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ABSTRACT: Acute myeloid leukemia (AML) is a hematologic malignancy for which allogeneic hematopoietic cell transplantation (allo-HCT) often remains the only curative therapeutic approach. However, incapability of T cells to recognize and eliminate residual leukemia stem cells might lead to an insufficient graft-versus-leukemia (GVL) effect and relapse. Here, we performed single-cell RNA-sequencing (scRNA-seq) on bone marrow (BM) T lymphocytes and CD34+ cells of 6 patients with AML 100 days after allo-HCT to identify T-cell signatures associated with either imminent relapse (REL) or durable complete remission (CR). We observed a higher frequency of cytotoxic CD8+ effector and gamma delta (γδ) T cells in CR vs REL samples. Pseudotime and gene regulatory network analyses revealed that CR CD8+ T cells were more advanced in maturation and had a stronger cytotoxicity signature, whereas REL samples were characterized by inflammatory tumor necrosis factor/NF-κB signaling and an immunosuppressive milieu. We identified ADGRG1/GPR56 as a surface marker enriched in CR CD8+ T cells and confirmed in a CD33-directed chimeric antigen receptor T cell/AML coculture model that GPR56 becomes upregulated on T cells upon antigen encounter and elimination of AML cells. We show that GPR56 continuously increases at the protein level on CD8+ T cells after allo-HCT and confirm faster interferon gamma (IFN-γ) secretion upon re-exposure to matched, but not unmatched, recipient AML cells in the GPR56+ vs GPR56- CD8+ T-cell fraction. Together, our data provide a single-cell reference map of BM-derived T cells after allo-HCT and propose GPR56 expression dynamics as a surrogate for antigen encounter after allo-HCT.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Médula Ósea/patología , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamiento farmacológico , Linfocitos T CD8-positivos/patología , RecurrenciaRESUMEN
Despite the arrival of novel therapies, multiple myeloma (MM) remains incurable and new treatment options are needed. Chimeric antigen receptor (CAR) T cells are genetically modified T cells that express a CAR directed against specific tumour antigens. CAR T cells are able to kill target tumour cells and may result in long-lasting immune responses in vivo. The rapid development of CAR technologies has led to clinical trials in haematological cancers including MM, and CAR T cells might evolve into a standard treatment in the next few years. Only small patient cohorts with relapsed or refractory disease have so far been investigated, but promising preliminary results with high response rates have been obtained in phase I clinical trials with B cell maturation antigen (BCMA), CD19, CD38 and κ-light-chain CAR T cells. Additional preclinical studies on CD38 and SLAMF7-CAR T cells in MM treatment yielded preclinical results that merit further investigation. Beyond the T cell approach, recent studies have focussed on CAR natural killer (NK) cells in order to increase the reactivity of these effector cells. Finally, to investigate the targeting of intracellular antigens, cellular therapies based on engineered T cell receptors (TCRs) are in development. In this review, we discuss results from preclinical and early-phase clinical trials testing the feasibility and safety of CAR T cell administration in MM, as well as early studies into approaches that utilise CAR NK cell and genetically modified TCRs.
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Inmunoterapia Adoptiva/tendencias , Inmunoterapia , Mieloma Múltiple/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , ADP-Ribosil Ciclasa 1/genética , Antígenos de Neoplasias/inmunología , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Receptores de Antígenos de Linfocitos T/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m2), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept. METHODS: GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life. RESULTS: Since this is the publication of a study protocol of an ongoing study, no results can be presented. DISCUSSION: This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab. TRIAL REGISTRATION: NCT02495922 on June 24th, 2015.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Lenalidomida/administración & dosificación , Melfalán/administración & dosificación , Mieloma Múltiple/terapia , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bortezomib/uso terapéutico , Quimioterapia de Consolidación , Dexametasona/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Quimioterapia de Inducción , Lenalidomida/uso terapéutico , Quimioterapia de Mantención , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Proyectos de Investigación , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Tumor-mediated immunosuppression via regulatory T-cells is a key player among the various immune-escape mechanisms in multiple myeloma. We analyzed the generation, distribution, function and immunophenotype of CD8+CD28- regulatory T-cells in patients with multiple myeloma. Functionality of CD8+CD28- T-cells was assessed by immunological assays using ex vivo generated antigen-specific T-cells from patients with plasma cell dyscrasias and healthy donors. Detailed analysis of distribution, immunophenotype and cytotoxic potential of CD8+CD28- T-cells was performed by flow cytometry and ELISA. We found that the amount of CD8+CD28- T-cells was directly correlated with the suppression of antigen-specific T-cell responses in patients with plasma cell dyscrasia. Analyzing the CD8+CD28- T-cells in detail, increased numbers of these cells were observed in the bone marrow (i.e., tumor microenvironment) of patients with plasma cell dyscrasia. Furthermore, we identified the expression of lymphocyte function-associated antigen 1 (LFA-1) as a marker of immunosuppression and defined the CD8+CD28-CD57+LFA-1high population as the relevant immunosuppressive compartment. These regulatory T-cells act as immunosuppressors via soluble factors and incubation with IL-10 augmented their immunosuppressive capacity. The immunosuppressive regulatory network of IL-10 and the CD8+CD28-CD57+LFA-1high regulatory T-cells show unique characteristics and contribute to the tumor immune escape mechanism in patients with multiple myeloma.
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Antígenos CD28/inmunología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Interleucina-10/farmacología , Mieloma Múltiple/inmunología , Paraproteinemias/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Estudios de Casos y Controles , Células Cultivadas , Humanos , Activación de Linfocitos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Paraproteinemias/metabolismo , Paraproteinemias/patología , Subgrupos de Linfocitos T/efectos de los fármacos , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
In multiple myeloma (MM), the synergy between immunomodulatory drugs (IMiDs) and monoclonal antibodies (MABs) has been demonstrated in several pivotal trials. However, disease refractory to either class of compounds remains a major therapeutic challenge. We here report on 3 heavily pretreated MM patients who were refractory to pomalidomide as well as to MABs against CD38 (daratumumab) or CD20 (rituximab), respectively, but who responded to retreatment with the same agents in combination. Responses were durable with PFS of 7, 10 (ongoing), and 30 months from initiation of combination treatment. The combination of IMiDs with MABs directed against MM cell surface antigens can overcome refractoriness to both agents.
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Inhibidores de la Angiogénesis/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Anciano , Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales , Humanos , Mieloma Múltiple/mortalidad , Análisis de Supervivencia , Talidomida/farmacología , Talidomida/uso terapéuticoRESUMEN
OBJECTIVE: To improve monitoring of myeloid neoplasms by flow cytometry-based minimal residual disease (MRD) analysis, we analyzed the significance of leukemia-associated immunophenotype (LAIP) markers in 44 patients. METHODS: In a pilot study cohort, peripheral blood or bone marrow samples from 13 patients with myeloid neoplasms and one case of B lymphoblastic leukemia in complete hematologic remission after allogeneic bone marrow or stem cell transplantation were subjected to selection for leukemia-specific phenotypes by fluorescence-activated cell sorting using individual marker combinations, followed by PCR-based chimerism analysis. RESULTS: The feasibility of this method could be demonstrated, with selection being successful in 12 cases, including two cases where mixed chimerism was found exclusively in sorted cells. Interestingly, four specimens displayed full donor chimerism in cells expressing the presumably aberrant combination CD34+ /CD7+ . Further analyses, including assessment of an independent cohort of 25 patients not affected by neoplastic bone marrow infiltration, revealed that normal myeloid precursors usually include a population coexpressing CD34, CD13, CD33, and CD7. CONCLUSION: We conclude that the combination CD34+ /CD7+ might not be suitable as an LAIP for MRD diagnostics and that a subset of normal myeloid precursors in the bone marrow expresses CD7.
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Antígenos CD34/metabolismo , Antígenos CD7/metabolismo , Células Progenitoras Mieloides/metabolismo , Antígenos CD7/genética , Biomarcadores , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Expresión Génica , Humanos , Inmunofenotipificación , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Células Progenitoras Mieloides/patología , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Neoplasia Residual/metabolismoRESUMEN
BACKGROUND: A low platelet count before mobilization has recurrently been identified as risk factor for poor mobilization. METHODS: To determine the relevance of this finding for peripheral blood stem cell (PBSC) mobilization, including pre-emptive or rescue plerixafor in the case of poor mobilization, we retrospectively analyzed all patients undergoing PBSC collection at our institution between January 2014 and December 2015 (n = 380). RESULTS: In total, 99% of the patients (377/380) successfully collected a minimum of 2 × 106 CD34+ cells/kg body weight sufficient for a single transplant. Rescue or pre-emptive plerixafor was administered to 11% of the patients (42/380). No correlations between the platelet count before mobilization and the number of peripheral blood CD34+ cells or the CD34+ cell collection result were detected in the entire population or the subgroups according to diagnosis (newly diagnosed multiple myeloma, relapsed multiple myeloma, lymphoma, amyloid light-chain amyloidosis, sarcoma, or germ cell tumor). However, patients requiring pre-emptive or rescue plerixafor had a significantly lower platelet count before mobilization (217/nl vs. 245/nl; p = 0.004). CONCLUSION: With the current state of the art PBSC mobilization strategies, the platelet count before mobilization was not associated with the CD34+ cell collection result but was associated with the need for pre-emptive or rescue application of plerixafor.
RESUMEN
Terumo BCT recently introduced a new system for mononuclear cell (MNC) collection that uses a Spectra Optia apheresis machine equipped with a redesigned disposable kit and software program (version 11.2). It allows for the continuous collection of MNCs, unlike the original Spectra Optia system (version 7.2), which included a chamber for two-step cell separation. The aim of this study was to compare the two apheresis systems in regard to specific performance parameters. A retrospective data analysis of 150 patients who had undergone peripheral blood stem cell collection between March of 2014 and May of 2015 at our institution was performed. For the matched comparison, patients were divided into two groups by diagnosis and by previous forms of therapy received: a homogeneous group of patients with multiple myeloma (MM) that had received first line therapy ("MM" group, n = 88) and a heterogeneous group that included all of the other patients ("other" group, n = 62). No significant differences in CD34+ collection yields between both collection regimens were found (pMM = 0.19, pother = 0.74) in either group. Moreover, similar performance ratios (collected/predicted CD34+ cell number in %) were observed (pMM = 0.89, pother = 0.1). No relevant variations in platelet or hemoglobin loss were found between the two systems. We conclude that the new continuous Spectra Optia MNC system is equally efficient in collecting CD34+ cells and can be used without sacrificing collection efficiency levels when treating a broad variety of autologous patients. J. Clin. Apheresis 32:27-34, 2017. © 2016 Wiley Periodicals, Inc.
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Movilización de Célula Madre Hematopoyética/métodos , Leucaféresis/métodos , Células Madre de Sangre Periférica/citología , Antígenos CD34/análisis , Autoinjertos , Movilización de Célula Madre Hematopoyética/normas , Humanos , Leucaféresis/instrumentación , Mieloma Múltiple/terapia , Estudios RetrospectivosRESUMEN
Despite high-dose chemotherapy followed by autologs stem-cell transplantation as well as novel therapeutic agents, multiple myeloma (MM) remains incurable. Following the general trend towards personalized therapy, targeted immunotherapy as a new approach in the therapy of MM has emerged. Better progression-free survival and overall survival after tandem autologs/allogeneic stem cell transplantation suggest a graft versus myeloma effect strongly supporting the usefulness of immunological therapies for MM patients. How to induce a powerful antimyeloma effect is the key issue in this field. Pivotal is the definition of appropriate tumor antigen targets and effective methods for expansion of T cells with clinical activity. Besides a comprehensive list of tumor antigens for T cell-based approaches, eight promising antigens, CS1, Dickkopf-1, HM1.24, Human telomerase reverse transcriptase, MAGE-A3, New York Esophageal-1, Receptor of hyaluronic acid mediated motility and Wilms' tumor gene 1, are described in detail to provide a background for potential clinical use. Results from both closed and on-going clinical trials are summarized in this review. On the basis of the preclinical and clinical data, we elaborate on three encouraging therapeutic options, vaccine-enhanced donor lymphocyte infusion, chimeric antigen receptors-transfected T cells as well as vaccines with multiple antigen peptides, to pave the way towards clinically significant immune responses against MM.
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Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Linfocitos T Citotóxicos/inmunología , Animales , Antígenos de Neoplasias/inmunología , Ensayos Clínicos como Asunto , Humanos , Inmunoterapia/métodosRESUMEN
Although functionally competent cytotoxic, T cells are frequently observed in malignant diseases, they possess little ability to react against tumor cells. This phenomenon is particularly apparent in multiple myeloma. We here demonstrate that cytotoxic T cells reacted against myeloma antigens when presented by autologous dendritic cells, but not by myeloma cells. We further show by gene expression profiling and flow cytometry that, similar to many other malignant tumors, freshly isolated myeloma cells expressed several carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) at varying proportions. Binding and crosslinking of CEACAM-6 by cytotoxic T cells inhibited their activation and resulted in T-cell unresponsiveness. Blocking of CEACAM-6 on the surface of myeloma cells by specific monoclonal antibodies or CEACAM-6 gene knock down by short interfering RNA restored T-cell reactivity against malignant plasma cells. These findings suggest that CEACAM-6 plays an important role in the regulation of CD8+ T-cell responses against multiple myeloma; therefore, therapeutic targeting of CEACAM-6 may be a promising strategy to improve myeloma immunotherapy.
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Antígenos CD/inmunología , Linfocitos T CD8-positivos/inmunología , Moléculas de Adhesión Celular/inmunología , Mieloma Múltiple/inmunología , Linfocitos T Citotóxicos/inmunología , Antígenos CD/genética , Antígenos CD/metabolismo , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Técnicas de Cocultivo , Citotoxicidad Inmunológica/genética , Citotoxicidad Inmunológica/inmunología , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Proteínas Ligadas a GPI/metabolismo , Humanos , Inmunoterapia/métodos , Células MCF-7 , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , ARN Interferente Pequeño/genética , Transducción de Señal/inmunología , Linfocitos T Citotóxicos/metabolismo , Células Tumorales Cultivadas , Células U937RESUMEN
BACKGROUND: Harvest of more than one CD34+ stem cell transplant has become the standard, to ensure the option for a second autologous transplantation in patients with relapsed or progressive multiple myeloma (MM). Additional administration of the CXCR-4 inhibitor plerixafor has been shown to increase the efficiency of CD34+ stem cell harvest. However, the algorithm when to apply plerixafor is still under debate. STUDY DESIGN AND METHODS: In this retrospective study, 46 MM patients were categorized into four groups according to their CD34+ stem cell count in peripheral blood (PB) and mobilization with or without plerixafor: Group A comprised poor mobilizers with CD34+ cell counts of fewer than 20 × 10(6) /L in PB. Group B included inadequate mobilizers with CD34+ cell counts of 20 × 10(6) /L or more in PB and a low CD34+ stem cell yield in the first leukapheresis session. Patients receiving plerixafor preemptively (Group A1) and as a rescue strategy (Group B1) were compared to patients continuing stem cell collection with granulocyte-colony-stimulating factor alone (Groups A2 and B2). RESULTS: In both, the preemptive and the rescue settings, plerixafor enhanced the CD34+ stem cell yield significantly. Poor mobilization and administration of plerixafor was not associated with delayed engraftment. CONCLUSION: Our data demonstrate that administration of plerixafor is safe and effective and facilitates a significantly higher CD34+ stem cell harvest. Based on the presented data, we propose an algorithm for the use of plerixafor for CD34+ stem cell mobilization and harvesting in poor mobilizing myeloma patients.
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Fármacos Anti-VIH/administración & dosificación , Movilización de Célula Madre Hematopoyética , Compuestos Heterocíclicos/administración & dosificación , Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Fármacos Anti-VIH/efectos adversos , Autoinjertos , Bencilaminas , Ciclamas , Femenino , Compuestos Heterocíclicos/efectos adversos , Humanos , Leucaféresis/métodos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Receptores CXCR4 , Estudios RetrospectivosRESUMEN
While extensive data demonstrated that plerixafor improves stem cell harvest in difficult-to-mobilize patients, economic concerns limit a broader application. We retrospectively assessed the effect of an early plerixafor rescue regimen for mobilization in patients with multiple myeloma. Patients were intended for high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ABSCT) and therefore received cyclophosphamide-based mobilization chemotherapy and consecutive stimulation with granulocyte colony-stimulating factor (G-CSF). Fifteen patients with poor stem cell harvest in the first leukapheresis session received plerixafor. Data were compared with a matched historic control group of 45 patients who also had a poor stem cell yield in the first apheresis session, but continued mobilization with G-CSF alone. Patients in the plerixafor group collected significantly more CD34+ cells in total (median 4.9 vs. 3.7 [range 1.6-14.1 vs. 1.1-8.0] × 10(6) CD34+ cells /kg bw; P < 0.05), and also more CD34+ cells per leukapheresis procedure (P < 0.001). Consequently, they required a significantly lower number of leukapheresis procedures to achieve the collection goal (median 2.0 vs. 4.0 [range 2-3 vs. 2-9] procedures; P < 0.001). The efficiency of the collected stem cells in terms of hematologic engraftment after ABSCT was found to be equal in both groups. These data demonstrate that rescue mobilization with plerixafor triggered by a low stem cell yield in the first leukapheresis session is effective. Although the actual economic benefit may vary depending on the local leukapheresis costs, the median saving of two leukapheresis procedures offsets most of the expenses for the substance in this setting. An exemplary cost calculation is provided to illustrate this effect.
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Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/farmacología , Leucaféresis/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencilaminas , Recuento de Células Sanguíneas , Terapia Combinada , Costos y Análisis de Costo , Ciclamas , Ciclofosfamida/administración & dosificación , Evaluación de Medicamentos , Sinergismo Farmacológico , Supervivencia de Injerto , Movilización de Célula Madre Hematopoyética/economía , Trasplante de Células Madre Hematopoyéticas/economía , Humanos , Leucaféresis/estadística & datos numéricos , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
PURPOSE: The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity. METHODS: This academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations (HRCAs). Patients received Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan. TNE patients received two additional Isa-KRd cycles postinduction. This prespecified interim analysis (IA) reports the primary end point, MRD negativity (<10-5, next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS). RESULTS: Among 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for ≥1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm. CONCLUSION: Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.
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Mieloma Múltiple , Humanos , Persona de Mediana Edad , Mieloma Múltiple/terapia , Lenalidomida/uso terapéutico , Lenalidomida/farmacología , Estudios Prospectivos , Dexametasona/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies. Here we provide a comprehensive multiomics analysis including deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive MM, plasma cell leukemia and the premalignancy monoclonal gammopathy of undetermined significance, as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells are highly deregulated as compared with healthy plasma cells and is both defined by chromosomal alterations as well as posttranscriptional regulation. A prognostic protein signature was identified that is associated with aggressive disease independent of established risk factors in MM. Integration with functional genetics and single-cell RNA sequencing revealed general and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include potential targets for (immuno)therapies. Our study demonstrates the potential of proteogenomics in cancer and provides an easily accessible resource for investigating protein regulation and new therapeutic approaches in MM.
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Mieloma Múltiple , Proteogenómica , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Proteogenómica/métodos , Pronóstico , Femenino , Masculino , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Proteoma/análisis , Células Plasmáticas/metabolismo , Persona de Mediana Edad , Anciano , Regulación Neoplásica de la Expresión GénicaRESUMEN
The aim of this study was to investigate whether the specific T cell response against the multiple myeloma Ag HM1.24 is enhanced by the immunomodulatory drug lenalidomide (Revlimid). Ag-specific CD3(+)CD8(+) T cells against the HM1.24 Ag were expanded in vitro by dendritic cells in 29 healthy donors and 26 patients with plasma cell dyscrasias. Ag-specific activation was analyzed by IFN-γ, granzyme B, and perforin secretion using ELISA, ELISPOT assay, and intracellular staining, and generation of Ag-specific T cells was analyzed by tetramer staining. Expression of T cell maturation markers (CD45RA, CD45R0, CCR7, and CD28) was investigated by flow cytometry. We found that activation of HM1.24-specific T cells from healthy donors and patients with plasma cell dyscrasias was enhanced significantly by lenalidomide and furthermore that the impact of lenalidomide on T cells depends on the duration of the exposure. Notably, lenalidomide supports the downregulation of CD45RA on T cells upon activation, observed in healthy donors and in patients in vitro and also in patients during lenalidomide therapy in vivo. We showed for the first time, to our knowledge, that lenalidomide enhances the Ag-specific activation of T cells and the subsequent downregulation of CD45RA expression of T cells in vitro and in vivo.
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Regulación hacia Abajo/inmunología , Epítopos de Linfocito T/metabolismo , Antígenos Comunes de Leucocito/antagonistas & inhibidores , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Subgrupos de Linfocitos T/inmunología , Talidomida/análogos & derivados , Regulación hacia Arriba/inmunología , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Células Cultivadas , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Epítopos de Linfocito T/biosíntesis , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lenalidomida , Antígenos Comunes de Leucocito/biosíntesis , Activación de Linfocitos/inmunología , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Paraproteinemias/inmunología , Paraproteinemias/metabolismo , Paraproteinemias/patología , Subgrupos de Linfocitos T/efectos de los fármacos , Talidomida/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BCMA-specific chimeric-antigen receptor (CAR-) T cell therapy has led to high response rates and durable remissions in patients with relapsed refractory multiple myeloma. However, little data are available for patients after prior allogeneic stem cell transplantation (allo-SCT) in whom T cells are chimeric. In this study, we aimed to assess the safety and efficacy of patient-derived donor CAR-T therapy in myeloma patients with prior allo-SCT, particularly with regard to graft-versus-host disease (GVHD). We report a comprehensive clinical analysis of 3 patients who had previously undergone allo-SCT for high-risk myeloma and were treated with idecabtagene vicleucel (ide-cel) at our institution. Ide-cel was well tolerated, with no clinically relevant immune effector cell-associated neurotoxicity syndrome or cytokine release syndrome observed in any patient. Importantly, no new GVHD was observed, even though all patients had a history of GVHD. All patients responded to treatment with at least a very good partial remission. Two patients relapsed within 6 months, and 1 patient was still in stringent complete remission at the time of this report. Our findings demonstrate that treatment with ide-cel is feasible, very well tolerated, and effective in patients with relapsed/refractory multiple myeloma after prior allo-SCT.
RESUMEN
Introduction: Infections are a leading cause of morbidity and mortality in patients with multiple myeloma (MM). Methods: To examine the effects of modern second-generation novel agent therapy on immune cell subsets, in particular CD4+-T-cells, and infectious complications in patients with relapsed/refractory MM (RRMM), we conducted a prospective cohort study in 112 RRMM patients. Results: Substantially decreased CD4+-T-cells <200/µl before initiation of relapse therapy were detected in 27.7% of patients and were associated with a higher number of previous lines of therapy. Relapse therapy with carfilzomib or pomalidomide showed a significant further decrease of CD4+-T-cells. All novel agents led to a significant decrease of B-cell counts. Overall, infections were frequent with 21.3% of patients requiring antibacterial therapy within the first 3 months of relapse therapy, 5.6% requiring hospitalization. However, in the setting of standard antimicrobial prophylaxis in RRMM patients with very low CD4+-T-cells, no significant association of CD4+T-cell count and an increased risk of infection could be detected. Discussion: Our findings imply that reduced CD4+-T-cell numbers and infections are common in patients with RRMM. We also demonstrate an association with the number of previous therapies and certain substances suggesting an increased need for personalized prophylaxis strategies for opportunistic infections in this patient cohort.
RESUMEN
The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based "Mediators of apoptosis combinatorial score" (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN. SIGNIFICANCE: Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making. This article is highlighted in the In This Issue feature, p. 1275.
Asunto(s)
Leucemia Mieloide Aguda , Proteómica , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Azacitidina/farmacología , Azacitidina/uso terapéutico , Células Madre/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. METHODS: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. CONCLUSION: Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.