RESUMO
BACKGROUND: Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. METHODS: We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. FINDINGS: From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. INTERPRETATION: The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. FUNDING: National Cancer Institute.
Assuntos
Neoplasias da Mama , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radiocirurgia , Humanos , Feminino , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias da Mama/radioterapia , Neoplasias da Mama/etiologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
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.
Assuntos
Linfoma de Célula do Manto , Adulto , Humanos , Lenalidomida/uso terapêutico , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Prognóstico , ImunoterapiaRESUMO
PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population.
Assuntos
Neoplasias de Mama Triplo Negativas , Benzamidas , Estudos de Viabilidade , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Nitrilas/uso terapêutico , Feniltioidantoína/efeitos adversos , Receptores Androgênicos/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
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.
Assuntos
Citocinas , Linfoma Difuso de Grandes Células B , Atividades Cotidianas , Idoso , Envelhecimento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Pessoa de Meia-Idade , Projetos Piloto , Prednisona/efeitos adversos , Estudos Prospectivos , Rituximab , Resultado do Tratamento , Vincristina/efeitos adversosRESUMO
BACKGROUND: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. METHODS: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. FINDINGS: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. INTERPRETATION: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. FUNDING: Novartis Pharmaceuticals.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Tiazóis/administração & dosagem , Adolescente , Adulto , Idoso , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Antagonistas do Receptor de Estrogênio/administração & dosagem , Feminino , Fulvestranto/administração & dosagem , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/genéticaRESUMO
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.
Assuntos
Doença de Hodgkin/patologia , Doença de Hodgkin/terapia , Linfócitos/patologia , Adolescente , Adulto , Idoso , Animais , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Resultado do Tratamento , Conduta Expectante , Adulto JovemRESUMO
PURPOSE: The phosphatidylinositol 3-kinase (PI3K) pathway is involved in several physiological processes, including glucose metabolism, cell proliferation, and cell growth. Hyperactivation of this signaling pathway has been associated with tumorigenesis and resistance to treatment in various cancer types. Mutations that activate PIK3CA, encoding the PI3K isoform p110α, are common in breast cancer, particularly in the hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) subtype. A number of PI3K inhibitors have been developed and evaluated for potential clinical use in combinations targeting multiple signaling pathways in cancer. The purpose of this review is to provide an overview of PI3K inhibitor mechanisms of action for antitumor activity and adverse events in advanced breast cancer (ABC). METHODS: Published results from phase 3 trials evaluating the efficacy and safety of PI3K inhibitors in patients with ABC and relevant literature were reviewed. RESULTS: Although PI3K inhibitors have been shown to prolong progression-free survival (PFS), the therapeutic index is often unfavorable. Adverse events, such as hyperglycemia, rash, and diarrhea are frequently observed in these patients. In particular, hyperglycemia is intrinsically linked to the inhibition of PI3Kα, a key mediator of insulin signaling. Off-target effects, including mood disorders and liver toxicity, have also been associated with some PI3K inhibitors. CONCLUSION: Recent clinical trial results show that specifically targeting PI3Kα can improve PFS and clinical benefit. Broad inhibition of class I PI3Ks appears to result in an unfavorable safety profile due to off-target effects, limiting the clinical utility of the early PI3K inhibitors.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias da Mama/patologia , Feminino , Humanos , PrognósticoRESUMO
PURPOSE: Rash develops in approximately 50% of patients receiving alpelisib for breast cancer, often requiring dose modifications. Here, we describe the clinicopathologic, laboratory, and management characteristics of alpelisib-related dermatologic adverse events (dAEs). METHODS: A single center-retrospective analysis was conducted. Data were abstracted from electronic medical records. RESULTS: A total of 102 patients (mean age 56 years, range 27-83) receiving alpelisib most frequently in combination with endocrine therapy (79, 77.5%) were included. We identified 41 (40.2%) patients with all-grade rash distributed primarily along the trunk (78%) and extremities (70%) that developed approximately within two weeks of treatment initiation (mean 12.8 ± 1.5 days) and lasted one-week (mean duration 7.1 ± 0.8 days). Of 29 patients with documented morphology of alpelisib-related dAEs, 26 (89.7%) had maculopapular rash. Histology showed perivascular and interface lymphocytic dermatitis. All-grade rash correlated with an increase in serum eosinophils from 2.7 to 4.4%, p < 0.05, and prophylaxis with non-sedating antihistamines (n = 43) was correlated with a reduction of grade 1/2 rash (OR 0.39, p = 0.09). Sixteen (84.2%) of 19 patients with grade 3 dAEs resulted in interruption of alpelisib, which were managed with antihistamines, topical and systemic corticosteroids. We did not observe rash recurrence in 12 (75%) patients who were re-challenged. CONCLUSIONS: A maculopapular rash associated with increased blood eosinophils occurs frequently with alpelisib. While grade 3 rash leads to alpelisib therapy interruption, dermatologic improvement is evident with systemic corticosteroids; and most patients can continue oncologic treatment at a maintained or reduced dose upon re-challenge with alpelisib.
Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Toxidermias/etiologia , Exantema/induzido quimicamente , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Tiazóis/efeitos adversos , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/complicações , Relação Dose-Resposta a Droga , Toxidermias/tratamento farmacológico , Eosinofilia/induzido quimicamente , Eosinofilia/tratamento farmacológico , Exantema/tratamento farmacológico , Feminino , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Tiazóis/administração & dosagem , Tiazóis/uso terapêuticoRESUMO
In the postrituximab era, approximately half of the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation with curative intent. The Bruton tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non-germinal center (non-GC) cell of origin. We conducted a single-center phase 1 study evaluating dose-escalated ibrutinib, in a 3-by-3 design, in combination with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in physiologically transplant-eligible rel/ref DLBCL patients. Twenty-one patients have been treated and are evaluable for toxicity with no dose-limiting toxicities observed through expansion with ibrutinib at 840 mg daily at dose level 3. Of the 20 patients evaluable for response, per modern International Conference on Malignant Lymphoma criteria, 11 patients achieved complete remission (CR) and 7 patients achieved partial remission for an overall response rate of 90%. All evaluable patients with non-GC DLBCL achieved a metabolic CR. Ibrutinib in combination with R-ICE demonstrates tolerability and efficacy in rel/ref DLBCL, particularly of non-GC phenotype. This treatment program warrants further investigation in later-phase studies. This trial was registered at www.clinicaltrials.gov as #NCT02219737.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Adenina/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Piperidinas , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Indução de Remissão , Rituximab/administração & dosagem , Rituximab/efeitos adversosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Lenalidomida , Linfoma de Célula do Manto , Neoplasia Residual , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/terapia , Linfoma de Célula do Manto/patologia , Lenalidomida/uso terapêutico , Lenalidomida/administração & dosagem , Neoplasia Residual/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/administração & dosagem , Imunoterapia/métodosRESUMO
This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV + AVD, and 25 patients BV + AVD + 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events (≥grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV + AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV + AVD + ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was registered at www.clinicaltrials.gov as #NCT01868451.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Doença de Hodgkin/terapia , Adolescente , Adulto , Brentuximab Vedotin , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Doença de Hodgkin/patologia , Humanos , Imunoconjugados/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Prognóstico , Vimblastina/administração & dosagem , Adulto JovemRESUMO
The standard treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in frail elderly patients has not been established. A variation was made on rituximab (R), cyclophosphamide (C), etoposide (E), procarbazine and prednisone (P), substituting vorinostat (V) for procarbazine. Patients ≥aged 60 years with relapsed/refractory DLBCL, not candidates for autologous stem cell transplantation, were treated R-CVEP [R 375 mg/m(2) intravenously (IV), day 1; C 600 mg/m(2) IV days 1, 8: E 70 mg/m(2) IV day 1, 140 mg/m(2) days 2, 3 orally (PO); V (300 vs. 400 mg) PO and P 60 mg/m(2) PO days 1-10] every 28 d for six cycles. Quality of life (QoL) was assessed in addition to response. Thirty patients (median age 76 years, 69-88) were enrolled (one died before treatment). Maximum tolerated dose (MTD) for V was 300 mg. For 23 patients at MTD (six phase I + 17 phase II), two were discontinued for toxicity, one withdrew consent, eight achieved complete response (35%), five achieved partial response (22%) and seven progressed (25%). Median overall survival was 17·5 months. Median progression-free survival was 9·2 months. Nine patients are alive. QoL declined during treatment but improved above baseline for patients who completed treatment. In conclusion, R-CVEP was tolerated at MTD and produced durable responses with improved QoL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Cuidados Paliativos , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Dose Máxima Tolerável , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Recidiva , Rituximab , Transplante de Células-Tronco , Taxa de Sobrevida , VorinostatRESUMO
This dose-finding study evaluated safety of venetoclax plus Bendamustine-Rituximab-Ibrutinib in relapsed/refractory MCL. Six 28-day cycles were administered in a 3 + 3 dose-escalation design. Dose level 1 (DL1) included Bendamustine 90 mg/m2 on day 1-2, Rituximab 375 mg/m2 on day 1, and Ibrutinib 560 mg daily. Venetoclax was dosed with ramp-up and at 400 mg starting in Cycle 2 for 5 days. The most common adverse events were thrombocytopenia (80%), constipation (60%), and fatigue (60%). Rare hematologic grade 3-4 AEs, 1 dose-limiting toxicity at DL1 (prolonged grade 3 thrombocytopenia), and delayed hematologic toxicity were observed. DL-1 with Bendamustine dose-reduced to 70 mg/m2 (n = 3) revealed no significant toxicity. The overall and complete response rates were both 80% (8/10). This study underscored that venetoclax combined with chemoimmunotherapy is complicated by hematologic toxicity, limiting future development. Although a maximum tolerated dose was not formally established given early study closure, this study demonstrated preliminary tolerability and efficacy of Bendamustine-Rituximab-Ibrutinib-Venetoclax at DL-1.
Assuntos
Adenina/análogos & derivados , Compostos Bicíclicos Heterocíclicos com Pontes , Linfoma de Célula do Manto , Piperidinas , Sulfonamidas , Trombocitopenia , Humanos , Adulto , Rituximab , Cloridrato de BendamustinaRESUMO
Our group applied mathematical modeling to capecitabine dosing and predicted 7 days of treatment followed by 7 days of rest (7-7) would improve efficacy and minimize toxicity. The conventional schedule of capecitabine limits full dosing in combination with other agents due to toxicity. Lapatinib inhibits the tyrosine kinase of HER2 and has activity when added to conventionally scheduled capecitabine for the treatment of patients with trastuzumab-refractory, HER2-positive, metastatic breast cancer (MBC). We performed this study to evaluate the activity and tolerability of capecitabine 7-7 with lapatinib in patients with trastuzumab-refractory MBC. Eligible patients had measurable, HER2-positive, MBC that progressed following exposure to trastuzumab. Treatment consisted of capecitabine 2,000 mg orally twice daily, 7-7 and lapatinib 1,250 mg orally daily. The primary endpoint was response rate. Secondary endpoints included toxicity, progression-free survival, and stable disease ≥ 6 months. Twenty-three patients were treated on study. More than 60% had prior chemotherapy for MBC and all had prior trastuzumab. After a median of 23 weeks (range 2-96+), five patients had partial responses (23; 95 CI, 7-44%) and six (27; 95 CI, 10-48%) had stable disease ≥ 6 months. Median progression-free survival was 9.4 months. The most common treatment-related toxicities ≥ grade (gr) 2 were hand-foot syndrome (gr 2 43%; gr 3 4% gr 4 0%), diarrhea (gr 2 26%; gr 3/4 0%), elevated liver chemistries (gr 2 17%; gr 3/4 0%), and anemia (gr 2 13%; gr 3 4%; gr 4 4%). No grade ≥ 3 nausea, vomiting, or diarrhea events occurred. This study demonstrated feasibility and after meeting biostatistical requirements for continued accrual was terminated in anticipation of slow enrollment. Capecitabine 7-7 with lapatinib was well tolerated with minimal gastrointestinal toxicity. Antitumor activity was observed in patients with trastuzumab-refractory MBC.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Quinazolinas/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Lapatinib , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/uso terapêutico , Receptor ErbB-2/metabolismo , TrastuzumabRESUMO
This study evaluated ofatumumab (Ofa), an anti-CD20 monoclonal antibody, alone or with bendamustine (Benda), in transplant-ineligible patients with mantle cell lymphoma. Low-risk patients received Ofa monotherapy. Non-responders received subsequent treatment with Benda-Ofa. Six patients received Ofa monotherapy and 3 patients crossed over to Bend-Ofa. Twenty-four high-risk patients were initially treated with Benda-Ofa. The overall response rate for patients treated with Ofa monotherapy was 1/6 (17%) and 23/25 (92%) for patients treated with Benda-Ofa. With a median follow-up of 8.6 years, all Ofa patients progressed with a median progression-free survival (PFS) of 0.6 years (95% CI 0.31-NR) and remain alive. With a median follow-up of 6.3 years, Bend-Ofa treated patients had median PFS 2.5 years (95% CI 1.8-NR) and a median overall survival of 7.4 years (95% CI 5.8-NR). Benda-Ofa had a favorable adverse event profile and efficacy similar, but not clearly superior, to those reported for Benda-Rituximab.
Assuntos
Linfoma de Célula do Manto , Idoso , Humanos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/etiologiaRESUMO
PURPOSE: Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition. PATIENTS AND METHODS: We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247. RESULTS: Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance. CONCLUSIONS: BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.
Assuntos
Ácidos Nucleicos Livres , Linfoma Difuso de Grandes Células B , Linfoma de Célula do Manto , Adenina/análogos & derivados , Adulto , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Morfolinas , Fosfatidilinositol 3-Quinases , Piperidinas , Pirazóis , PirimidinasRESUMO
PURPOSE: Lynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals. EXPERIMENTAL DESIGN: A retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6, or PMS2 who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA. RESULTS: A total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor-positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response. CONCLUSIONS: A subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.
Assuntos
Neoplasias da Mama , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL/genética , Estudos RetrospectivosRESUMO
Few publications exist concerning allogeneic hematopoietic cell transplant (alloHCT) outcomes in non-Japanese patients with HTLV-1-associated ATLL. We detail the patient and disease characteristics, transplant approach, and clinical outcomes in 17 patients with ATLL at our institution who underwent alloHCT. We report favorable outcomes, with 8/17 in ongoing remission, 2/17 with prolonged (>6 years) disease-free survival, and a low incidence of transplant-related mortality (2/17). These results validate the feasibility and efficacy of alloHCT in non-Japanese patients with ATLL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Linfoma , Intervalo Livre de Doença , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/terapiaRESUMO
PURPOSE: To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma. METHODS: In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4-negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4. RESULTS: Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering-defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible. CONCLUSION: BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4-negative patients.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin/uso terapêutico , Quimiorradioterapia , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/mortalidade , Dacarbazina/uso terapêutico , Progressão da Doença , Doxorrubicina/uso terapêutico , Feminino , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Tomografia por Emissão de Pósitrons , Intervalo Livre de Progressão , Medição de Risco , Fatores de Risco , Fatores de Tempo , Estados Unidos , Vimblastina/uso terapêutico , Adulto JovemRESUMO
PURPOSE: Granulocyte-colony stimulating factor (G-CSF) was used in CALGB 9741 to support dose-dense sequential chemotherapy with doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) (Citron et al. J Clin Oncol 21:1431-1439, 2003). However, myelosuppression is not known to be dose or schedule limiting for paclitaxel. We therefore conducted this trial to determine the need for routine G-CSF, using the pegylated product (pG-CSF), support during the paclitaxel component of dose-dense sequential chemotherapy in women with early stage breast carcinoma (BC). PATIENTS AND METHODS: Eligible patients received dose-dense chemotherapy consisting of four cycles of AC followed by four cycles of P at two week intervals. pG-CSF (Neulasta) was administered after each of four cycles of AC but was held after P. Planned enrollment was 59 pts. RESULTS: Of the first 15 patients, nine completed therapy without delays due to neutropenia but 6 (40%) did not, leading to implementation of the pre-specified early termination rule. Overall, 85% of P doses were successfully delivered on time. The mean treatment delay for the entire group due to neutropenia was 0.75 days. There was no significant correlation between neutropenia and prior WBC, ANC, or concurrent treatment with trastuzumab. Pts with neutropenia tended to be younger (Mean age 43.5) and have a lower BSA (1.65 m(2)). There were no febrile episodes due to omission of pG-CSF. CONCLUSION: When paclitaxel is administered in a dose-dense fashion without growth factor support brief treatment delays are common. Further study is needed to identify the minimal pG-CSF administration that will avoid treatment delays.