Fanconi Anemia: Hematopoietic Stem Cell Transplant or Gene Therapy?

FA is a rare, multi-organ cancer-prone IBMFS associated with hematological malignancies and STs. The androgen therapy, hematopoietic growth factors, HSCT, and GT, still in the clinical trial, are various treatments for this disease. Here, we aimed to compare the advantages and disadvantages of HSCT and GT in FA cures. We perform an advanced electronic search of “FA” AND (genetics OR treatment OR HSCT OR GT OR Mosaicism), and “Allo-HSCT” AND (conditioning regimen OR complications OR GvHD OR infection OR cost) MeSH terms in non-citation and citation databases. Besides, the gray literature was searched too. This article will provide a summary of the advantages and disadvantages of HSCT and GT of FA disease. Our results show that GT has a good potential in FA treatments in the future. Furthermore, it has higher advantages and fewer disadvantages in comparison with HSCT. Systematic Review Registration: CRD42021247364 ID on PROSPERO database.

Fanconi Anemia: Hematopoietic Stem Cell Transplant or Gene Therapy?

FA is a rare, multi-organ cancer-prone IBMFS associated with hematological malignancies and STs. The androgen therapy, hematopoietic growth factors, HSCT, and GT, still in the clinical trial, are various treatments for this disease. Here, we aimed to compare the advantages and disadvantages of HSCT and GT in FA cures. We perform an advanced electronic search of “FA” AND (genetics OR treatment OR HSCT OR GT OR Mosaicism), and “Allo-HSCT” AND (conditioning regimen OR complications OR GvHD OR infection OR cost) MeSH terms in non-citation and citation databases. Besides, the gray literature was searched too. This article will provide a summary of the advantages and disadvantages of HSCT and GT of FA disease. Our results show that GT has a good potential in FA treatments in the future. Furthermore, it has higher advantages and fewer disadvantages in comparison with HSCT. Systematic Review Registration: CRD42021247364 ID on PROSPERO database.

Characterization and Prognosis of Temozolomide-Induced Aplastic Anemia

Introduction: Temozolomide-induced aplastic anemia (TIAA) is a very rare and highly challenging complication of temozolomide (TMZ) chemotherapy. TMZ is a mainstay of therapy in patients with central nervous system (CNS) malignancies. Single-patient case reports and small case series have described variable morbidity and mortality associated with TIAA. However, quantitative evidence describing prognosis, clinical characteristics, and treatment of this entity is absent or very limited. Methods: We performed a 5-center, 22-year observational cohort study of patients with CNS malignancies treated with temozolomide who developed TIAA, retrospectively analyzing prognosis, complications, and recovery. We compared patients who achieved meaningful hematologic recovery [partial hematologic recovery (PHR) or complete hematologic recovery (CHR)] to those who did not recover [refractory disease (RD)]. We used descriptive statistics, T-tests, and chi-square tests to evaluate patient characteristics, outcomes, and laboratory values. Overall time to hematologic recovery and overall survival of patients with PHR, CHR, and RD were estimated using the Kaplan-Meier method and compared using the log-rank test, and a multivariable logistic model evaluated potential predictors of achieving CHR. TIAA was defined using adapted evidence-based severe aplastic anemia criteria incorporating profound cytopenias and a minimum duration (4 weeks) without hematologic recovery (TABLE 1). Results: Study Population and TIAA Prevalence. Of 3,821 patients with CNS malignancies receiving TMZ, 34 patients (0.89%) met criteria for TIAA (FIGURE 1). Onset was rapid, with 29 patients (85.3%) developing TIAA before completing a second TMZ cycle (TABLE 2). Complications and Outcomes of Hematologic Recovery. 23 patients (67.6%) ultimately achieved a hematologic recovery and the remaining 11 patients (32.4%) had refractory disease. Figure 2A illustrates the time from TIAA diagnosis to PHR and CHR for the cohort. In Kaplan-Meier survival analysis, the median time from TIAA diagnosis to PHR was 84 days and the median time to CHR was 134 days. Patients without recovery were more likely to develop serious complications (TABLE 3), including febrile neutropenia (72.7% vs. 30.4%, P=0.03), major infection (45.5% vs. 8.7%, P=0.02), hospitalization (81.8% vs. 43.5%, P=0.04), and death (100.0% vs. 60.9%, P=0.02). This increased risk of complications in patients not achieving hematologic recovery was observed despite a similar median time from TMZ initiation to TIAA diagnosis in the two groups (45 days vs. 40 days). Figure 2B illustrates the overall survival in the entire cohort and by each hematologic recovery subgroup. In Kaplan-Meier survival analysis, median overall survival from the time of TIAA diagnosis was as follows: entire cohort, 355 days; achieved PHR, 752 days; achieved CHR, 1414 days; refractory disease, 28 days (P<0.0001 for comparison of PHR, CHR, and refractory disease). In a multivariable logistic model, none of the evaluated covariates (age, sex, TMZ dose, body surface area, and use of hematopoietic growth factors) were significantly associated with achieving CHR. Treatment of TIAA and Outcomes of Therapy. 29 patients (85.3%) received hematopoietic growth factors (TABLE 3); no patients were treated with immunosuppression or hematopoietic stem cell transplant. Hematologic recovery rates were numerically higher in patients receiving thrombopoietin receptor agonists vs. those who did not (81.8% vs. 54.2%, P=0.15), but were not higher in patients receiving granulocyte colony stimulating factors vs. those who did not (68.0% vs. 66.7%, P=0.99). Conclusions: TIAA occurs in less than 1% of patients receiving temozolomide for CNS malignancies, occurring rapidly after TMZ initiation, but is highly morbid and often fatal when it occurs, precluding further use of cytotoxic therapy in the vast majority of patients. In the one-third who do not recover, risks of febrile neutropenia, infection, and hospitalization are increased, and overall survival greatly diminished. Hematologic recovery is potentially aided by the use of thrombopoietin receptor agonists, as has been demonstrated in classical autoimmune aplastic anemia. Further study of TIAA treatment is needed for this serious complication of TMZ therapy. Figure 1 Figure 1. Disclosures Forst: Eli Lilly: Current holder of individual stocks in a privately-held company. Al-Samkari: Rigel: Consultancy; Argenx: Consultancy; Moderna: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

Head and neck tumor cells treated with hypofractionated irradiation die via apoptosis and are better taken up by M1-like macrophages

Purpose The incidence of head and neck squamous cell carcinomas (HNSCC) is increasing worldwide, especially when triggered by the human papilloma virus (HPV). Radiotherapy has immune-modulatory properties, but the role of macrophages present in HNSCC and having contact with irradiated tumor cells remains unclear. The influence of irradiated (2 × 5Gy) HNSCC cells on the (re-)polarization and phagocytosis of human macrophages, either non-polarized or with a more M1 or M2 phenotype, was therefore investigated. Methods Human monocytes were differentiated with the hematopoietic growth factors M‑CSF (m) or GM-CSF (g) and additionally pre-polarized with either interleukin (IL)-4 and IL-10 or interferon (IFN)-γ and lipopolysaccharides (LPS), respectively. Subsequently, they were added to previously irradiated (2 × 5Gy) and mock-treated HPV-positive (UD-SCC-2) and HPV-negative (Cal33) HNSCC cells including their supernatants. Results The HNSCC cells treated with hypofractionated irradiation died via apoptosis and were strongly phagocytosed by M0m and M2 macrophages. M0g and M1 macrophages phagocytosed the tumor cells to a lesser extent. Irradiated HNSCC cells were better phagocytosed by M1 macrophages compared to mock-treated controls. The polarization status of the macrophages was not significantly changed, except for the expression of CD206 on M2 macrophages, which was reduced after phagocytosis of irradiated HPV-negative cells. Further, a significant increase in the uptake of irradiated HPV-positive cells by M0g macrophages when compared to HPV-negative cells was observed. Conclusion HNSCC cells treated with hypofractionated irradiation foster phagocytosis by anti-tumorigenic M1 macrophages. The data provide the first evidence on the impact of the HPV status of HNSCC cells on the modulation of the macrophage response to irradiated tumor cells.

Not all hematopoietic growth factors are created equal: should we gain information for their use with immunotherapy?

Myeloid growth factors, either granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF, are widely used to reduce the incidence and severity of chemotherapy-induced neutropenia by prophylactic or therapeutic administration. However, their activity in the novel therapeutic regimens, which often rely on the association between immunotherapy and chemotherapy, has not been thoroughly characterized yet. This paper presents some of the preclinical and clinical research regarding the putative interplay between myeloid growth factors and the immune system, advocating further studies to elucidate their potential positive or negative consequences on the outcomes when administered with immunotherapeutic agents.

Improving Outcomes of Chemotherapy: Established and Novel Options for Myeloprotection in the COVID-19 Era

Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HPSCs) often results in myelosuppression that adversely affects patient health and quality of life. Currently, chemotherapy-induced myelosuppression is managed with chemotherapy dose delays/reductions and lineage-specific supportive care interventions, such as hematopoietic growth factors and blood transfusions. However, the COVID-19 pandemic has created additional challenges for the optimal management of myelosuppression. In this review, we discuss the impact of this side effect on patients treated with myelosuppressive chemotherapy, with a focus on the prevention of myelosuppression in the COVID-19 era. During the COVID-19 pandemic, short-term recommendations on the use of supportive care interventions have been issued with the aim of minimizing the risk of infection, reducing the need for hospitalization, and preserving limited blood supplies. Recently, trilaciclib, an intravenous cyclin-dependent kinase 4 and 6 inhibitor, was approved to decrease the incidence of myelosuppression in adult patients when administered prior to platinum/etoposide-containing or topotecan-containing chemotherapy for extensive-stage small cell lung cancer (ES-SCLC). Approval was based on data from three phase 2 placebo-controlled clinical studies in patients with ES-SCLC, showing that administering trilaciclib prior to chemotherapy significantly reduced multilineage myelosuppression, with patients receiving trilaciclib having fewer chemotherapy dose delays/reductions and myelosuppression/sepsis-related hospitalizations, and less need for supportive care interventions, compared with patients receiving placebo. Several other novel agents are currently in clinical development for the prevention or treatment of multilineage or single-lineage myelosuppression in patients with various tumor types. The availability of treatments that could enable patients to maintain standard-of-care chemotherapy regimens without the need for additional interventions would be valuable to physicians, patients, and health systems.

THE USE OF NEW IMMUNOMODULATORS AT SECONDARY IMMUNODEFICIENCY

В данной статье рассматривается использование нового иммуномодулятора у животных, страдающих вторичным иммунодефицитом за период последнего года. В исследованиях России и Китая в качестве новых иммуномодуляторов применялись Ganodermalucidum (Gl-PS) полисахариды и стимфорт на фоне введения циклофосфана. Иммуномодуляция играет важную роль в кроветворении. На мышах исследовали возможный механизм активации миелопоэза при миелосупрессии, вызванной циклофосфамидом. Показано, что иммуномодулятор обладает способностью корригировать количественный и субпопуляционный состав МЛ селезенки, структуру центральных и периферических органов лимфопоэза, эффекторные функции клеток иммунитета, нарушенные при введении цитостатика. В настоящем исследовании invivo и invitro обнаружили, что иммуномодуляторы избирательно связываются со стромальными клетками костного мозга, стимулирует секрецию гемопоэтических факторов роста и усиливают клоногенную активность гемопоэтических и стромальных клеток, способствуя гемопоэзу у мышей с миелосупрессией. This article reviews the use of a new immunomodulator in animals for secondary immunodeficiency in the past year. In a study in Russia and China, Ganoderma lucidum (Gl-PS) polysaccharides and stimforte were used as new immunomodulators against the background of cyclophosphamide administration. Immunomodulation plays an important role in blood formation. A possible mechanism of myelopoiesis activation in cyclophosphamide-induced myelosuppression was investigated in mice. It was shown that the immunomodulator has the ability to correct the quantitative and subpopulation composition of spleen ML, the structure of the central and peripheral organs of lymphopoiesis, the effector functions of immunity cells, impaired by the introduction of a cytostatic. In the present study, in vivo and in vitro, it was found that immunomodulators selectively bind to bone marrow stromal cells, stimulate the secretion of hematopoietic growth factors and enhance the clonogenic activity of hematopoietic and stromal cells, promoting hematopoiesis in mice with myelosuppression.

Tumor-Derived Autophagosomes (DRibbles) Activate Human B Cells to Induce Efficient Antigen-Specific Human Memory T-Cell Responses

We have reported that tumor-derived autophagosomes (DRibbles) were efficient carriers of tumor antigens and DRibbles antigens could be present by DRibbles-activated B cells to stimulate effect and naïve T cells in mice. However, the effect of DRibbles on human B cells remains unclear. Herein, we found that DRibbles can also efficiently induce proliferation and activation of human B cells and lead to the production of chemokines, cytokines and hematopoietic growth factors. We further demonstrated human B cells can effectively phagocytose DRibbles directly and cross-present DRibbles antigens to stimulate antigen-specific memory T cells. Furthermore, we found that membrane-bound high-mobility group B1 (HMGB1) on DRibbles was crucial for inducing human B cells activation. Therefore, these findings provide further evidence to promote the clinical application of B-DRibbles vaccines.