RESUMEN
Chemoimmunotherapy followed by consolidative high-dose therapy with autologous stem cell rescue was a standard upfront treatment for fit patients with mantle cell lymphoma (MCL) in first remission; however, treatment paradigms are evolving in the era of novel therapies. Lenalidomide is an immunomodulatory agent with known efficacy in treating MCL. We conducted a single-center, investigator-initiated, phase II study of immunochemotherapy incorporating lenalidomide, without autologous stem cell transplant consolidation, enriching for patients with high-risk MCL (clinicaltrials gov. Identifier: NCT02633137). Patients received four cycles of lenalidomide-R-CHOP, two cycles of R-HiDAC, and six cycles of R-lenalidomide. The primary endpoint was rate of 3-year progression-free survival. We measured measurable residual disease (MRD) using a next-generation sequencing-based assay after each phase of treatment and at 6 months following end-oftreatment. We enrolled 49 patients of which 47 were response evaluable. By intent-to-treat, rates of overall and complete response were equivalent at 88% (43/49), one patient with stable disease, and two patients had disease progression during study; 3-year progression-free survival was 63% (primary endpoint not met) and differed by TP53 status (78% wild-type vs. 38% ALT; P=0.043). MRD status was prognostic and predicted long-term outcomes following R-HiDAC and at 6 months following end-of-treatment. In a high-dose therapy-sparing, intensive approach, we achieved favorable outcomes in TP53- wild-type MCL, including high-risk cases. We confirmed that sequential MRD assessment is a powerful prognostic tool in patients with MCL.
Asunto(s)
Linfoma de Células del Manto , Adulto , Humanos , Lenalidomida/uso terapéutico , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pronóstico , InmunoterapiaRESUMEN
Diffuse large B-cell lymphoma (DLBCL) predominantly affects older adults with suboptimal therapeutic outcomes due to increased treatment-related mortality and toxicities in vulnerable patients, clinically defined by geriatric impairments such as functional limitation, multimorbidity, or cognitive deficits. In this prospective pilot study, we evaluated a rituximab/prednisone prephase treatment strategy in 33 older, vulnerable patients with newly diagnosed DLBCL, defined by either age ≥70 years or age 60-70 years with Karnofsky performance scale (KPS) <80. A single dose of rituximab 375 mg/m2 between 3-10 days and oral prednisone for at least 5 days prior to the first dose of chemoimmunotherapy was administered. All patients completed prephase treatment and all but one commenced anthracycline-based chemoimmunotherapy. Only one early cycle death occurred. Toxicity events, defined by either unplanned hospitalization, unplanned dose reduction/delay, or chemotherapy discontinuation, occurred in 22 patients (67%). Sixteen patients (48%) experienced grade 3 or higher non-hematologic toxicities and/or grade 4 or higher hematologic toxicities. With a median follow-up of 4.4 years, both 5-year progression-free survival and overall survival were at 81% (95% confidence interval: 69-96). Importantly, we found that phenotypic impairments in basic and instrumental activities of daily living, physical function, mobility, KPS, and Cancer and Aging Research Group chemotherapy toxicity risk score were significantly associated with senescence-associated, proinflammatory cytokine milieu which was readily reversed with prephase treatment, potentially explaining its clinical effectiveness. Prephase therapy with rituximab/prednisone should be considered for all older, vulnerable DLBCL patients prior to curative intent, anthracycline-based chemoimmunotherapy. This trial was registered as clinicaltrials gov. Identifier: NCT89028394.
Asunto(s)
Citocinas , Linfoma de Células B Grandes Difuso , Actividades Cotidianas , Anciano , Envejecimiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/uso terapéutico , Doxorrubicina/efectos adversos , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Persona de Mediana Edad , Proyectos Piloto , Prednisona/efectos adversos , Estudios Prospectivos , Rituximab , Resultado del Tratamiento , Vincristina/efectos adversosRESUMEN
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of lymphoma that, like other Hodgkin lymphomas, has historically been treated aggressively. However, in most cases, NLPHL has an indolent course, which raises the question of to what extent these patients require aggressive upfront treatment. We describe the management and outcomes of consecutive NLPHL patients diagnosed at Memorial Sloan Kettering Cancer Center (MSK), with a focus on evaluating active surveillance. All patients aged 16 years or older diagnosed and followed at MSK between 1974 and 2016 were included. Treatment outcomes were compared between management with active surveillance and other strategies. We identified 163 consecutive patients who were treated with radiotherapy alone (46%), active surveillance (23%), chemotherapy (16%), combined modality (12%), or rituximab monotherapy (4%). Median follow-up was 69 months. Five-year progression-free survival (PFS), second PFS (PFS2), and overall survival (OS) estimates were 85% (95% confidence interval [CI], 78-90), 97% (95% CI, 92-99), and 99% (95% CI, 95-100), respectively. Only 1 of 7 deaths was lymphoma related. Patients managed with active surveillance had slightly shorter PFS than those receiving any active treatment, with 5-year PFS of 77% (95% CI, 56-89) vs 87% (95% CI, 79-92; P = .017). This difference did not translate into better PFS2 or OS. Only 10 patients managed with active surveillance (27%) eventually required treatment, after a median of 61 months, and none died. NLPHL has an excellent prognosis. Within the limitations of a retrospective analysis, active surveillance is a viable initial management strategy for selected NLPHL patients.
Asunto(s)
Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/terapia , Linfocitos/patología , Adolescente , Adulto , Anciano , Animales , Manejo de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Resultado del Tratamiento , Espera Vigilante , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Lenalidomida , Linfoma de Células del Manto , Neoplasia Residual , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/terapia , Linfoma de Células del Manto/patología , Lenalidomida/uso terapéutico , Lenalidomida/administración & dosificación , Neoplasia Residual/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Talidomida/administración & dosificación , Inmunoterapia/métodosRESUMEN
Treatment options are limited for patients with non-clear cell renal cell carcinoma (nccRCC). Patients with nccRCC experienced a favorable objective response rate (ORR) in a phase 2 trial of cabozantinib plus nivolumab. We now report updated efficacy and safety results at median follow-up of 34 mo for patients with papillary, unclassified, or translocation-associated RCC. Cabozantinib and nivolumab were administered at standard doses to patients with metastatic nccRCC that had progressed on zero or one line of systemic therapy. The primary endpoint was the ORR according to Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Forty patients were treated. At median follow-up of 34 mo for survivors, the ORR was 48% (95% confidence interval [CI] 31.5-63.9%). Median PFS was 13 mo (95% CI 7-16); the 12-mo and 24-mo PFS rates were 51% (95% CI 34-65%) and 23% (95% CI 11-37%), respectively. Median OS was 28 mo (95% CI 23-43); the 18-mo and 36-mo OS rates were 70% (95% CI 53-82%) and 44% (95% CI 28-60%), respectively. No new safety signals were seen with cabozantinib and nivolumab. This extended follow-up analysis demonstrates promising efficacy, and highlights the potential for sustained responses with cabozantinib plus nivolumab in patients with metastatic nccRCC.
Asunto(s)
Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales , Neoplasias Renales , Nivolumab , Piridinas , Humanos , Anilidas/uso terapéutico , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Piridinas/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months for PTCL with a TP53 mutation (n = 21) vs 10.5 months for PTCL without a TP53 mutation (n = 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n = 9), CDKN2A-deleted PTCL correlated with inferior OS, with a median of 17.6 months vs 56.7 months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.
Asunto(s)
Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/genética , Pronóstico , Estudios Retrospectivos , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , MutaciónRESUMEN
Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin B-cell lymphoma that has historically been difficult to define, though is now formally recognized by the World Health Organization Classification. To better characterize the clinical outcomes of patients with NMZL, we reviewed a sequential cohort of 187 patients with NMZL to describe baseline characteristics, survival outcomes, and time-to-event data. Initial management strategies were classified into five categories: observation, radiation, anti-CD20 monoclonal antibody therapy, chemoimmunotherapy, or other. Baseline Follicular Lymphoma International Prognostic Index scores were calculated to evaluate prognosis. A total of 187 patients were analyzed. The five-year overall survival was 91% (95% confidence interval [CI], 87-95), with a median follow-up time of 71 months (range, 8-253) among survivors. A total of 139 patients received active treatment at any point, with a median follow-up time of 56 months (range, 13-253) among survivors who were never treated. The probability of remaining untreated at five years was 25% (95% CI, 19-33). For those initially observed, the median time to active treatment was 72 months (95% CI, 49-not reached). For those who received at least one active treatment, the cumulative incidence of receiving a second active treatment at 60 months was 37%. Transformation to large B-cell lymphoma was rare, with a cumulative incidence of 15% at 10 years. In summary, our series is a large cohort of uniformly diagnosed NMZL with detailed analyses of survival and time to event analyses. We showed that NMZL commonly presents as an indolent lymphoma for which initial observation is often a reasonable strategy.
Asunto(s)
Antineoplásicos , Linfoma de Células B de la Zona Marginal , Humanos , Estudios Retrospectivos , Linfoma de Células B de la Zona Marginal/terapia , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Pronóstico , Antineoplásicos/uso terapéutico , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
R ± DHAX has been traditionally administered to inpatient due to the timing of chemotherapy administration and the perceived need for close monitoring of adverse effects. To administer R ± DHAX outpatient, a multidisciplinary task force created clinical and educational guidelines which were implemented through two phases: pilot and expansion. The pilot program determined the feasibility of transitioning R ± DHAX outpatient at a single infusion site. The expansion phase led to a service-wide implementation across all outpatient sites. A total of 40 patients were included, of which 23 patients completed all cycles, outpatient, 12 transitioned inpatient to outpatient administration, and 5 transitioned outpatient to inpatient administration. The success rate of outpatient R ± DHAX administration was 90% (36 patients successfully completed outpatient administration/40 total patients). No cytarabine-related cerebellar or ophthalmic toxicity was reported. Outpatient R ± DHAX saved 192 hospital days. R ± DHAX could be successfully administered outpatient with minimal safety concerns and reduced hospital bed utilization.
Asunto(s)
Citarabina , Linfoma , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona , Humanos , Linfoma/tratamiento farmacológico , Pacientes Ambulatorios , Oxaliplatino , RituximabRESUMEN
PURPOSE: To assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non-clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients had advanced non-clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response. RESULTS: A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n = 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n = 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations. CONCLUSION: Cabozantinib plus nivolumab showed promising efficacy in most non-clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non-clear-cell RCC variants warrant further study as predictors of response.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Genómica , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Nivolumab/uso terapéutico , PiridinasRESUMEN
Between 1998 and 2009, a total of 295 patients (median age 58, 53% females) with newly diagnosed early-stage follicular lymphoma (FL) were managed at Memorial Sloan Kettering Cancer Center. Approximately half of patients (137, 46%) underwent initial observation and half (158, 54%) immediate treatment: radiation alone (n = 108), systemic treatment alone (n = 29), or combined modality treatment (n = 21). Median follow-up was 8.4 years (range 0.3-17.2), and 10-year overall survival (OS) was 87.2%. OS was similar between initially-observed and immediately-treated patients (hazard ratio [HR]: 1.25, 95% CI: 0.67-2.36, p = 0.49). For patients receiving radiation alone, 5-year OS was 98.0%. Patients selected for systemic therapy alone had high-risk baseline features and had shorter OS than patients treated with radiation alone (HR 3.38, 95% CI 1.29-8.86, p = 0.01). Combined modality treatment did not yield superior survival compared with radiation alone (P > 0.05) but was associated with better progression-free survival (HR 0.36, 95% CI 0.14-0.90, p = 0.03). The rate of transformation increased steadily over time and was 4.2% at 5 years and 10.8% at 10 years. This modern-era analysis rationalized the role of initial observation in patients with early-stage FL although patients receiving radiation therapy also demonstrate excellent outcome.
Asunto(s)
Linfoma Folicular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Femenino , Humanos , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
PURPOSE: We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) (ClinicalTrials.gov identifier: NCT03618550). METHODS: Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m2 IV, days 1 and 8), vinorelbine (20 mg/m2 IV, days 1 and 8), and liposomal doxorubicin (15 mg/m2, days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT. RESULTS: Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66-27.06 months). CONCLUSION: Second-line therapy with pembro-GVD is a highly effective and well-tolerated regimen that can efficiently bridge patients with rel/ref cHL to HDT/AHCT.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Desoxicitidina/análogos & derivados , Doxorrubicina/análogos & derivados , Enfermedad de Hodgkin/tratamiento farmacológico , Vinorelbina/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Brentuximab Vedotina/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Esquema de Medicación , Femenino , Florida , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Inducción de Remisión , Factores de Tiempo , Resultado del Tratamiento , Vinorelbina/efectos adversos , Adulto Joven , GemcitabinaRESUMEN
BACKGROUND: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. METHODS: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25â000 cells per µL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10â000 leukocytes [<10-4]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. FINDINGS: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. INTERPRETATION: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. FUNDING: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Anciano , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neoplasia Residual , Piperidinas , Pirazoles , Pirimidinas , SulfonamidasRESUMEN
High-grade B-cell lymphoma (HGBL) with translocations involving MYC and BCL2 or BCL6 comprises â¼10% of cases of diffuse large B-cell lymphoma (DLBCL) and carries a poor prognosis. The incidence, prognosis, and optimal therapy for DLBCL harboring extra copies of the genes MYC, BCL2, and BCL6, rather than their genetic translocations, are unknown. In this retrospective, single-center study we identified 144 DLBCL cases including 46 patients with classic HGBL with double-hit or triple-hit chromosomal translocations (DHL), 55 with extra copies of MYC in addition to aberrations (extra copies or translocations) of BCL2 and/or BCL6 but did not meet the criteria for HGBL (EC group), and 43 without any aberrations of MYC, BCL2, or BCL6 (wild type [WT]). Unfavorable baseline characteristics had similar frequency in the EC and WT groups, but were significantly more prevalent in the DHL group. With a median follow-up of 36 months, the 2-year event-free survival (EFS) was similar between the WT and EC groups at 77% (95% confidence interval [CI], 65-90) and 82% (95% CI, 72-93), respectively. In contrast, the 2-year EFS of the DHL group was 63% (95% CI, 51-79). The 2-year overall survival in the WT, EC, and DHL groups was 86% (95% CI, 76-97), 89% (95% CI, 81-98), and 74% (95% CI, 62-88), respectively. Among patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the EC group had outcomes similar to those of the WT group. Our results indicate that patients with DLBCL with extra gene copies of MYC, BCL2, and BCL6 fare differently from those with HGBL and respond well to standard R-CHOP therapy.
Asunto(s)
Linfoma de Células B Grandes Difuso , Proteínas Proto-Oncogénicas c-myc , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-myc/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. METHODS: In this retrospective study, we identified 1088 patients with grade I-IIIA FL; of whom, 238 patients with stage II-IV disease were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and 346 patients were treated with rituximab-based chemotherapy. Patients (N = 484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (positron-emission tomography [PET] versus computed tomography [CT]) and early POD status using event-defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. RESULTS: In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had a 5-year OS of 57.6% for CT-staged patients compared with 70.6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53.9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients than in PET-staged patients (16.7% versus 6.3%, respectively), which was associated with a 9.7-fold higher risk of death. CONCLUSION: In FL, pre-treatment PET staging reduced the prognostic impact of early POD compared with CT staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Estadificación de Neoplasias/métodos , Tomografía de Emisión de Positrones/métodos , Adulto , Anciano , Anciano de 80 o más Años , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma Folicular/diagnóstico por imagen , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Pronóstico , Estudios Retrospectivos , Rituximab/administración & dosificación , Tomografía Computarizada por Rayos X/métodos , Vincristina/administración & dosificación , Adulto JovenRESUMEN
The prognosis of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Chimeric antigen receptor (CAR) T-cell therapy has been approved for R/R DLBCL after 2 prior lines of therapy based on data from single-arm phase 2 trials, with complete responses (CRs) in 40% to 60% of patients. However, a direct comparison with other treatments is not available and, moreover, its true efficacy in real-world patients is unknown. In this single center, retrospective, observational study of 215 patients, we compared outcomes in patients treated with CAR T-cell therapy (n = 69) with a historical population treated with alternate therapies (n = 146). Patients treated with CAR T cell vs alternate therapies demonstrated a CR rate of 52% vs 22% (P < .001), median progression-free survival (PFS) of 5.2 vs 2.3 months (P = .01), and median overall survival (OS) of 19.3 vs 6.5 months (P = .006), and this advantage appeared to persist irrespective of the number of lines of prior therapy. After adjusting for unfavorable pretreatment disease characteristics, superior overall response rate in the CAR T cohort remained significant; however, differences in PFS and OS between cohorts did not. In addition, patients who responded to alternate therapies demonstrated prolonged remissions comparable to those who responded to CAR T therapy. We contend that in select clinical scenarios alternate therapies may be as efficacious as CAR T therapy; thus, additional study is warranted, ideally with randomized prospective trials.
Asunto(s)
Antígenos CD19 , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/terapia , Estudios Prospectivos , Estudios Retrospectivos , Linfocitos TRESUMEN
Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1-3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.
Asunto(s)
Linfoma Folicular/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/mortalidad , Linfoma Folicular/terapia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Vigilancia en Salud Pública , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Análisis de Supervivencia , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenAsunto(s)
Linfoma de Células del Manto , Recurrencia Local de Neoplasia , Adenina/análogos & derivados , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Quinazolinas/uso terapéuticoRESUMEN
Peripheral T-cell lymphomas (PTCLs) comprise a rare and heterogeneous subset of non-Hodgkin's lymphomas (NHLs) that arise from post-thymic T-cells or natural killer (NK)-cells at nodal or extranodal sites. Worldwide, PTCLs represent approximately 12% of all NHLs and the 2008 World Health Organization (WHO) classification includes over 20 biologically and clinically distinct T/NK-cell neoplasms that differ significantly in presentation, pathology, and response to therapy. Because of the rarity and heterogeneity of these diseases, large clinical trials have not been conducted and optimal therapy is not well defined. Most subtypes are treated with similar combination chemotherapy regimens as used for aggressive B-cell NHL, but with poorer outcomes. New treatment combinations and novel agents are currently being explored for PTCLs and this review highlights a number of options that appear promising.