Validation and modification of simplified Geriatric Assessment and Elderly Prognostic Index: Effective tools for older patients with diffuse large B-cell lymphoma.

Geriatric assessment can aid in optimizing treatment strategies and supportive interventions for older patients with diffuse large B-cell lymphoma (DLBCL). Fondazione Italiana Linformi has recently introduced novel geriatric assessment tools, simplified Geriatric Assessment (sGA) and Elderly Prognostic Index (EPI), aimed at tailoring the treatment and predicting the outcomes for older patients with DLBCL. The objectives of this study are the validation and possible modification of the sGA and EPI in China. In the study, both sGA and EPI demonstrated the predictive capabilities for overall survival (OS) and early mortality (both p < 0.05) in older individuals with DLBCL. Albumin, serving as an independent predictive biomarker for OS (p = 0.006), was utilized to adjust the measurements, resulting in the establishment of sGA-A and EPI-A. The sGA-A effectively addressed the shortcomings of the sGA and EPI in predicting PFS and surpassed them in predicting OS and early mortality. Nevertheless, there is insufficient evidence to support the use of sGA and EPI as treatment guidance tools. In conclusion, the modified sGA-A model proved to be a successful instrument for geriatric assessment of older patients with DLBCL.

Low-dose decitabine for previously untreated acute myeloid leukemia ineligible for intensive chemotherapy aged 65 years or older: a prospective study based on comprehensive geriatric assessment.

Background: The outcome of patients with acute myeloid leukemia (AML) aged ⩾65 years is poor. Effective treatment options are limited for patients with AML who cannot tolerate intensive chemotherapy. Objectives: We aimed to evaluate the efficacy of low-dose decitabine in previously untreated patients with AML aged ⩾65 years who were ineligible for intensive chemotherapy based on a comprehensive geriatric assessment. Design: We performed a prospective, multicenter, open-label, and non-randomized study. Methods: Patients were enrolled at four centers in Beijing between 1 January 2017 and 31 December 2020. They were treated with decitabine at a dose of 6 mg/m2 for 10 days. The treatment was repeated every 28 days for one cycle for a total of six cycles. The primary endpoint of our study was overall survival (OS) at the end of the first year after enrolment. The secondary endpoints included overall response rate, leukemia-free survival, relapse rate, treatment-related mortality (TRM), quality of life, safety, and transfusion dependence. Patients were continuously monitored for toxicity. Results: Overall, 47 patients (30 males and 17 females) participated in this study. The median age of the enrolled patients was 78 (range, 65-90) years. The median follow-up time was 22.2 (range, 4.6-38.8) months. Fifteen (31.9%) patients achieved complete remission (CR), 11 (23.4%) patients achieved partial remission, 3 (6.4%) patients achieved hematological improvement only, and 18 (38.3%) patients did not achieve remission. The median time to obtain CR was 2 months. The median CR was 8.5 months. Of the patients, 36 (76.6%) patients completed six cycles of treatment with low-dose decitabine, and the 1-year OS was 36.1%. According to instrumental activities of daily living scales, age, comorbidities, and albumin (IACA) scores, the median survival was 11.2 months in the unfit group and 6 months in the frail group. The 1-year OS rates in the unfit and frail groups were 49.2% and 23.4%, respectively. Grade ⩾3 non-hematological toxicity was observed in 70.2% (33/47) of the patients. TRM occurred in three patients. No early deaths occurred after treatment. Conclusion: In newly diagnosed older patients with AML whose IACA assessment was unfit or frail for standard chemotherapy, treatment with low-dose decitabine demonstrated clinical activity and good security in our study.

IGH rod-like tracer: An AlphaFold2 structural similarity extraction-based predictive biomarker for MRD monitoring in pre-B-ALL.

Sequence variation resulting from the evolution of IGH clones and immunophenotypic drift makes it difficult to track abnormal B cells in children with precursor B cell acute lymphoblastic leukemia (pre-B-ALL) by flow cytometry, qPCR, or next-generation sequencing (NGS). The V-(D)-J regions of immunoglobulin and T cell receptor of 47 pre-B-ALL samples were sequenced using the Illumina NovaSeq platform. The IGH rod-like tracer consensus sequence was extracted based on its rod-like alpha-helices structural similarity predicted by AlphaFold2. Additional data from published 203 pre-B-ALL samples were applied for validation. NGS-IGH (+) patients with pre-B-ALL had a poor prognosis. Consistent CDR3-coded protein structures in NGS-IGH (+) samples could be extracted as a potential follow-up marker for pre-B-ALL children during treatment. IGH rod-like tracer from quantitative immune repertoire sequencing may serve as a class of biomarker with significant predictive values for the dynamic monitoring of MRD in pre-B-ALL children.

CDK7 inhibition induces apoptosis in acute myeloid leukemia cells and exerts synergistic antileukemic effects with azacitidine in vitro and in vivo.

THZ1, a CDK7 inhibitor, has potent antitumor effects in several cancers; however, its role in Acute myeloid leukemia (AML) is unclear. We explored the effects and potential mechanisms of THZ1, alone and in combination with azacitidine (AZA), in AML cells and xenograft models. THZ1 decreased cell viability, induced apoptosis in a dose and time-dependent manner, induced G0/G1 cell cycle arrest, decreased phosphorylated CDK1 and CDK2 expression, and inhibited RNA Pol II phosphorylation at multiple serine sites. The combination of AZA and THZ1 exhibited synergistic antileukemic effects in AML cell lines and primary cells with MCL1 and c-MYC downregulation. Moreover, the combination therapy significantly decreased tumor burden and prolonged animal survival in xenograft mice models. Our data demonstrate that CDK7 inhibition induces the apoptosis of AML cells and exerts a synergistic antileukemia effect with AZA in vitro and in vivo, which supports future exploration of this combination in clinical studies.

Single cell sequencing reveals cell populations that predict primary resistance to imatinib in chronic myeloid leukemia.

The treatment of chronic myeloid leukemia (CML), a disease caused by t(9;22)(q34;q11) reciprocal translocation, has advanced largely through the use of targeted tyrosine kinase inhibitors (TKIs). To identify molecular differences that might distinguish TKI responders from non-responders, we performed single cell RNA sequencing on cells (n = 41,723 cells) obtained from the peripheral blood of four CML patients at different stages of treatment to generate single cell expression profiles. Analysis of our single cell expression profiles in conjunction with those previously obtained from the bone marrow of additional CML patients and healthy donors (total = 69,263 cells) demonstrated that imatinib treatment significantly altered leukocyte population compositions in both responders and non-responders, and affected the expression profiles of multiple cell populations, including non-neoplastic cell types. Notably, in imatinib poor-responders, patient-specific pre-treatment unique stem/progenitor cells became enriched in peripheral blood compared to the responders. These results indicate that resistance to TKIs might be intrinsic in some CML patients rather than acquired, and that non-neoplastic immune cell types may also play vital roles in dispersing the responsiveness of patients to TKIs. Furthermore, these results demonstrated the potential utility of peripheral blood as a diagnostic tool in the TKI sensitivity of CML patients.

Comprehensive Geriatric Assessment (CGA): A Simple Tool for Guiding the Treatment of Older Adults with Diffuse Large B-Cell Lymphoma in China.

BACKGROUND: We aimed to validate a simple Comprehensive Geriatric Assessment (CGA) in older adults with diffuse large B-cell lymphoma (DLBCL) in China and to evaluate the tolerability and efficacy of CGA-driven therapy. MATERIALS AND METHODS: In total, 78 patients with DLBCL aged ≥60 years were evaluated using CGA with the following parameters: age ≥ 80 years, activities of daily living (ADL), instrumental ADL, and modified cumulative illness rating score for geriatrics. Patients were grouped as fit, unfit, or frail. Patients classified as fit received standard-dose rituximab plus CHOP, whereas patients in the latter two groups received reduced-dose or reduced-agent therapy. The overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and toxicities in the three groups were evaluated. RESULTS: According to the CGA, 45 (57.5%) patients were classified as fit, 5 (6.4%) as unfit, and 28 (35.9%) as frail. The ORR was 82.1% (64/78) among all the patients, including 55 patients (70.6%) who achieved complete response and 9 patients (11.5%) who achieved partial response. In the fit and unfit + frail groups, it achieved 97.8% and 60.6%, respectively. In total, 26 (33.3%) patients (10/45 [22.2%] fit and 16/33 [48.5%] unfit + frail) showed disease progression or recurrence. The median follow-up time was 18 months (range, 5-62). The 3-year OS and PFS rates were 82% and 58%, respectively. There were no treatment-related deaths. CONCLUSION: A simple CGA in older adults with DLBCL may be an effective tool for guiding therapeutic strategies in China. IMPLICATIONS FOR PRACTICE: Diffuse large B-cell lymphoma (DLBCL) is the most common malignant lymphoma in older adults. The simple tool, Comprehensive Geriatric Assessment (CGA), is proved to be an effective method to identify older adults with DLBCL who are suitable for standard-dose R-CHOP regimen therapy. This is the first prospective trial in China to evaluate the tolerability and efficacy of CGA-driven therapy for older adults with DLBCL, and the result showed that this simple CGA may be an effective tool for guiding therapeutic strategies.

A new tool for comprehensive geriatric assessment in elderly patients with acute myeloid leukemia: a pilot study from China.

BACKGROUND: Acute myeloid leukemia (AML) is a common type of hematological malignancy in elderly people. Geriatricians have developed comprehensive geriatric assessment (CGA) methods for elderly patients; however, the tools used for CGA in AML are not uniform. Thus, we aimed to validate the instrumental activities of daily living (IADL) scales, age, comorbidities (Charlson Comorbidity Index), and albumin (IACA) index, which is a new tool for CGA, in elderly patients with AML. METHODS: Patients aged ≥60 years who had been diagnosed with AML were screened for eligibility. Among the IACA low-, intermediate-, and high-risk groups, continuous variables were compared using the Mann-Whitney U test, and categorical variables were compared using χ and Fisher exact tests. In addition, probabilities of overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: A total of 21, 34, and 6 patients were categorized into IACA low-risk (0 point), intermediate-risk (1-2 points), and high-risk (≥3 points) groups, respectively. The rates of relapse/progression-related mortality were 23.8%, 58.8%, and 100.0% in the IACA low-, intermediate-, and high-risk groups, respectively (χ = 12.81, P < 0.001). The 2-year probabilities of OS were 47.7% (95% confidence interval [CI] 22.8%-72.6%) and 20.2% (95% CI 5.9%-34.5%) in the IACA low- and intermediate-risk groups, respectively (χ = 5.99, P = 0.014), which were significantly higher than those in the high-risk group (low-risk [47.7% (95% CI 22.8%-72.6%)] vs. high-risk [0], χ = 20.80, P < 0.001; intermediate-risk [20.2% (95% CI 5.9%-34.5%)] vs. high-risk [0], χ = 7.56, P = 0.006; respectively). In the IACA low-risk group, the 2-year probability of OS in patients receiving induction chemotherapy (50.8% [95% CI 24.1%-77.5%]) was significantly higher than that in those receiving best supportive care (0, χ = 25.74, P < 0.001). CONCLUSION: We suggest that the IACA index might be a simple and effective tool for comprehensive geriatric assessment in elderly AML patients.

Impact of lenalidomide exposure on blood cell collection for autotransplants in persons with POEMS syndrome.

INTRODUCTION: Lenalidomide is an effective therapy of POEMS syndrome. However, there is concern that exposure to lenalidomide may reduce the efficiency of blood cell collection in persons who may eventually receive an autotransplant. We studied the impact of lenalidomide therapy on subsequent blood cell mobilization and collection including frequency of blood CD34+ cells and CXCR4 expression before and after mobilization with cyclophosphamide and granulocyte-colony stimulating factor (G-CSF). MATERIAL AND METHODS: Forty-three subjects with POEMS were assigned to receive lenalidomide and dexamethasone for 2-4 28 d cycles (n = 19) or no therapy (n = 24). All subjects then received cyclophosphamide and G-CSF. Neither cohort had substantial numbers of blood CD34+ cells before mobilization. RESULTS: Mobilization increased blood CD34+ frequency in lenalidomide-treated subjects and controls similarly (0.25% (95% confidence interval (CI): 0.03-1.39% vs. 0.32%, 0.04-1.47%), p = 0.472). Increases in blood CD34+ numbers were also similar (10 × 106/l) (5-77 × 106/l) vs. 14 × 106/l (6-101 × 106/l), p = 0.312). Mean CXCR4 fluorescence intensity on bone marrow cells from controls decreased from 58 ±34 (mean ± SD) to 31 ±16 after mobilization (p = NS). In contrast, mean CXCR4 intensity on bone marrow cells in lenalidomide-treated subjects increased from 55 ±43 to 89 ±40 (p = 0.017, comparing the deviation between two groups). Median numbers of CD34+ cells collected in lenalidomide-treated subjects and controls were 2.3 × 106/kg (0.6-6.8 × 106/kg) and 2.8106/kg (1.0-8.9 × 106/kg; p = 0.521). CONCLUSIONS: Brief lenalidomide treatment for POEMS did not reduce numbers of CD34+ blood cells collected but increased CXCR4 expression on bone marrow CD34+ cells.

PD-1 expression on the surface of peripheral blood CD4+ T cell and its association with the prognosis of patients with diffuse large B-cell lymphoma.

The aim of the study was to investigate the relationship between PD-1 expression on the surface of CD4+ T cells and prognosis of patients with diffuse large B-cell lymphoma (DLBCL). Sixty patients who were newly diagnosed with DLBCL and 39 healthy controls were enrolled. In CD4+ T cells of DLBCL patients, the median MFI of PD-1 were 541.5 (range: 348.25-758.75), significantly higher than 250 (range: 211-326) in healthy controls (P < 0.001). The ZAP70, PI3K, and NFAT mRNA expression levels of patients were 0.47, 0.47, and 0.62 times, respectively, of those of the healthy controls (P < 0.05). In patients with the percentage of PD-1 on CD4+ T cells ≥30.25%, their EFS and OS were significantly lower than patients with PD-1+ CD4+ T cells <30.25% (P < 0.05). The possible explanation is that high PD-1 expression on CD4+ cells of DLBCL patients may impair T-cell function and thus contribute to poor prognosis. There was no relationship between PD-1 surface expression on CD4+ T cells and PD-1 expression within the biopsy of tumor microenvironments from DLBCL patients.

[Diagnostic value of three evaluation methods of ¹8F-FDG PET/CT in detecting bone marrow infiltration in patients with newly diagnosed diffuse large B-cell lymphoma].

OBJECTIVE: To evaluate three methods of ¹8F-FDG PET/CT in detecting bone marrow infiltration in patients with newly diagnosed diffuse large B-cell lymphoma. METHODS: Seventy-seven patients with newly diagnosed diffuse large B-cell lymphoma from July 2012 to June 2014 were retrospectively analyzed. All patients received both ¹8F-FDG PET/CT scan and bone marrow biopsy in the region of the posterior iliac crests. There were three evaluation methods of ¹8F-FDG PET/CT to detect bone marrow infiltration, including visual comparison (the FDG uptake in bone marrow of iliac crests was higher than the normal liver tissue), the maximal standardized uptake values (SUV(max)) in bone marrow of iliac crests (more than or equal to 2.5), the ratio of maximal standardized uptake values of iliac crests bone marrow to liver parenchyma intensity (more than 1). All results were compared with the bone marrow biopsy. RESULTS: Visual comparison of ¹8F-FDG PET/CT could be used to diagnose bone marrow infiltration, with the sensitivity of 100.00%, specificity of 80.00%, positive predictive value of 48.00%, and negative predictive value of 100.00%. When the SUV(max) of iliac crests was used as the diagnostic threshold, the sensitivity was 75.00%, with 92.31% specificity, 64.29% positive predictive value, and 95.24% negative predictive value. The ratio of SUV(max) had the best diagnostic efficiency, with sensitivity of 100.00%, specificity of 90.77%, positive predictive value of 66.67%, and negative predictive value of 100.00%. CONCLUSION: The ratio of SUV(max) is a valuable diagnostic method in detecting diffuse large B-cell lymphoatic bone marrow involvement.

Oxidative stress contributes to abnormal glucose metabolism and insulin sensitivity in two hyperlipidemia models.

OBJECTIVE: Lipid metabolism disturbance can result in insulin resistance and glucose intolerance; however, the features of glucose metabolism are still elusive in different dyslipidemia. Our study intended to explore the characteristics and molecular mechanisms of glucose metabolism abnormal in hypercholesterolemia and hypertriglyceridemia models. METHODS: Two mouse models were used in this study, one was lipoprotein lipase gene-deleted (LPL(+/-)) mice, and the other was high fat dietary (HFD) mice. Levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterin (HDL-c) and low-density lipoprotein-cholesterin (LDL-c) in serum were measured by full-automatic biochemical analyzer. Intraperitoneal glucose tolerance test (IPGTT) was performed to evaluate insulin sensitivity and ß-cell function. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) levels in serum were measured by colorimetric determination. mRNA expression of superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase 1 (Gpx1), nuclear factor erythroid 2-related factor 2 (Nrf2a) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) in liver, skeletal muscle, visceral fat and subcutaneous fat were measured by Real-Time PCR. RESULTS: Compared with HFD mice, the levels of serum TG were significantly higher in LPL(+/-) mice, whereas the levels of TC, HDL-c, LDL-c were significantly lower. The plasma glucose levels were increased at each time point of intra-peritoneal glucose tolerance test (IPGTT) in both groups. Furthermore, the level of serum fasting insulin and homeostasis model assessment index-insulin resistance (HOMA-IR) increased with a decreased ISI in both groups. In addition, the plasma MDA of HFD group was higher than that of lipoprotein lipase-deficiency (LPL(+/-)) group, while the activity of T-SOD in HFD group was lower than that in LPL(+/-) group. Real-Time PCR revealed that the expressions of SOD1, CAT and Gpx1 in liver and subcutaneous fat were lower in HFD group than those in LPL(+/-) group, but higher in skeletal muscle and visceral fat. CONCLUSIONS: There are different in glucose metabolism between high TG mice and high TC mice. Impaired insulin sensitivity is more serious in HFD mice than that in LPL(+/-) mice. Oxidative stress could contribute to insulin resistance in hyperlipidemia mice.

A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy.

OBJECTIVE: To evaluate the effects and safety of 300-600 mg α-lipoic acid (ALA) given i.v. for diabetic peripheral neuropathy (DPN). METHODS: We searched the databases of Medline, Embase, and Cochrane central register of Controlled Trials and Chinese biological medicine for clinical trials of ALA in the treatment of DPN. Data were extracted to examine methodological quality and describe characteristics of studies. The primary outcomes were efficacy, median motor nerve conduction velocity (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, and peroneal SNCV. Secondary outcomes were adverse events. RESULTS: Fifteen randomized controlled trials met the inclusion criteria. The treatment group involved the administration of ALA 300-600 mg i.v. per day. And the control group used the same interventions except for ALA. Compared with the control group, nerve conduction velocities increased significantly in the treatment group. The weighted mean differences in nerve conduction velocities were 4.63 (95% confidence interval 3.58-5.67) for median MNCV, 3.17 (1.75-4.59) for median SNCV, 4.25 (2.78-5.72) for peroneal MNCV, and 3.65 (1.50-5.80) for peroneal SNCV in favor of the treatment group. The odds ratio in terms of efficacy was 4.03 (2.73-5.94) for ALA. Furthermore, no serious adverse events were observed during the treatment period. CONCLUSIONS: The results of this meta-analysis provide evidence that treatment with ALA (300-600 mg/day i.v. for 2-4 weeks) is safe and that the treatment can significantly improve both nerve conduction velocity and positive neuropathic symptoms. However, the evidence may not be strong because most of the studies included in this meta-analysis have poor methodological quality.