukemia (AML) remains extremely poor. Venetoclax (VEN)-based regimens have shown promise in treating R/R AML.
OBJECTIVE: This phase 2 study aimed to systematically evaluate the efficacy and safety of the VAA regimen (VEN plus Cytarabine and Azacitidine) in R/R AML patients.
METHODS: Thirty R/R AML patients were enrolled. The study adopted a stepwise ramp-up of VEN dosing, starting with 100 mg on day 1, escalating to 200 mg on day 2, and reaching 400 mg from day 3 to day 9. Cytarabine (10 mg/m2, q12h) was administered intravenously twice daily from days 1 to 10, and Azacitidine (75 mg/m2) was administered via subcutaneous injection once daily from days 1-7. The primary efficacy endpoint was the composite complete remission rate (CRc), including complete response (CR) and complete response with incomplete blood count recovery (CRi). Secondary endpoints included overall survival (OS), duration of response (DOR), and safety analysis.
RESULTS: The CRc rate was 63.3% (19/30), with CR in 36.7% of patients and CRi in 26.7%. Notably, 14 (73.7%) of 19 patients achieving CRc showed undetectable measurable residual disease by flow cytometry. With a median follow-up of 10.7 months, the median OS had not been reached, and the median DOR was 18.3 months. The most common grade 3-4 adverse events (AEs) were neutropenia (100%), anemia (96.7%), thrombocytopenia (90.0%), and leukopenia (90.0%). Infections, with pneumonia being the most prevalent (43.3%), were observed, including one fatal case of Pseudomonas aeruginosa septicemia. There were no treatment-related deaths.
CONCLUSIONS: The VAA regimen is an effective and safe option for patients with R/R AML, demonstrating a high CRc rate and manageable safety profile.

OBJECTIVE: To explore the association between preoperative WBC count and the long-term survival outcomes and clinical outcomes in different stage patients who underwent surgical resection for colorectal cancer (CRC).
METHODS: A cohort of 8121 Chinese patients who underwent surgical resection for CRC from January 1, 2008 to December 31, 2014 were enrolled as part of the retrospective cohort were retrospectively analyzed. Based on that the preoperative WBC optimal cut-off value was 7*109/L (7,000/µL), the high preoperative WBC group and the low preoperative WBC group was defined. Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce confounding. The impact of preoperative WBC count on overall survival (OS) and disease-free survival (DFS) was investigated using the Kaplan-Meier method and Univariate Cox proportional hazards models in different stage subgroup respectively.
RESULTS: After IPTW, the clinical characters in the high preoperative WBC count group and the low preoperative WBC count group were balanced. Kaplan-Meier analysis showed that the 5-year OS rate were significantly lower in the high preoperative WBC count group overall, in stage II and IV. The 5-year DFS rate was significantly lower overall, in stage II and III in the high preoperative WBC count group. High preoperative WBC count was associated with poorer OS overall in stage II and stage IV.
CONCLUSIONS: This study suggests that preoperative WBC count is an independent risk factor for survival in patients undergoing colorectal surgery and may need to consider the stage of cancer when applied to predict long-term adverse outcome prognosis.

OBJECTIVE: Myelosuppressive chemotherapy-induced neutropenia (CIN) remains a major limitation of cancer treatment efficacy, necessitating very expensive supportive care. Lithium carbonate, an inexpensive drug, can increase the number of neutrophils, possibly providing an efficacious and cost-effective alternative for treating CIN. The aim of this study was to determine whether lithium therapy can attenuate chemotherapy-induced neutropenia and leukopenia in breast cancer patients.
METHODS: A total of 50 breast cancer patients were enrolled in this prospective, interventional, randomized, controlled, and single-blind study. The patients were divided into two groups: a control group (group 1, N = 25 patients) and a lithium-treated (treatment) group (group 2, N = 25 patients). Group 1 patients were further subclassified into a non-neutropenic control group (N = 16) and a neutropenic control (N = 9) based on the subsequent development of severe neutropenia, or not. The control group received 4 cycles of doxorubicin or epirubicin plus cyclophosphamide followed by 2 cycles of paclitaxel. The treatment group received the same regimen as the control group as well as oral lithium carbonate throughout the chemotherapy cycles.
RESULTS: The results showed that the absolute neutrophil count (ANC) was increased in the lithium-treated group, while it was markedly reduced in both the non-neutropenic and neutropenic control groups (by 55.56% and 65.42% post-4 chemotherapy cycles, and by 19.57% and 39.90% post-6 cycles, respectively). The same pattern of alterations was observed for the total white blood cell count in both the control and treatment groups. In addition, the incidence and period prevalence were greatly reduced in the lithium-treated group compared to non-neutropenic and neutropenic control groups.
CONCLUSIONS: Lithium therapy ameliorated chemotherapy-induced leukopenia and neutropenia in breast cancer patients. This may provide a new strategy for cost-effective treatment of CIN, particularly in Egyptian cancer patients.

BACKGROUND: Available treatments for older patients with primary diffuse large B-cell CNS lymphoma (PCNSL) offer progression-free survival of up to 16 months. We aimed to investigate an intensified treatment of high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) in older patients with PCNSL.
METHODS: MARTA was a prospective, single-arm, phase 2 study done at 15 research hospitals in Germany. Patients aged 65 years or older with newly diagnosed, untreated PCNSL were enrolled if they had an Eastern Cooperative Oncology Group performance status of 0-2 and were fit for high-dose chemotherapy and autologous HSCT. Induction treatment consisted of two 21-day cycles of high-dose intravenous methotrexate 3·5 g/m2 (day 1), intravenous cytarabine 2 g/m2 twice daily (days 2 and 3), and intravenous rituximab 375 mg/m2 (days 0 and 4) followed by high-dose chemotherapy with intravenous rituximab 375 mg/m2 (day -8), intravenous busulfan 3·2 mg/kg (days -7 and -6), and intravenous thiotepa 5 mg/kg (days -5 and -4) plus autologous HSCT. The primary endpoint was progression-free survival at 12 months in all patients who met eligibility criteria and started treatment. The study was registered with the German clinical trial registry, DRKS00011932, and recruitment is complete.
RESULTS: Between Nov 28, 2017, and Sept 16, 2020, 54 patients started induction treatment and 51 were included in the full analysis set. Median age was 71 years (IQR 68-75); 27 (53%) patients were female and 24 (47%) were male. At a median follow-up of 23·0 months (IQR 16·8-37·4), 23 (45%) of 51 patients progressed, relapsed, or died. 12-month progression-free survival was 58·8% (80% CI 48·9-68·2; 95% CI 44·1-70·9). During induction treatment, the most common grade 3-5 toxicities were thrombocytopenia and leukopenia (each in 52 [96%] of 54 patients). During high-dose chemotherapy and autologous HSCT, the most common grade 3-5 toxicity was leukopenia (37 [100%] of 37 patients). Treatment-related deaths were reported in three (6%) of 54 patients, all due to infectious complications.
CONCLUSIONS: Although the primary efficacy threshold was not met, short induction followed by high-dose chemotherapy and autologous HSCT is active in selected older patients with PCNSL and could serve as a benchmark for comparative trials.
BACKGROUND: Else Kröner-Fresenius Foundation, Riemser Pharma, and Medical Center-University of Freiburg.

BACKGROUND: We aimed to compare the frequency of myelosuppression in patients initiating azathioprine (AZA) at full dose versus those undergoing gradual dose escalation.
METHODS: Forty patients with inflammatory bowel disease were recruited over one year and randomized into two groups of 20. Group A initiated AZA at a full dose of 2 mg/kg, while group B started at 1 mg/kg with subsequent dose increases at regular intervals.
RESULTS: Seventeen patients from each group were included in the final analysis. During follow-up, two patients (11.8%) from group A and four patients (23.5%) from group B experienced relapses (p=0.65). Myelosuppression occurred in two patients (11.8%) from each group. Absolute neutrophil counts in group A tended to have lower median values than those in group B, particularly four weeks after AZA initiation. Univariate analysis identified serum proteins, albumin, and bilirubin as significantly associated with leukopenia, but these factors were not significant according to multivariate analysis.
CONCLUSIONS: The incidence of myelosuppression was similar between the groups. Patients with full-dose initiation of AZA had numerically fewer relapses during the follow-up period.