RESUMEN
OBJECTIVES: Efficacy and safety of letermovir as prophylaxis for clinically significant cytomegalovirus infections (csCVMi) was evaluated in randomised controlled trials while most of the real-world studies are single-centre experiences. METHODS: We performed a retrospective, multi-centre case-control study at six German university hospitals to evaluate clinical experiences in patients receiving CMV prophylaxis with letermovir (n = 200) compared to controls without CMV prophylaxis (n = 200) during a 48-week follow-up period after allogeneic hematopoietic cell transplantation (aHCT). RESULTS: The incidence of csCMVi after aHCT was significantly reduced in the letermovir (34%, n = 68) compared to the control group (56%, n = 112; p < 0.001). Letermovir as CMV prophylaxis (OR 0.362) was found to be the only independent variable associated with the prevention of csCMVi. Patients receiving letermovir showed significantly better survival compared to the control group (HR = 1.735, 95% CI: 1.111-2.712; p = 0.014). Of all csCMVi, 46% (n = 31) occurred after discontinuation of letermovir prophylaxis. Severe neutropenia (<500 neutrophils/µL) on the day of the stem cell infusion was the only independent variable for an increased risk of csCMVi after the end of letermovir prophylaxis. CONCLUSIONS: Our study highlights the preventive effects of letermovir on csCMVi after aHCT. A substantial proportion of patients developed a csCMVi after discontinuation of letermovir. In particular, patients with severe neutropenia require specific attention after drug discontinuation.
Asunto(s)
Acetatos , Antivirales , Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Quinazolinas , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Masculino , Infecciones por Citomegalovirus/prevención & control , Femenino , Persona de Mediana Edad , Quinazolinas/uso terapéutico , Estudios Retrospectivos , Antivirales/uso terapéutico , Adulto , Acetatos/uso terapéutico , Acetatos/administración & dosificación , Estudios de Casos y Controles , Anciano , Trasplante Homólogo/efectos adversos , Adulto Joven , Citomegalovirus , Adolescente , Alemania/epidemiología , IncidenciaRESUMEN
Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting T cell (Tc) immunoglobulin and mucin-containing molecule 3 (TIM-3) for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti-TIM-3 Ab treatment improved survival of mice bearing leukemia with oncogene-induced TIM-3 ligand expression. Conversely, leukemia cells with low ligand expression were anti-TIM-3 treatment resistant. In vitro, TIM-3 blockade or genetic deletion in CD8+ Tc enhanced Tc activation, proliferation, and IFN-γ production while enhancing GVL effects, preventing Tc exhaustion, and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and activation in vitro, suggesting that anti-TIM-3 treatment-mediated GVL effects are Tc induced. In contrast to anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) treatment, anti-TIM-3-treatment did not enhance acute graft-versus-host disease (aGVHD). TIM-3 and its ligands were frequently expressed in acute myeloid leukemia (AML) cells of patients with post-allo-HCT relapse. We decipher the connections between oncogenic mutations found in AML and TIM-3 ligand expression and identify anti-TIM-3 treatment as a strategy for enhancing GVL effects via metabolic and transcriptional Tc reprogramming without exacerbation of aGVHD. Our findings support clinical testing of anti-TIM-3 Ab in patients with AML relapse after allo-HCT.
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Receptor 2 Celular del Virus de la Hepatitis A , Animales , Receptor 2 Celular del Virus de la Hepatitis A/genética , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Ratones , Trasplante de Células Madre Hematopoyéticas , Efecto Injerto vs Leucemia/inmunología , Efecto Injerto vs Leucemia/genética , Humanos , Aloinjertos , Ligandos , Oncogenes , Linfocitos T CD8-positivos/inmunología , Ratones Noqueados , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patología , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Regulación Leucémica de la Expresión GénicaRESUMEN
Metastasis arises from cancer cell-intrinsic adaptations and permissive tumor microenvironments (TME) that are distinct across different organs. Deciphering the mechanisms underpinning organotropism could provide novel preventive and therapeutic strategies for patients with cancer. Rogava and colleagues identified Pip4k2c as a driver of liver metastasis, acting by sensitizing cancer cells to insulin-dependent PI3K/AKT signaling, which could be reversed by dual pharmacologic inhibition of PI3K and SGLT2 or a ketogenic diet. The study highlights the importance of tumor microenvironment communication in the context of systemic physiology and points toward potential combination therapies.
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Neoplasias Hepáticas , Transducción de Señal , Microambiente Tumoral , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for acute myeloid leukemia (AML). The inherent graft-versus-leukemia activity (GvL) may be optimized by donor lymphocyte infusions (DLI). Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML between 2009 and 2017. The median age at transplantation was 57 years (range 19-79), and the pre-transplant status was active disease in 58% and complete remission (CR) in 42% of cases. In a combined landmark analysis, patients in CR on day +30 and alive on day +100 were included. In this cohort (n=292), 93 patients received cryopreserved aliquots of peripheral blood-derived grafts for DLI (32%) and median survival was 55.7 months (2-year/5-year probability: 62%/49%). Median survival for patients receiving a first dose of DLI "preemptively," in the absence of relapse and guided by risk marker monitoring (preDLI; n=42), or only after hematological relapse (relDLI; n=51) was 40.9 months (2-year/5-year: 64%/43%) vs 10.4 months (2-year/5-year: 26%/10%), respectively. Survival was inferior when preDLI was initiated at a time of genetic risk marker detection vs mixed chimerism or clinical risk only. Time to first-dose preDLI vs time to first-dose relDLI was similar, suggesting that early warning and intrinsically lower dynamics of AML recurrence may contribute to effectiveness of preDLI-modified GvL activity. Future refinements of the preemptive DLI concept will benefit from collaborative efforts to diagnose measurable residual disease more reliably across the heterogeneous genomic spectrum of AML.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Transfusión de Linfocitos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Donantes de Tejidos , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Preclinical drug development for human chronic lymphocytic leukemia (CLL) requires robust xenograft models recapitulating the entire spectrum of the disease, including all prognostic subgroups. Current CLL xenograft models are hampered by inefficient engraftment of good prognostic CLLs, overgrowth with co-transplanted T cells, and the need for allogeneic humanization or irradiation. Therefore, we aimed to establish an effective and reproducible xenograft protocol which allows engraftment of all CLL subtypes without the need of humanization or irradiation. Unmanipulated NOD.Cg-PrkdcscidIl2rgtm1Sug/JicTac (NOG) mice in contrast to C.Cg-Rag2tm1Fwa-/-Il2rgtm1Sug/JicTac (BRG) mice allowed engraftment of all tested CLL subgroups with 100% success rate, if CLL cells were fresh, injected simultaneously intra-peritoneally and intravenously, and co-transferred with low fractions of autologous T cells (2%-4%). CLL transplanted NOG mice (24 different patients) developed CLL pseudofollicles in the spleen, which increased over 4-6 weeks, and were then limited by the expanding autologous T cells. Ibrutinib treatment studies were performed to validate our model, and recapitulated treatment responses seen in patients. In conclusion, we developed an easy-to-use CLL xenograft protocol which allows reliable engraftment for all CLL subgroups without humanization or irradiation of mice. This protocol can be widely used to study CLL biology and to explore novel drug candidates.