RESUMO
Multiple Myeloma (MM) is a malignant growth of clonal plasma cells, typically arising from asymptomatic precursor conditions, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Profound immunological dysfunctions and cytokine deregulation are known to characterize the evolution of the disease, allowing immune escape and proliferation of neoplastic plasma cells. In the past decades, several studies have shown that the immune system can recognize MGUS and MM clonal cells, suggesting that anti-myeloma T cell immunity could be harnessed for therapeutic purposes. In line with this notion, chimeric antigen receptor T cell (CAR-T) therapy is emerging as a novel treatment in MM, especially in the relapsed/refractory disease setting. In this review, we focus on the pivotal contribution of T cell impairment in the immunopathogenesis of plasma cell dyscrasias and, in particular, in the disease progression from MGUS to SMM and MM, highlighting the potentials of T cell-based immunotherapeutic approaches in these settings.
Assuntos
Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Paraproteinemias , Mieloma Múltiplo Latente , Progressão da Doença , Humanos , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Paraproteinemias/terapia , Linfócitos T/patologiaRESUMO
BACKGROUND: Breaking bad news (BBN) may be associated with increasing risk of burnout in practising physicians. However, there is little research on the association between the way bad news is broken and burnout. We investigated the association between physicians' self-efficacy regarding communication to patients and risk of burnout. METHODS: We performed a cross-sectional study by proposing an ad-hoc survey exploring attitudes and practice regarding BBN and the Maslach Burnout Inventory - Human Service Survey to 379 physicians from two University Hospitals in Italy. Associations were assessed by multivariable logistic regression models. RESULTS: Two-hundred twenty-six (60%) physicians returned the questionnaires. 76% of physicians acquired communication skills by observing mentors or colleagues, 64% considered BBN as discussing a poor prognosis, 56% reported discussing prognosis as the most difficult task, 38 and 37% did not plan a BBN encounter and considered it stressful. The overall burnout rate was 59%. Considering BBN a stressful task was independently associated with high risk of burnout (OR 3.01; p = 0.013). Planning the encounter (OR = 0.43, p = 0.037), mastering communication skills (OR = 0.19, p = 0.034) and the self-evaluation as good or very good at BBN (OR 0.32; 0.15 to 0.71; p = 0.0) were associated with low risk of burnout. CONCLUSIONS: Our findings suggest that some physicians' BBN attitudes and knowledge of conceptual frameworks may influence the risk of burnout and support the notion that increasing knowledge about communication skills may protect clinicians from burnout. Further research is needed in this area.
Assuntos
Esgotamento Profissional/psicologia , Médicos/psicologia , Autoeficácia , Revelação da Verdade , Adulto , Estudos Transversais , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Relações Médico-Paciente , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
Although the emergence of bone marrow (BM)-resident p190BCR-ABL-specific T lymphocytes has been correlated with hematologic and cytogenetic remissions in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) undergoing maintenance tyrosine-kinase inhibitor treatment, little is known about the possibility of culturing these cells ex vivo and using them in T-cell therapy strategies. We investigated the feasibility of expanding/priming p190BCR-ABL-specific T cells in vitro by stimulation with dendritic cells pulsed with p190BCR-ABL peptides derived from the BCR-ABL junctional region and alternative splicing, and of adoptively administering them to patients with relapsed disease. We report on the feasibility of producing clinical-grade BCR-ABL-specific cytotoxic T lymphocytes (CTLs), endowed with antileukemia activity, from Ph+ ALL patients and healthy donors. We treated 3 patients with Ph+ ALL with autologous or allogeneic p190BCR-ABL-specific CTLs. No postinfusion toxicity was observed, except for a grade II skin graft-versus-host disease in the patient treated for hematologic relapse. All patients achieved a molecular or hematologic complete remission (CR) after T-cell therapy, upon emergence of p190BCR-ABL-specific T cells in the BM. Our results show that p190BCR-ABL-specific CTLs are capable of controlling treatment-refractory Ph+ ALL in vivo, and support the development of adoptive immunotherapeutic approaches with BCR-ABL CTLs in Ph+ ALL.
Assuntos
Transferência Adotiva/métodos , Proteínas de Fusão bcr-abl/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/transplante , Adulto , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologiaAssuntos
Leucemia Mieloide Aguda , Células-Tronco de Sangue Periférico , Humanos , Adulto , Estudos de Viabilidade , Estaurosporina/uso terapêutico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Tirosina Quinase 3 Semelhante a fms/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Chronic/recurrent behaviour may be encountered in some distinct atypical or malignant lymphoproliferations, while recurrences are not generally observed in reactive/benign lymphadenopathies. We retrospectively analysed a consecutive series of 486 human immunodeficiency virus-negative adults, who underwent lymphadenectomy. Neoplastic and benign/reactive histopathological pictures were documented in 299 (61·5%) and 187 (38·5%) cases, respectively. Of note, seven of the 111 (6·3%) patients with benign lymphadenopathy without well-defined aetiology, showed chronic/recurrent behaviour, without constitutional symptoms. Enlarged lymph nodes were round in shape and hypoechoic, mimicking lymphoma. Reactive follicular hyperplasia and paracortical expansion were observed. Human herpesvirus (HHV)-6B positive staining in follicular dendritic cells (FDCs) was documented in all seven patients. Serological, molecular and immunological examinations suggested HHV-6B reactivation. Among the remaining 104 cases with reactive lymphoid hyperplasia in the absence of well-known aetiology and without recurrences, positivity for HHV-6B on FDCs was found in three cases, whereas in seven further patients, a scanty positivity was documented in rare, scattered cells in inter-follicular regions. Immunohistochemistry for HHV-6A and HHV-6B was invariably negative on 134 lymph nodes, with either benign pictures with known aetiology or malignant lymphoproliferative disorders, tested as further controls. Future studies are warranted to investigate a potential association between HHV-6B reactivation and chronic/recurrent benign lymphadenopathy.
Assuntos
Herpesvirus Humano 6/fisiologia , Doenças Linfáticas/virologia , Infecções por Roseolovirus/complicações , Adulto , Idoso , Doença Crônica , Células Dendríticas/patologia , Feminino , Humanos , Hiperplasia/virologia , Imuno-Histoquímica , Excisão de Linfonodo , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/virologia , Recidiva , Estudos Retrospectivos , Ativação ViralRESUMO
Bone marrow has already been described as an enrichment site for several antigen-specific T lymphocytes, but the presence of mould-specific T cells has never been investigated in the bone marrow. We have previously demonstrated that mould-specific T cells emerge in the peripheral blood of patients with invasive fungal infections (IFI) but tend to become undetectable after disease resolution. In seven patients with a history of IFI, we investigated the presence of mould-specific T cells secreting different cytokines in bone marrow and peripheral blood paired samples. The results showed that the frequencies of mould-specific T cells secreting the protective cytokine IFNγ are significantly higher in bone marrow (BM) and are mainly represented by CD8+ T lymphocytes with effector phenotype. A putative disappearance of such protective BM responses after myeloablative therapy could contribute to the increased risk of IFI in hematologic patients.
Assuntos
Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Fungemia/imunologia , Fungos/imunologia , Adulto , Idoso , Sangue/imunologia , Estudos de Coortes , Feminino , Humanos , Interferon gama/metabolismo , Masculino , Pessoa de Meia-IdadeAssuntos
Anemia Aplástica/epidemiologia , Tuberculose Latente/epidemiologia , Leucemia Mieloide Aguda/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/tratamento farmacológico , Antituberculosos/uso terapêutico , Vacina BCG , Terapia Combinada , Comorbidade , Neutropenia Febril/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Testes de Liberação de Interferon-gama , Isoniazida/uso terapêutico , Tuberculose Latente/diagnóstico por imagem , Tuberculose Latente/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: We investigated the performance of enzyme linked immunospot (ELISpot) assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematologic malignancies. METHODS: We prospectively enrolled two cohorts of patients undergoing intensive myelosuppressive or immunosuppressive treatments at high risk for IA. ELISpot was performed to detect Aspergillus-specific T cells producing Interleukin-10. RESULTS: In the discovery cohort, a derived cut-off of 40 spot forming cells (SFCs)/106 PBMCs has shown to correctly classify IA cases with a sensitivity and specificity of 89.5% and 88.6%, respectively. This cut-off is lowered to 25 SFC when considering the subset of possible IA patients, with sensitivity and specificity of 76% and 93%, respectively. The application of the 40 SFCs cut-off to the validation cohort resulted in a positivity rate of 83.3% in proven/probable cases and a negativity rate of 92.5% in possible/non-IA cases. Adopting the 25 SCFs cut-off, the assay resulted positive in 83.3% of proven/probable cases while it resulted negative in 66.7% of possible/non-IA cases. CONCLUSIONS: ELISpot shows promises in the diagnosis of IA and the possibility to use two distinct cut-offs with similar diagnostic performances according to patients' different pre-test probability of infection can widen its use in patients at risk.
Assuntos
ELISPOT , Humanos , ELISPOT/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Estudos Prospectivos , Aspergilose/diagnóstico , Aspergilose/imunologia , Interleucina-10/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/diagnóstico , Sensibilidade e Especificidade , Linfócitos T/imunologiaRESUMO
Mucorales-specific T cells were investigated in 28 hematologic patients during the course of their treatment. Three developed proven invasive mucormycosis (IM), 17 had infections of known origin but other than IM, and 8 never had fever during the period of observation. Mucorales-specific T cells could be detected only in patients with IM, both at diagnosis and throughout the entire course of the IM, but neither before nor for long after resolution of the infection. Such T cells predominantly produced IL-4, IFN-γ, IL-10, and to a lesser extent IL-17 and belonged to either CD4(+) or CD8(+) subsets. The specific T cells that produced IFN-γ were able to directly induce damage to Mucorales hyphae. None of the 25 patients without IM had Mucorales-specific T cells. Specific T cells contribute to human immune responses against fungi of the order Mucorales and could be evaluated as a surrogate diagnostic marker of IM.
Assuntos
Biomarcadores , Mucorales/imunologia , Mucormicose , Linfócitos T/imunologia , Linfócitos T/microbiologia , Humanos , Imunofenotipagem , Mucormicose/diagnóstico , Mucormicose/epidemiologia , Mucormicose/imunologia , Fatores de RiscoRESUMO
Recommendations and guidelines for management of SARS-COV-2 infection in hematologic patients were developed in the very difficult context of dealing with novel viral variants from one pandemic wave to another, with different susceptibility to available drugs and vaccines. Moreover, the largest SARS-COV-2 case series in patients treated for hematologic malignancies, including stem cell transplant recipients, was published before the Omicron surge, and refers mainly to Alpha and Delta viral variants. These infections had very high mortality, in a period when antivirals and monoclonal antibodies were mostly unavailable. Here, we report for the first time a SARS-COV-2 Omicron variant outbreak inside a Bone Marrow Transplant (BMT) Unit, describing the characteristics, clinical course, and infection outcomes shortly before and shortly after myeloablative transplantation. We detail how infections were treated off-label and managed inside the BMT ward, to guarantee the best possible outcomes while avoiding risks for non-infected inpatients. The positive outcomes observed suggest that it may not be absolutely necessary to obtain SARS-CoV-2 PCR negativity before BMT in hematologic patients after treated infection, in cases with long-term PCR positivity and high-risk hematologic disease.
Assuntos
COVID-19 , Transplante de Células-Tronco Hematopoéticas , Humanos , SARS-CoV-2 , Surtos de Doenças , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
OBJECTIVES: Although early palliative care (EPC) is beneficial in acute myeloid leukaemia, little is known about EPC value in multiple myeloma (MM). We compared quality indicators for palliative and end-of-life (EOL) care in patients with MM receiving EPC with those of patients who received usual haematological care (UHC). METHODS: This observational, retrospective study was based on 290 consecutive patients with MM. The following indicators were abstracted: providing psychological support, assessing/managing pain, discussing goals of care, promoting advance care plan, accessing home care services; no anti-MM treatment within 14 and 30 days and hospice length of stay >7 days before death; no cardiopulmonary resuscitation, no intubation, <2 hospitalisations and emergency department visits within 30 days before death. Comparisons were performed using unadjusted and confounder-adjusted regression models. RESULTS: 55 patients received EPC and 231 UHC. Compared with UHC patients, EPC patients had a significantly higher number of quality indicators of care (mean 2.62±1.25 vs 1.12±0.95; p<0.0001)); a significant reduction of pain intensity over time (p<0.01) and a trend towards reduced aggressiveness at EOL, with the same survival (5.3 vs 5.46 years; p=0.74)). CONCLUSIONS: Our data support the value of integrating EPC into MM routine practice and lay the groundwork for future prospective comparative studies.
RESUMO
Multiple Myeloma (MM) typically originates from underlying precursor conditions, known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Validated risk factors, related to the main features of the clonal plasma cells, are employed in the current prognostic models to assess long-term probabilities of progression to MM. In addition, new prognostic immunologic parameters, measuring protective MM-specific T-cell responses, could help to identify patients with shorter time-to-progression. In this report, we described a novel Multi-antigenic Myeloma-specific (MaMs) T-cell assay, based on ELISpot technology, providing simultaneous evaluation of T-cell responses towards ten different MM-associated antigens. When performed during long-term follow-up (mean 28 months) of 33 patients with either MGUS or SMM, such deca-antigenic myeloma-specific immunoassay allowed to significantly distinguish between stable vs. progressive disease (p < 0.001), independently from the Mayo Clinic risk category. Here, we report the first clinical experience showing that a wide (multi-antigen), standardized (irrespective to patients' HLA), MM-specific T-cell assay may routinely be applied, as a promising prognostic tool, during the follow-up of MGUS/SMM patients. Larger studies are needed to improve the antigenic panel and further explore the prognostic value of MaMs test in the risk assessment of patients with monoclonal gammopathies.
RESUMO
Imatinib mesylate has been demonstrated to allow the emergence of T cells directed against chronic myeloid leukemia cells. A total of 10 Philadelphia chromosome-positive acute lymphoblastic leukemia patients receiving high-dose imatinib mesylate maintenance underwent long-term immunological monitoring (range, 2-65 months) of (p190)BCR-ABL-specific T cells in the bone marrow and peripheral blood. (p190)BCR-ABL-specific T lymphocytes were detected in all patients, more frequently in bone marrow than in peripheral blood samples (67% vs 25%, P < .01) and resulted significantly associated with lower minimal residual disease values (P < .001), whereas absent at leukemia relapse. Specific T cells were mainly effector memory CD8(+) and CD4(+) T cells, producing interferon-gamma, tumor necrosis factor-alpha, and interleukin-2 (median percentage of positive cells: 3.34, 3.04, and 3.58, respectively). Cytotoxic subsets able to lyse BCR-ABL-positive leukemia blasts also were detectable. Whether these autologous (p190)BCR-ABL-specific T cells may be detectable under other tyrosine-kinase inhibitors, expanded ex vivo, and exploited for immunotherapy remains to be addressed.
Assuntos
Antineoplásicos/administração & dosagem , Células da Medula Óssea/imunologia , Proteínas de Fusão bcr-abl/imunologia , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Pirimidinas/administração & dosagem , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Linfócitos T CD4-Positivos/imunologia , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Interferon gama/imunologia , Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de TempoRESUMO
OBJECTIVES: Early palliative supportive care has been associated with many advantages in patients with advanced cancer. However, this model is underutilised in patients with haematological malignancies. We investigated the presence and described the frequency of quality indicators for palliative care and end-of-life care in a cohort of patients with acute myeloid leukaemia receiving early palliative supportive care. METHODS: This is an observational, retrospective study based on 215 patients consecutively enrolled at a haematology early palliative supportive care clinic in Modena, Italy. Comprehensive hospital chart reviews were performed to abstract the presence of well-established quality indicators for palliative care and for aggressiveness of care near the end of life. RESULTS: 131 patients received a full early palliative supportive care intervention. All patients had at least one and 67 (51%) patients had four or more quality indicators for palliative care. Only 2.7% of them received chemotherapy in the last 14 days of life. None underwent intubation or cardiopulmonary resuscitation and was admitted to intensive care unit during the last month of life. Only 4% had either multiple hospitalisations or two or more emergency department access. Approximately half of them died at home or in a hospice. More than 40% did not receive transfusions within 7 days of death. The remaining 84 patients, considered late referrals to palliative care, demonstrated sensibly lower frequencies of the same indicators. CONCLUSIONS: Patients with acute myeloid leukaemia receiving early palliative supportive care demonstrated high frequency of quality indicators for palliative care and low rates of treatment aggressiveness at the end of life.
Assuntos
Anemia Aplástica/diagnóstico , Anemia Aplástica/epidemiologia , Leucemia/diagnóstico , Leucemia/epidemiologia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Respirovirus/epidemiologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/complicações , Anemia Aplástica/terapia , Feminino , Humanos , Leucemia/complicações , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Vírus da Parainfluenza 3 Humana/fisiologia , Prognóstico , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/diagnóstico , Vírus Sinciciais Respiratórios/fisiologia , Infecções Respiratórias/complicações , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/epidemiologia , Infecções por Respirovirus/complicações , Infecções por Respirovirus/diagnóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Clinical charts from 63 consecutive highly immunocompromised haematologic patients presenting with pulmonary nodular lesions on CT scan, classified as either probable or possible invasive fungal disease (IFD) according to the revised EORTC/MSG classification, were retrospectively studied. Histopathological analysis of lung tissues, available for 23 patients, demonstrated proven IFD in 17 cases (14 invasive aspergillosis and 3 invasive zygomycosis), diffuse alveolar damage in one and organising pneumonia (OP) in five cases. In the OP cases, three of which have been defined as probable IFD according to EORTC/MSG classification, extensive immunohistochemical, molecular and immunological analyses for fungi were negative. Our case descriptions extend the notion that OP may be encountered as a distinct histopathological entity in pulmonary nodular lesions in patients with leukaemia with probable/possible IFD.
Assuntos
Pneumonia em Organização Criptogênica/diagnóstico , Pneumonia em Organização Criptogênica/etiologia , Leucemia Mieloide Aguda/complicações , Pneumopatias Fúngicas/diagnóstico , Pneumopatias Fúngicas/etiologia , Idoso , Líquido da Lavagem Broncoalveolar/microbiologia , Diagnóstico Diferencial , Feminino , Humanos , Hospedeiro Imunocomprometido , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/etiologia , Leucemia Mieloide Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/etiologia , Estudos Retrospectivos , Zigomicose/diagnóstico , Zigomicose/etiologiaRESUMO
Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT.
Assuntos
Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Segunda Neoplasia Primária , Idoso , Aloenxertos , Ensaios de Uso Compassivo , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/terapia , Taxa de SobrevidaAssuntos
Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T Citotóxicos/imunologia , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Feminino , Humanos , Mesilato de Imatinib , Memória Imunológica , Imunofenotipagem , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Indução de Remissão , Linfócitos T Citotóxicos/metabolismoRESUMO
Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1-mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9-14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9-14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ-producing and IL2-producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1-mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1-mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1-mutated AML patients.