Efficacy and toxicity of Decitabine in patients with acute myeloid leukemia (AML): A multicenter real-world experience

To evaluate the efficacy and adverse effects of venetoclax(VEN) in combination with hypomethylating agents(HMAs) in acute myeloid leukemia(AML) or myelodysplastic syndrome(MDS). Clinical studies we...

The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis

Aging results from the progressive dysregulation of several molecular pathways and mTOR and AMPK signaling have been suggested to play a role in the complex changes in key biological networks involved in cellular senescence. Moreover, multiple factors, including poor nutritional balance, drive immunosenescence progression, one of the meaningful aspects of aging. Unsurprisingly, nutraceutical and pharmacological interventions could help maintain an optimal biological response by providing essential bioactive micronutrients required for the development, maintenance, and the expression of the immune response at all stages of life. In this regard, many studies have provided evidence of potential antiaging properties of resveratrol, as well as rapamycin and metformin. Indeed, in vitro and in vivo models have demonstrated for these molecules a number of positive effects associated with healthy aging. The current review focuses on the mechanisms of action of these three important compounds and their suggested use for the clinical treatment of immunosenescence and aging.

https://www.mdpi.com/1424-8247/15/8/912/pdf?version=1659425934

Immunomodulatory and Antiaging Mechanisms of Resveratrol, Rapamycin, and Metformin: Focus on mTOR and AMPK Signaling Networks

β-thalassemia is caused by autosomal mutations in the β-globin gene, which induce the absence or low-level synthesis of β-globin in erythroid cells. It is widely accepted that a high production of fetal hemoglobin (HbF) is beneficial for patients with β-thalassemia. Sirolimus, also known as rapamycin, is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopicus that serves as a strong HbF inducer in vitro and in vivo. In this study, we report biochemical, molecular, and clinical results of a sirolimus-based NCT03877809 clinical trial (a personalized medicine approach for β-thalassemia transfusion-dependent patients: testing sirolimus in a first pilot clinical trial, Sirthalaclin).Accumulation of γ-globin mRNA was analyzed using reverse-transcription quantitative polymerase chain reaction (PCR), while the hemoglobin pattern was analyzed using high-performance liquid chromatography (HPLC). The immunophenotype was analyzed using a fluorescence-activated cell sorter (FACS), with antibodies against CD3, CD4, CD8, CD14, CD19, CD25 (for analysis of peripheral blood mononuclear cells), or CD71 and CD235a (for analysis of in vitro cultured erythroid precursors).The results were obtained in eight patients with the β+/β+ and β+/β0 genotypes, who were treated with a starting dosage of 1 mg/day sirolimus for 24-48 weeks. The first finding of this study was that the expression of γ-globin mRNA increased in the blood and erythroid precursor cells isolated from β-thalassemia patients treated with low-dose sirolimus. This trial also led to the important finding that sirolimus influences erythropoiesis and reduces biochemical markers associated with ineffective erythropoiesis (excess free α-globin chains, bilirubin, soluble transferrin receptor, and ferritin). A decrease in the transfusion demand index was observed in most (7/8) of the patients. The drug was well tolerated, with minor effects on the immunophenotype, and an only side effect of frequently occurring stomatitis.The data obtained indicate that low doses of sirolimus modify hematopoiesis and induce increased expression of γ-globin genes in a subset of patients with β-thalassemia. Further clinical trials are warranted, possibly including testing of the drug in patients with less severe forms of the disease and exploring combination therapies. 

https://journals.sagepub.com/doi/pdf/10.1177/20406207221100648

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Corticosteroids remain a crucial component of first-line therapy for immune thrombocytopenia (ITP) due to low cost, high initial response rates, and acceptable short-term tolerability. However, extended and recurrent use of corticosteroids is associated with substantial toxicity. Survey studies indicate that >95% of patients with ITP treated with corticosteroids report adverse effects, more than one-third of whom require reduction or discontinuation of treatment. In light of the heavy treatment burden of prolonged corticosteroid exposure, clinical practice guidelines recommend limiting corticosteroid treatment to no more than 6 weeks in adults with ITP receiving initial therapy. For patients who require subsequent therapy, clinical practice guidelines recommend treatments more suitable for long-term disease control such as thrombopoietin receptor agonists, rituximab, other immune-modulating medications, or splenectomy, rather than repeated courses of corticosteroids. Despite these recommendations, real-world evidence suggests that corticosteroids remain the most frequently used treatment for adults with ITP, not only in the first line, but also in the second and third line. In this review, we summarize evidence on the efficacy, safety, and tolerability of corticosteroids; discuss the problem of overuse; and suggest strategies for curtailing the excessive use of corticosteroids in adults with ITP.

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Corticosteroid overuse in adults with immune thrombocytopenia: Cause for concern.

Sirolimus is effective for primary relapsed/refractory autoimmune cytopenia: a multicenter study

Aim: This meta-analysis aimed to compare the efficacy, survival benefit and safety of hypomethylating agents (HMA) monotherapy and combination with chemotherapy in patients with intermediate/high-risk MDS or AML. Methods: Related articles published between January 2009 and April 2019 were selected and patients were separated as monotherapy group and combination group for meta-analysis. Studies on HMA combination therapy were further divided into two subgroups according to the intensity of combined chemotherapy. Meanwhile, subgroups with similar patients' baseline characteristics were selected for further analysis. Complete response (CR) rate, overall response (ORR) rate, two-year overall survival (OS) rate, one-month and 24-month death rate and the proportion of adverse events (AE) were pooled and compared. Results: 21 RCT or cohort studies with 1764 patients (1266 patients for monotherapy group and 498 patients for HMA combination group) were selected for meta-analysis. For the pooled data, the age of patients was significantly younger and the percentage of patients with favorable/intermediate cytogenetic risk was significantly higher in the HMA combination group than that in the HMA monotherapy group. Combination therapy group had a significantly higher CR and ORR rate (55% vs 22%, P=0.000 for CR and 67% vs 42%, P=0.000 for ORR), and a higher two-year OS rate (37% vs 21%, P=0.000). However, the incidence of infection and gastrointestinal disorder was significantly higher (51% vs 23% for infection, P=0.000; 21% vs 0% for gastrointestinal disorder, P=0.000) in combination group. In subgroups with different intensity of combined chemotherapy, all baseline characteristics were compatible except that the percentage of patients with favorable/intermediate cytogenetic risk was significantly lower (63% vs 88%, P=0.000) in the HMA + high-intensity chemotherapy subgroup, and this group presented with a lower CR and ORR rate (46% vs 65% for CR, P=0.000; 57% vs 79% for ORR, P=0.000), but a compatible two-month to 24-month death rate compared with HMA + low-intensity chemotherapy subgroup (9% vs 14% for 2-month death rate, P=0.060; 58% vs 65% for 24-month death rate, P=0.242). In subgroup with similar patients' baseline characteristics, 208 and 205 patients were included in combination group and HMA monotherapy group, respectively. Although combination group had a significantly higher CR rate (62% vs 24%, P=0.000) and ORR rate (68% vs 48%, P=0.000), it finally had a lower two-year OS (30% vs 45%, P=0.001) compared with monotherapy group, and the death rate was significantly higher since the ninth month in combination therapy group than that in the monotherapy group (42% vs 31%, P=0.032). In this subgroup, patients with HMA+ high-intensity chemotherapy had a compatible CR, ORR and 1.5-year OS rate as compared with baseline-compatible patients with HMA + low-intensity chemotherapy. Conclusions: HMA combined with chemotherapy could increase CR rate and ORR rate in all patients. HMA combined with high-intensity chemotherapy can rescue the 2-year OS with less favorable cytogenetic stratification to some extent. For patients with similar older age and risk stratification, combination therapy even had a lower long-term OS regardless of the intensity of combined chemotherapy.

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Comparison of Hypomethylator Monotherapy with Hypomethylator plus Chemotherapy for Intermediate/High-Risk MDS or AML: A Meta-Analysis.

Background and Aims: This study aimed at comparing the efficacy and safety of eltrombopag (EPAG) plus immunosuppressive therapies (ISTs) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the frontline treatment for severe aplastic anemia (SAA) patients. Methods: Four electronic databases and Clinicaltrials.gov were comprehensively searched from January 2010 to August 2020. Studies that aimed at evaluating the efficacy and safety of EPAG+IST or haplo-HSCT in SAA patients were included. One-/2-year overall survival (OS), complete response (CR), and overall response rates (ORRs) were indirectly compared between EPAG+IST and haplo-HSCT. Results: A total of 447 patients involved in 10 cohort studies were found to be eligible for this study. A narrative synthesis was performed due to lack of data directly comparing the outcome of EPAG+IST and haplo-HSCT. Consistent with the analysis results in the whole population, subgroup analyses in the age-matched population showed that there was no significant difference in ORR between EPAG+IST and haplo-HSCT groups. However, the CR rate was lower in the EPAG+IST group when compared with the haplo-HSCT group. The incidence rate of clonal evolution/SAA relapse ranged at 8-14 and 19-31% in the EPAG+IST group but not reported in the haplo-HSCT group. The incidence rate for acute graft vs. host disease (aGVHD) and chronic graft vs. host disease (cGVHD) ranged at 52-57 and 12-67%, respectively, for the haplo-HSCT group. The main causes of deaths were infections in the EPAG+IST group, and GVHD and infections in the haplo-HSCT group. Conclusion: EPAG+IST has a comparable ORR and 1-/2-year OS but lower CR rate when indirectly compared with haplo-HSCT in the frontline treatment of patients with SAA. Patients treated with haplo-HSCT may exhibit a high incidence of GVHD, whereas patients treated with EPAG+IST may experience more relapses or clone evolution.

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Comparisons Between Frontline Therapy and a Combination of Eltrombopag Plus Immunosuppression Therapy and Human Leukocyte Antigen-Haploidentical Hematopoietic Stem Cell Transplantation in Patients With Severe Aplastic Anemia: A Systematic Review.

Aim The effect of recombinant human thrombopoietin (rhTPO) is largely unknown in lower-risk myelodysplastic syndrome (LR-MDS). This study aimed at investigating the safety and efficacy of rhTPO in patients with LR-MDS. Methods LR-MDS patients receiving stanozolol (2 mg, t.i.d.) and supportive care alone (non-rhTPO) or additional rhTPO were enrolled in this study prospectively. rhTPO was given at 15,000 U (q.d.) for 7 days/month for at least 3 months. Patients stopped rhTPO if the platelet count was higher than 50 × 109/L or had no effects after 3 months of treatment. The overall response (OR), complete response (CR), platelet response, side effects, clone evolution, and clinical outcome were evaluated. Result Thirty-five patients were enrolled: 20 (57.1%) patients in the rhTPO group and 15 (42.9%) patients in the non-rhTPO group. The demographic and baseline characteristics were balanced between the two groups. Platelet response was higher at 1 and 2 months as compared with that in the non-rhTPO group (p = 0.006 and p = 0.001, respectively). Meanwhile, the rhTPO group had a shorter time to achieve a platelet transfusion-free state compared with the non-rhTPO group (p = 0.034). Hematologic response was higher at 1 and 2 months compared with that in the non-rhTPO group (p = 0.006 and p = 0.001, respectively). There was no significant difference in the overall response or complete response at 1, 2, 3, 6, and 12 months between the two groups. One patient in the rhTPO group evolved into higher-risk MDS at 9 months. No significant difference in disease progression, infection, gastrointestinal disorders, or drug-related liver/renal injuries was found between the two groups (p > 0.05). Conclusion Adding short-term rhTPO can accelerate the early platelet response and decrease platelet transfusion, with no obvious side effects. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT04324060?cond=NCT04324060&draw=2, identifier NCT04324060.

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Jiang Ji

Papers

Sirolimus is effective for primary relapsed/refractory autoimmune cytopenia: a multicenter study

Comparison of Hypomethylator Monotherapy with Hypomethylator plus Chemotherapy for Intermediate/High-Risk MDS or AML: A Meta-Analysis.

Comparisons Between Frontline Therapy and a Combination of Eltrombopag Plus Immunosuppression Therapy and Human Leukocyte Antigen-Haploidentical Hematopoietic Stem Cell Transplantation in Patients With Severe Aplastic Anemia: A Systematic Review.

Recombinant Human Thrombopoietin Accelerates the Recovery of Platelet in Patients With Lower-Risk Myelodysplastic Syndrome: A Proof-of-Concept Study.