RESUMO
ABSTRACT: Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as #ISRCTN32667607.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Transtornos Linfoproliferativos , Piperidinas , Rituximab , Humanos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Piperidinas/administração & dosagem , Pessoa de Meia-Idade , Feminino , Masculino , Adenina/análogos & derivados , Adenina/uso terapêutico , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Idoso , Adulto , Rituximab/efeitos adversos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Órgãos/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Ciclofosfamida/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Estudos Prospectivos , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagemAssuntos
Biomarcadores Tumorais/análise , Linfoma Difuso de Grandes Células B/química , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-myc/análise , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Estudos Retrospectivos , Fatores de Tempo , Translocação GenéticaRESUMO
Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation-specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Linfocítica Crônica de Células B , Linfoma Folicular , Doença Enxerto-Hospedeiro/etiologia , Humanos , Leucemia Linfocítica Crônica de Células B/terapia , Estudos RetrospectivosRESUMO
Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.
Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Humanos , Recidiva , Sulfonamidas/farmacologiaRESUMO
Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi-centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre-National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1-15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3-kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi-exposed patients, 92% (CR 38%) in Pi3Ki-exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow-up of 15·6 months, 1-year progression-free survival was 65·0% and 1-year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression-free or discontinuation-free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes.
Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido/epidemiologiaAssuntos
Neoplasias Encefálicas , Plasmócitos , Linfoma Plasmablástico , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Feminino , Humanos , Plasmócitos/metabolismo , Plasmócitos/patologia , Linfoma Plasmablástico/diagnóstico por imagem , Linfoma Plasmablástico/metabolismo , Linfoma Plasmablástico/patologia , Linfoma Plasmablástico/terapiaAssuntos
Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Purinas/administração & dosagem , Quinazolinonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de Sobrevida , Reino Unido/epidemiologiaRESUMO
Relapsed or refractory classical Hodgkin lymphoma (cHL) is associated with a poor outcome when standard chemotherapy fails. Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate licensed for use at relapse after autologous stem cell transplant (ASCT) or following two prior therapies in those unsuitable for ASCT. There are limited data assessing the ability of BV to enable curative SCT. We performed a UK-wide retrospective study of 99 SCT-naïve relapsed/refractory cHL. All had received 2 prior lines and were deemed fit for transplant but had an insufficient remission to proceed. The median age was 32 years. Most had nodular sclerosis subtype, Eastern Cooperative Oncology Group performance status 0-1 and advanced stage disease. The median progression-free survival (PFS) was 5·6 months and median overall survival (OS) was 37·2 months. The overall response rate was 56% (29% complete response; 27% partial response). 61% reached SCT: 34% immediately post-BV and 27% following an inadequate BV response but were salvaged and underwent deferred SCT. Patients consolidated with SCT had a superior PFS and OS to those not receiving SCT (P < 0·001). BV is an effective, non-toxic bridge to immediate SCT in 34% and deferred SCT in 27%. 39% never reached SCT with a PFS of 3·0 months, demonstrating the unmet need to improve outcomes in those unsuitable for SCT post-BV.
Assuntos
Antineoplásicos/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Imunoconjugados/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin , Contraindicações , Progressão da Doença , Feminino , Humanos , Imunoconjugados/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Terapia de Salvação/métodos , Transplante de Células-Tronco , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemAssuntos
Neoplasias Duodenais/complicações , Neoplasias Esofágicas/complicações , Sarcoma Histiocítico/complicações , Neoplasias Primárias Múltiplas/complicações , Neoplasias Gástricas/complicações , Redução de Peso , Adulto , Anemia/etiologia , Transtornos de Deglutição/etiologia , Endoscopia Gastrointestinal , Evolução Fatal , Humanos , Metástase Linfática , Masculino , SudoreseRESUMO
Lenalidomide is an immunomodulatory agent with activity in a range of haematological cancers including chronic lymphocytic leukaemia (CLL). However, major questions remain concerning its effectiveness in patients with T-cell depletion or deletion of TP53 on chromosome 17p. This case report provides insight into these questions by showing that lenalidomide/dexamethasone in combination can be highly effective as induction therapy for refractory 17p-CLL, that remission quality can be improved by subsequent maintenance with lenalidomide alone and that the anti-leukaemic effects of lenalidomide and its stimulatory effects on non-malignant B cells are preserved despite prolonged T-cell depletion resulting from prior alemtuzumab/methylprednisolone.