RESUMO
Marginal zone lymphoma (MZL) is the most common indolent lymphoma primarily arising in the central nervous system (CNS). To date, 207 cases of primary CNS MZL (PCNSMZL) were published, mostly as single case reports or small case series. It most commonly presents as extra-axial dural-based masses, more frequently in middle-aged women, displaying an insidious onset, with a long history of symptoms preceding the diagnosis. PCNSMZL can be radiographically mistaken for meningioma. PCNSMZL consists of CD20+ , CD3- small B lymphocytes with varying degrees of plasmacytic differentiation and low proliferation index. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality. Other recurrent genetic abnormalities involve TNFAIP3 and NOTCH2. Ethiopathogenesis was poorly investigated. Due to its rarity, standard of care remains to be defined; it exhibits an excellent prognosis after varied treatments, such as surgery, radiotherapy, chemotherapy or their combinations. Nevertheless, each treatment should be considered after an accurate analysis of overtreatment risk. Short follow-up is a major limitation in reported PCNSMZL cases, which restrains our knowledge on long-term results and iatrogenic sequels. This review was focussed on presentation, differential diagnoses, pathological findings, treatment options and clinical outcomes of PCNSMZL; recommendations for best clinical practice are provided.
Assuntos
Linfoma de Zona Marginal Tipo Células B , Pessoa de Meia-Idade , Humanos , Feminino , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma de Zona Marginal Tipo Células B/genética , Linfócitos B/patologia , Tecido Linfoide/patologia , Translocação Genética , Sistema Nervoso Central/patologiaRESUMO
Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/prevenção & controle , Ciclofosfamida , Doxorrubicina , Humanos , Linfoma Difuso de Grandes Células B/patologia , Metotrexato , Recidiva Local de Neoplasia/tratamento farmacológico , Prednisona , Estudos Retrospectivos , Rituximab/uso terapêutico , VincristinaRESUMO
PURPOSE OF REVIEW: Patients with relapsed/refractory primary central nervous system lymphoma (rrPCNSL) have poor prognosis, with a median survival after relapse of 6.8âmonths. In this review, we discuss the evolving landscape and the possible future directions related to this important unmet clinical need. RECENT FINDINGS: The modern two-phase approach for newly diagnosed PCNSL based on an induction using high-dose methotrexate (HD-MTX) combinations and a subsequent consolidation, has significantly improved the outcome in this setting. However, this strategy is able to cure more or less 50% of patients. rrPCNSL patients have a very poor prognosis with a reported 5-year overall survival of 18%. Late relapses (after third year) and use of high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) represent important factors associated with a better outcome in this setting. On the basis of the growing acquisition of knowledge on the molecular characteristics of PCNSL, the use of non-chemotherapeutic drugs such as bruton tyrosine kinase inhibitors (BTK-is), immunomodulatory drugs (IMiDs) and immune checkpoint blockers (ICBs) is increasing in the last years along with the introduction of novel approaches (CAR-T cells and blood--brain barrier disruption). However, despite high responses in some cases, durations are often short, translating in outcome results still unsatisfactory. SUMMARY: Treatment of rrPCNSL patients is challenging. As no standard of care exist in this setting, it is of paramount importance to acquire new knowledge related to this condition and start multidisciplinary collaboration in order to improve pts outcome.
Assuntos
Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Transplante Autólogo , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Sistema Nervoso Central/patologia , Terapia CombinadaRESUMO
To optimise management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection identifying high-risk patients and maintaining treatment dose intensity is an important issue in patients with aggressive lymphomas. In the present study, we report on the presentation, management, and outcome of an international series of 91 patients with primary central nervous system lymphoma and SARS-CoV-2 infection. SARS-CoV-2 was diagnosed before/during first-line treatment in 64 patients, during follow-up in 21, and during salvage therapy in six. Among the 64 patients infected before/during first-line chemotherapy, 38 (59%) developed pneumonia and 26 (41%) did not clear the virus. Prolonged exposure to steroids before viral infection and/or treatment with high-dose cytarabine favoured pneumonia development and virus persistence and were associated with poorer survival; 81% of patients who did not clear virus died early from coronavirus disease 2019 (COVID-19). Vaccination was associated with lower pneumonia incidence and in-hospital mortality. Chemotherapy was initiated/resumed in 43 (67%) patients, more commonly among patients who did not develop pneumonia, cleared the virus, or did not receive steroids during infection. Chemotherapy resumption in patients with viral persistence should be indicated cautiously as it was associated with a poorer survival (6-month, 70% and 87%, p = 0.07). None of the 21 patients infected during follow-up died from COVID-19, requiring similar measures as infected subjects in the general population.
Assuntos
COVID-19 , Linfoma , Humanos , SARS-CoV-2 , Sistema Nervoso Central , Linfoma/tratamento farmacológicoRESUMO
A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double-hit lymphoma (n = 1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI = 60-80%) and 75% (95% CI = 66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/terapia , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/terapia , Citarabina/uso terapêutico , Linfoma de Células B/terapia , Adulto , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Linfoma de Burkitt/complicações , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Carmustina/uso terapêutico , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Infecções por HIV/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfoma de Células B/complicações , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Transplante Autólogo/efeitos adversosRESUMO
Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reaction. IL-6 and IL-10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme-linked immunosorbent assay. Mut-MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue-CSF samples. IL-10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL-6 transcripts was negligible. In CSF samples, mut-MYD88 and high IL-10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL-6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL-10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut-MYD88 and IL-10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated.
Assuntos
Biomarcadores Tumorais , Neoplasias do Sistema Nervoso Central , Interleucina-10/líquido cefalorraquidiano , Linfoma , Mutação de Sentido Incorreto , Fator 88 de Diferenciação Mieloide/genética , Proteínas de Neoplasias , Adulto , Idoso , Substituição de Aminoácidos , Biomarcadores Tumorais/líquido cefalorraquidiano , Biomarcadores Tumorais/genética , Biópsia , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Humanos , Interleucina-10/genética , Linfoma/líquido cefalorraquidiano , Linfoma/genética , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/líquido cefalorraquidiano , Proteínas de Neoplasias/líquido cefalorraquidiano , Proteínas de Neoplasias/genéticaRESUMO
Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor necrosis factor-α coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 µg/m2) afterward. This trial included 2 phases: an "explorative phase" addressing the effect of NGR-hTNF on drug pharmacokinetic parameters and on vessel permeability, assessed by dynamic contrast-enhanced magnetic resonance imaging and 99mTc-diethylene-triamine-pentacetic acid-single-photon emission computed tomography, and the expression of CD13 on tumor tissue; and an "expansion phase" with overall response rate as the primary end point, in which the 2-stage Simon Minimax design was used. At the first stage, if ≥4 responses were observed among 12 patients, the study accrual would have continued (sample size, 28). Herein, we report results of the explorative phase and the first-stage analysis (n = 12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/cerebrospinal fluid concentrations. The NGR-hTNF/R-CHOP combination was well tolerated: there were only 2 serious adverse events, and grade 4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with 9 confirmed responses (75%; 95% confidence interval, 51-99), 8 of which were complete. In conclusion, NGR-hTNF/R-CHOP was safe in these heavily pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral/peritumoral areas, which resulted in fast and sustained responses.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacocinética , Fator de Necrose Tumoral alfa/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Barreira Hematoencefálica/diagnóstico por imagem , Antígenos CD13/metabolismo , Permeabilidade da Membrana Celular , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/mortalidade , Masculino , Neuroimagem/métodos , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Projetos de Pesquisa , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento , Fator de Necrose Tumoral alfa/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
The MATRix chemoimmunotherapy regimen is highly effective in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL). However, nothing is known about its feasibility and efficacy in everyday practice, where patients are more often older/frailer than those enrolled in clinical trials. We conducted a retrospective study addressing tolerability/efficacy of MATRix in 156 consecutive patients with newly diagnosed PCNSL treated outside a clinical trial. Median age and ECOG Performance Status of considered patients were 62 years (range 28-78) and 2 (range 0-4). The overall response rate after MATRix was 79%. Nine (6%) treatment-related deaths were recorded. After a median follow-up of 27.4 months (95% confidence interval [CI] 24.4-31.9%), the two-year progression-free and overall survival were 56% (95% CI 48.4-64.9%) and 64.1% (95% CI 56.7-72.5%) respectively. Patients not eligible for the IELSG32 trial were treated with lower dose intensity and had substantially worse outcomes than those fulfilling inclusion criteria. This is the largest series of PCNSL patients treated with MATRix outside a trial and recapitulates the IELSG32 trial outcomes in the non-trial setting for patients who fit the trial criteria. These data underscore the feasibility and efficacy of MATRix as induction treatment for fit patients in routine practice.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia , Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Terapia Combinada , Comorbidade , Quimioterapia de Consolidação , Irradiação Craniana , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Quimioterapia de Indução , Internacionalidade , Estimativa de Kaplan-Meier , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma Relacionado a AIDS/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/radioterapia , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Transplante de Órgãos , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/terapia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Tiotepa/administração & dosagem , Tiotepa/efeitos adversosRESUMO
We report final results of a phase II trial addressing efficacy and feasibility of lenalidomide maintenance in patients with chemosensitive relapse of diffuse large B-cell lymphoma (DLBCL) not eligible for or failed after autologous stem cell transplantation (ASCT). Patients with relapsed DLBCL who achieved at least a partial response to salvage chemoimmunotherapy were enrolled and treated with lenalidomide 25 mg/day for 21 of 28 days for 2 years or until progression or unacceptable toxicity. Primary endpoint was 1-year PFS. Forty-six of 48 enrolled patients were assessable. Most patients had IPI ≥2, advanced stage and extranodal disease before the salvage treatment that led to trial registration; 28 (61%) patients were older than 70 years. Lenalidomide was well tolerated. With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Three patients died of complications during maintenance and three died due to second cancers at 32 to 64 months. There were 13 SAEs recorded in 12 patients; all these patients but two recovered. Lenalidomide was interrupted due to toxicity in other 6 patients, and 25 patients required dose reduction (transient in 21). At 1 year from registration, 31 patients were progression free. After a median follow-up of 65 (range 39-124) months, 22 patients remain progression free, with a 5-year PFS of 48% ± 7%. The duration of response to lenalidomide was longer than response to prior treatment in 30 (65%) patients. Benefit was observed both in de novo and transformed DLBCL, germinal-center-B-cell and nongerminal-center-B-cell subtypes. Twenty-six patients are alive (5-year OS 62% ± 7%). With the limitations of a nonrandomized design, these long-term results suggest that lenalidomide maintenance might bring benefit to patients with chemosensitive relapse of DLBCL not eligible for or failed after ASCT. Lenalidomide was associated with durable disease control and was well tolerated in this elderly population. Further investigations on immunomodulatory drugs as maintenance in these high-risk patients are warranted.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/patologia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de SobrevidaRESUMO
PURPOSE: To detect the presence of MYD88 L265P mutation in the aqueous humor of patients with cytologically proven vitreoretinal lymphoma. METHODS: Eight consecutive patients with bilateral vitreoretinal lymphoma (16 eyes) were prospectively evaluated. Genomic DNA was extracted from aqueous samples after paracentesis and vitreous humor samples after diagnostic vitrectomy. MYD88 codon 265 mutation was investigated by both amplification-refractory mutation system polymerase chain reaction approach and pyrosequencing assay in the aqueous humor of all patients and in the vitreous of 6 patients. A control group of 8 age-matched patients with established diagnosis of noninfectious uveitis was also tested for the presence of MYD88 L265P mutation in the aqueous humor. RESULTS: Eight patients (three men, five women) with mean age of 69.5 years (range 50-85 years) were considered. All the patients tested for MYD88 L265P in the vitreous (six) were positive, and this result was consistent with cytological examination in all samples but one. The MYD88 L265P mutation was found in the aqueous of 6 patients (75%), and in 3 of them, the mutation was present in both eyes. Results of MYD88 L265P mutation in aqueous and vitreous sample were consistent in 7 of the 8 eyes with available samples. The aqueous humor of the noninfectious uveitis control group was negative for the detection of MYD88 L265P mutation. CONCLUSION: MYD88 mutation was detected in the aqueous humor of 75% of patients with cytologically proven vitreoretinal lymphoma. This technique may be considered as an additional diagnostic tool in the detection of the disease.
Assuntos
Humor Aquoso/metabolismo , Biomarcadores Tumorais/genética , DNA de Neoplasias/genética , Linfoma Intraocular/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Macroglobulinemia de Waldenstrom/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Humanos , Linfoma Intraocular/diagnóstico , Linfoma Intraocular/cirurgia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Prospectivos , Microscopia com Lâmpada de Fenda , Vitrectomia , Corpo Vítreo/metabolismo , Corpo Vítreo/patologia , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/cirurgiaRESUMO
BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM = 607, FEAM = 431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM = 2011 versus FEAM = 2013, P < .001), Sorror score ≥3 (BEAM = 15% versus FEAM = 10%, P = .017), and radiotherapy use (BEAM = 18% versus FEAM = 10%, P < .001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM = 31% versus FEAM = 44%, P < .001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM = .1 versus FEAM = .19, P < .001). Response status at day 100 post-ASCT (overall response: BEAM = 91% versus FEAM = 88%, P = .42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P = .04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carmustina/farmacologia , Carmustina/uso terapêutico , Estudos de Coortes , Citarabina/farmacologia , Citarabina/uso terapêutico , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Feminino , Humanos , Itália , Linfoma/patologia , Masculino , Melfalan/farmacologia , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Estudos RetrospectivosAssuntos
Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Linfoma , Humanos , Tiotepa/uso terapêutico , Transplante Autólogo , Linfoma/patologia , Sistema Nervoso Central/patologia , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Transplante de Células-TroncoRESUMO
It is widely demonstrated that the PI3K-AKT-mTOR signalling is critical in normal myeloid and lymphoid development and function. Thus, it is not strange that this pathway is often deregulated in haematological tumours, providing a strong preclinical rationale for the use of drugs targeting the PI3K-AKT-mTOR axis in haematological malignancies. The main focus of this review is to examine the mammalian target of rapamycin (mTOR, also termed mechanistic target of rapamycin [MTOR]) signalling pathways and to provide a brief overview of rapalogs and second-generation mTOR inhibitors used to target its aberrant activation in cancer treatment. We will also discuss the results obtained with the use of these agents in patients with acute leukaemia, Hodgkin lymphoma, non-Hodgkin lymphomas, multiple myeloma and Waldenström macroglobulinaemia. Ongoing clinical trials in haematological malignancies that are investigating first- and second-generation mTOR inhibitors as single agents and as components of combination regimens are also presented.
Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antibióticos Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Everolimo/uso terapêutico , Humanos , Inibidores de Fosfoinositídeo-3 Quinase , Transdução de Sinais/fisiologia , Sirolimo/análogos & derivados , Sirolimo/uso terapêuticoRESUMO
Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34(+) bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics.
Assuntos
Processamento Alternativo , Leucemia Mieloide Aguda/genética , Receptor Notch2/genética , Tirosina Quinase 3 Semelhante a fms/genética , Linhagem Celular , Análise por Conglomerados , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Proteínas de Membrana/metabolismo , Prognóstico , Receptor Notch2/metabolismo , Ativação Transcricional , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
We recently demonstrated that Nicotinamide phosphoribosyltransferase (Nampt) inhibition depletes intracellular NAD⺠content leading, to autophagic multiple myeloma (MM) cell death. Bortezomib has remarkably improved MM patient outcome, but dose-limiting toxicities and development of resistance limit its long-term utility. Here we observed higher Nampt messenger RNA levels in bortezomib-resistant patient MM cells, which correlated with decreased overall survival. We demonstrated that combining the NAD⺠depleting agent FK866 with bortezomib induces synergistic anti-MM cell death and overcomes bortezomib resistance. This effect is associated with (1) activation of caspase-8, caspase-9, caspase-3, poly (ADP-ribose) polymerase, and downregulation of Mcl-1; (2) enhanced intracellular NAD⺠depletion; (3) inhibition of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities; (4) inhibition of nuclear factor κB signaling; and (5) inhibition of angiogenesis. Furthermore, Nampt knockdown significantly enhances the anti-MM effect of bortezomib, which can be rescued by ectopically overexpressing Nampt. In a murine xenograft MM model, low-dose combination FK866 and Bortezomib is well tolerated, significantly inhibits tumor growth, and prolongs host survival. Taken together, these findings indicate that intracellular NAD⺠level represents a major determinant in the ability of bortezomib to induce apoptosis in MM cells and provide proof of concept for the combination with FK866 as a new strategy to enhance sensitivity or overcome resistance to bortezomib.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , NAD/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/metabolismo , Pirazinas/farmacologia , Acrilamidas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Bortezomib , Estudos de Casos e Controles , Caspases/genética , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos SCID , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , NF-kappa B/genética , NF-kappa B/metabolismo , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/mortalidade , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/genética , Análise de Sequência com Séries de Oligonucleotídeos , Piperidinas/farmacologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The Hedgehog (Hh) pathway is required for cell-fate determination during the embryonic life, as well as cell growth and differentiation in the adult organism, where the inappropriate activation has been implicated in several cancers. Here we demonstrate that Hh signaling plays a significant role in growth and survival of multiple myeloma (MM) cells. We observed that CD138(+) MM cells express Hh genes and confirmed Smoothened (Smo)-dependent Hh signaling in MM using a novel synthetic Smo inhibitor, NVP-LDE225 (Novartis), which decreased MM cell viability by inducing specific down-regulation of Gli1 and Ptch1, hallmarks of Hh activity. In addition, we detected a nuclear localization of Gli1 in MM cells, which is completely abrogated by Forskolin, a Gli1-modulating compound, confirming Smo-independent mechanisms leading to Hh activation in MM. Finally, we identified that bone marrow stromal cells are a source of the Shh ligand, although they are resistant to the Hh inhibitor because of defective Smo expression and Ptch1 up-regulation. Further in vitro as well as in vivo studies showed antitumor efficacy of NVP-LDE225 in combination with bortezomib. Altogether, our data demonstrate activation of both canonical and noncanonical Hh pathway in MM, thus providing the rationale for testing Hh inhibitors in clinical trials to improve MM patient outcome.
Assuntos
Proteínas Hedgehog/metabolismo , Mieloma Múltiplo/metabolismo , Plasmócitos/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Ácidos Borônicos/farmacologia , Ácidos Borônicos/uso terapêutico , Bortezomib , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/genética , Humanos , Camundongos , Camundongos SCID , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Receptores Patched , Receptor Patched-1 , Plasmócitos/efeitos dos fármacos , Plasmócitos/patologia , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened , Sindecana-1/análiseRESUMO
Malignant cells have a higher nicotinamide adenine dinucleotide (NAD(+)) turnover rate than normal cells, making this biosynthetic pathway an attractive target for cancer treatment. Here we investigated the biologic role of a rate-limiting enzyme involved in NAD(+) synthesis, Nampt, in multiple myeloma (MM). Nampt-specific chemical inhibitor FK866 triggered cytotoxicity in MM cell lines and patient MM cells, but not normal donor as well as MM patients PBMCs. Importantly, FK866 in a dose-dependent fashion triggered cytotoxicity in MM cells resistant to conventional and novel anti-MM therapies and overcomes the protective effects of cytokines (IL-6, IGF-1) and bone marrow stromal cells. Nampt knockdown by RNAi confirmed its pivotal role in maintenance of both MM cell viability and intracellular NAD(+) stores. Interestingly, cytotoxicity of FK866 triggered autophagy, but not apoptosis. A transcriptional-dependent (TFEB) and independent (PI3K/mTORC1) activation of autophagy mediated FK866 MM cytotoxicity. Finally, FK866 demonstrated significant anti-MM activity in a xenograft-murine MM model, associated with down-regulation of ERK1/2 phosphorylation and proteolytic cleavage of LC3 in tumor cells. Our data therefore define a key role of Nampt in MM biology, providing the basis for a novel targeted therapeutic approach.
Assuntos
Acrilamidas/farmacologia , Antineoplásicos/farmacologia , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Piperidinas/farmacologia , Proteínas/antagonistas & inibidores , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Terapia de Alvo Molecular , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Complexos Multiproteicos , NAD/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Especificidade de Órgãos , Proteínas/genética , Proteínas/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Early diagnosis is crucial for the successful treatment of primary CNS lymphoma (PCNSL), a rapidly progressing tumour. Suspicion raised on brain MRI must be confirmed by a histopathological diagnosis of a tumour specimen collected by stereotactic biopsy. In rare cases, cerebrospinal fluid (CSF) or vitreous humour might aid in providing a cytological diagnosis. Several disease-related, patient-related, and treatment-related factors affect the timing and accuracy of diagnosis and patient outcome. Some molecules detected in CSF, aqueous and vitreous humour, and peripheral blood were proposed as diagnostic biomarkers for PCNSL; however, detection methods for most of these molecules are not yet standardised, have a long turnaround time, are expensive, and have little reproducibility among labs. By contrast, the MYD88Leu265Pro somatic hotspot mutation, revealed by PCR-based assay, is currently and reliably used during the diagnosis of some lymphomas, and IL-10, measured by enzyme-linked immunosorbent assay, is routinely used to diagnose and monitor different common metabolic and immunological diseases. Several independent studies have shown that MYD88Leu265Pro and IL-10 can be easily assessed in peripheral blood, plasma, aqueous and vitreous humour, and CSF of patients with PCNSL with substantial sensitivity and specificity, especially when evaluated in combination. In this Viewpoint, evidence supporting the routine use of MYD88Leu265Pro and IL-10 in diagnosing PCNSL is considered, and some examples of the frequent difficulties found in the diagnosis of PCNSL are provided, highlighting the role and indications of these two biomarkers to improve the timely recognition of this aggressive tumour.
Assuntos
Neoplasias do Sistema Nervoso Central , Interleucina-10 , Linfoma , Fator 88 de Diferenciação Mieloide , Humanos , Fator 88 de Diferenciação Mieloide/genética , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Interleucina-10/genética , Interleucina-10/líquido cefalorraquidiano , Linfoma/diagnóstico , Linfoma/genética , Biomarcadores Tumorais/genética , MutaçãoRESUMO
This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS.The guideline covers clinical, imaging and pathological diagnosis, staging and risk assessment, treatment and follow-up.Algorithms for first-line and salvage treatments are provided.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion.