RESUMEN
Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/prevención & control , Linfoma de Células B Grandes Difuso/prevención & control , Metotrexato/uso terapéutico , Recurrencia Local de Neoplasia/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Femenino , Humanos , Inyecciones Espinales , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Plasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1-196), the 3-year progression-free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3-year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper-CVAD or auto-SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.
Asunto(s)
Infecciones por VIH , Linfoma Plasmablástico , Humanos , Linfoma Plasmablástico/terapia , Linfoma Plasmablástico/patología , Estudios Retrospectivos , Recurrencia Local de Neoplasia/etiología , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Progresión , Infecciones por VIH/tratamiento farmacológico , PronósticoRESUMEN
Hematopoietic stem cell transplantation (HCT) has been an integral component in the treatment of many hematologic malignancies. Since the development of HCT nearly 50 years ago, the role of this modality has evolved as newer treatment approaches have been developed and integrated into the standard of care. In the last decade, novel and highly active targeted therapies and immunotherapies have been approved for many hematologic malignancies, raising the question of whether HCT continues to retain its prominent role in the treatment paradigms of various hematologic malignancies. In this review, the authors have described the current role of autologous and allogeneic HCT in the treatment of patients with acute leukemias, aggressive B-cell lymphomas, and multiple myeloma and discussed how novel targeted therapies and immunotherapies have changed the potential need, timing, and goal of HCT in patients with these diseases.
Asunto(s)
Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Inmunoterapia , Medicina de Precisión , Nivel de Atención , Trasplante Autólogo , Trasplante HomólogoRESUMEN
BACKGROUND: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso/terapia , Recurrencia Local de Neoplasia/terapia , Terapia Recuperativa/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Supervivencia sin Progresión , Estudios Retrospectivos , Terapia Recuperativa/normas , Nivel de Atención , Trasplante Autólogo/normas , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
While patients with double-hit lymphoma (DHL) are now frequently treated with intensive front-line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative-intent second-line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression-free/overall survival (PFS/OS) of 2/5·1 months and one-year PFS/OS of 10/19% following the start of second-line therapy. These outcomes may serve as a standard against which future second-line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non-cytotoxic therapies in the second-line setting for these patients.
Asunto(s)
Inmunoterapia/métodos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL, NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL, NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal=6, parenchymal=4, and both=1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR=3.5) and testicular (in men) or female pelvic (in women) involvement (OR=8.1). There was no significant difference in survival outcomes between HGBL, NOS patients with (median PFS=4 years) or without (median PFS=2.4 years) baseline CNS involvement (p=0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% versus 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-GCB subtype, and DEL phenotype, however, high CNS-IPI was not. The prognosis of relapsed HGBL, NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and CAR T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease. These patients represent an unmet need and should be prioritized for experimental approaches.
RESUMEN
Secondary involvement of the central nervous system (CNS) by diffuse large b-cell lymphoma (DLBCL) is a rare yet often catastrophic event for DLBCL patients. As standard first-line therapy for DLBCL with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) does not cross the blood-brain barrier, one approach to lessen the risk of CNS relapse has been to include additional agents, primarily methotrexate, directed at the CNS with standard R-CHOP although the timing, dose, and mode of administration differs widely across treating physicians. This practice derives from decades of non-randomized, often retrospective data with inconsistent outcomes. The current available tools and risk models are imprecise in their ability to predict which patients are truly at risk of secondary CNS relapse and more recent, large-scale real-world analyses call into question these longstanding practices. In a field lacking any prospective, randomized studies, this review synthesizes the available data investigating the utility of CNS prophylaxis in patients with DLBCL receiving 1st line therapy.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Humanos , Estudios Retrospectivos , Estudios Prospectivos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/etiología , Neoplasias del Sistema Nervioso Central/prevención & control , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Rituximab/uso terapéutico , Ciclofosfamida/efectos adversos , Prednisona/efectos adversos , Vincristina/efectos adversos , Sistema Nervioso Central/patología , Doxorrubicina/efectos adversos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , RecurrenciaRESUMEN
Brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is increasingly used for frontline treatment of stage III/IV classical Hodgkin lymphoma (cHL). Peripheral neuropathy (PN) was the most common and treatment-limiting side effect seen in clinical trials but has not been studied in a nontrial setting, in which clinicians may have different strategies for managing it. We conducted a multisite retrospective study to characterize PN in patients who received BV + AVD for newly diagnosed cHL. One hundred fifty-three patients from 10 US institutions were eligible. Thirty-four patients (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage, performance status, and comorbidities. PN was reported by 80% of patients during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of patients because of PN leading to BV discontinuation in 23%, dose reduction in 17%, and temporary hold in 4%. With a median follow-up of 24 months, PN resolution was documented in 36% and improvement in 33% at the last follow-up. Two-year progression-free survival (PFS) for the advanced-stage patients was 82.7% (95% confidence interval [CI], 0.76-0.90) and overall survival was 97.4% (95% CI, 0.94-1.00). Patients who discontinued BV because of PN did not have inferior PFS. In the nontrial setting, BV + AVD was associated with a high incidence of PN. In our cohort, which includes patients who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable.
Asunto(s)
Enfermedad de Hodgkin , Enfermedades del Sistema Nervioso Periférico , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brentuximab Vedotina/uso terapéutico , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Incidencia , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Estudios RetrospectivosRESUMEN
In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.
Asunto(s)
Linfoma de Células B Grandes Difuso , Humanos , Persona de Mediana Edad , Rituximab/uso terapéutico , Estudios Retrospectivos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Prednisona/uso terapéutico , Vincristina/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Etopósido , Lactato DeshidrogenasasRESUMEN
BACKGROUND: Outcomes in patients with relapsed/refractory (R/R) diffuse large b-cell lymphoma (DLBCL) who are ineligible for and/or fail high-dose chemotherapy and autologous stem cell transplantation in the second line are poor. There is no preferred palliative-intent treatment for patients in this setting. PATIENTS AND METHODS: A retrospective cohort study was performed using the nationwide de-identified electronic health record-derived Flatiron Health database. Event-free survival (EFS) and overall survival (OS) was evaluated for patients with R/R DLBCL who were ineligible for and/or failed autologous stem cell transplantation in the second line and received bendamustine, gemcitabine, or lenalidomide. RESULTS: Three hundred eighty-three patients were included. Therapy received was bendamustine in 158 patients, gemcitabine in 142 patients, and lenalidomide in 83 patients. The median EFS and OS for all patients was 4.1 months and 8.7 months, respectively. Compared with patients receiving bendamustine or gemcitabine, those receiving lenalidomide demonstrated significantly longer median EFS (6.8 vs. 3.8 months; P = .006) and median OS (15.4 vs. 7.7 months; P = .045). Survival outcomes were also improved for lenalidomide-treated patients specifically in the second- as well as third- or fourth-line settings. CONCLUSION: Use of lenalidomide resulted in prolonged EFS and OS as compared with bendamustine or gemcitabine in this cohort of patients with R/R DLBCL receiving palliative therapy. This first large-scale analysis of real-world outcomes for this patient population may guide current clinical management as well as serve as a benchmark for survival outcomes in the standard-of-care setting, which may aid in the design of future clinical trials.
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Linfoma de Células B Grandes Difuso/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL.
Asunto(s)
Citogenética/métodos , Linfoma de Células B Grandes Difuso/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019). METHODS: Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS). RESULTS: ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently. CONCLUSION: CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02135406. FUNDING: Novartis, NIH, Conquer Cancer Foundation.
Asunto(s)
Antígenos CD19/inmunología , Inmunoterapia Adoptiva/métodos , Melfalán/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/uso terapéutico , Anciano , Antígeno de Maduración de Linfocitos B/inmunología , Terapia Combinada/métodos , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Inmunidad Celular/efectos de los fármacos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Agonistas Mieloablativos/uso terapéutico , Receptores de Antígenos de Linfocitos T/administración & dosificación , Receptores de Antígenos de Linfocitos T/inmunología , Factores de Transcripción SOXB1/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Richter's transformation (RT) is the transformation of chronic lymphocytic leukemia (CLL) into rapidly progressive B-cell lymphoma. This disease has long been recognized as a difficult-to-treat illness with poor survival outcomes. Although the incidence of RT has been well documented in previous studies, less is understood in the era of novel therapeutics, such as kinase inhibitors (KIs). The present review discusses the current risk factors, incidence, and outcomes of patients with RT in the modern era of KI therapy. Although the outcomes remain poor for RT patients after KI therapy, the most up-to-date studies have shown no increased incidence of RT in this patient population. Additionally, the present review reports the outcomes from the most recent data on novel therapies under investigation for patients with RT.
Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patologíaRESUMEN
PET/computed tomography (CT) imaging has gained a prominent role in the diagnosis and staging of malignancies. In lymphoma the role of PET/CT imaging continues to evolve as the understanding of its use in prognostication and response assessment improves. Currently, many groups are studying the potential function of PET/CT imaging in helping to direct management decisions for treating clinicians. This article summarizes the most up-to-date literature surrounding the topic of PET/CT-adaptive treatment of different lymphoma subjects. Although more studies are necessary to solidify the role of PET/CT, it is clear that this imaging modality holds much promise for the development of response-adaptive treatment algorithms in the future.