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What is this summary about? This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck.How was the research done? The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL.What were the results? After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).
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Adenina , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Piperidinas , Inibidores de Proteínas Quinases , Pirazóis , Pirimidinas , Humanos , Piperidinas/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Antineoplásicos/uso terapêutico , Pirazinas/uso terapêutico , Tiazóis/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: Promotion of self-efficacy can enhance engagement with health care and treatment adherence in patients with cancer. We report the outcomes of a pilot trial of a digital health coach intervention in patients with leukemia with the aim of improving self-efficacy. METHODS: Adult patients with newly diagnosed acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) were randomized 1:1 to a digital health coach intervention or standard of care. The primary outcome of self-efficacy was measured by the Cancer Behavior Inventory (CBI) score. RESULTS: A total of 147 patients (37 AML, 110 CLL) were enrolled from July 2020 to December 2022. In the AML cohort, there was a mean increase in CBI score of 7.03 in the digital health coaching arm compared to a mean decrease of -3.57 in the control arm at 30 days (p = 0.219). There were no significant associations between the intervention and other patient-reported outcomes for patients with CLL. CONCLUSION: There were numerical, but not statistically significant increases in self-efficacy metrics in AML patients who received digital health coaching. Although this trial was underpowered due to enrollment limitations during a pandemic, digital health coaching may provide benefit to patients with hematologic malignancy and warrants further investigation.
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We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40-18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings.
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Protocolos de Quimioterapia Combinada Antineoplásica , Cladribina , Leucemia de Células Pilosas , Rituximab , Humanos , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/mortalidade , Leucemia de Células Pilosas/patologia , Cladribina/administração & dosagem , Cladribina/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Masculino , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Pessoa de Meia-Idade , Idoso , Adulto , Resultado do Tratamento , Idoso de 80 Anos ou mais , Seguimentos , Neoplasia ResidualRESUMO
Chronic lymphocytic leukemia (CLL) is a low-grade B-cell lymphoproliferative disorder. It is the most prevalent type of leukemia in the western countries, with a median age at diagnosis of 70 years. In 2023, it is estimated that there will be 18,740 new cases of CLL, and an estimated 4,490 people will die of this disease. It represents 1.0% of all new cancer cases in the U.S. The rate of new cases was 4.6 per 100,000 men and women per year based on 2016-2020 cases, age-adjusted. Death rates from CLL are higher among older adults, or those 75 and older. The death rate was 1.1 per 100,000 men and women per year based on 2016-2020 deaths, age-adjusted. A common question that patients with CLL ask during their first clinic visit is: "How long will it be before I would need treatment?" Although this might seem like a simple question, the answer is not straight forward. CLL is a heterogenous disease, with a variable clinical course. Some patients may present with an aggressive disease requiring early initiation of treatment, while others have an indolent course and some, having so called smoldering CLL, may never need treatment. The variability in disease course can make predicting disease prognosis a complicated process. This brings forth the importance of establishing prognostic models that can predict disease course, time to treatment, and survival outcomes in such a heterogenous disease. The Rai and Binet staging systems were developed in the late 1970s to early 1980s. They separated patients into different stages based on clinical characteristics and laboratory findings. These simple staging systems are still in use; however, several prognostic markers need to be added for an individualized assessment and, with the recent development of genomic techniques leading to better understanding of CLL at the molecular level, newer prognostic markers have emerged.
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PURPOSE: Compare the association of individual comorbidities, comorbidity indices, and survival in older adults with non-Hodgkin lymphoma (NHL), including in specific NHL subtypes. METHODS: Data source was SEER-Medicare, a population-based registry of adults age 65 years and older with cancer. We included all incident cases of NHL diagnosed during 2008-2017 who met study inclusion criteria. Comorbidities were classified using the three-factor risk estimate scale (TRES), Charlson comorbidity index (CCI), and National Cancer Institute (NCI) comorbidity index categories and weights. Overall survival (OS) and lymphoma-specific survival, with death from other causes treated as a competing risk, were estimated using the Kaplan-Meier method from time of diagnosis. Multivariable Cox models were constructed, and Harrel C-statistics were used to compare comorbidity models. A two-sided P value of <.05 was considered significant. RESULTS: A total of 40,486 patients with newly diagnosed NHL were included. Patients with aggressive NHL had higher rates of baseline comorbidity. Despite differences in baseline comorbidity between NHL subtypes, cardiovascular, pulmonary, diabetes, and renal comorbidities were frequent and consistently associated with OS in most NHL subtypes. These categories were used to construct a candidate comorbidity score, the non-Hodgkin lymphoma 5 (NHL-5). Comparing three validated comorbidity scores, TRES, CCI, NCI, and the novel NHL-5 score, we found similar associations with OS and lymphoma-specific survival, which was confirmed in sensitivity analyses by NHL subtypes. CONCLUSION: The optimal measure of comorbidity in NHL is unknown. Here, we demonstrate that the three-category TRES and five-category NHL-5 scores perform as well as the 14-16 category CCI and NCI scores in terms of association with OS and lymphoma-specific survival. These simple scores could be more easily used in clinical practice without prognostic loss.
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Comorbidade , Linfoma não Hodgkin , Programa de SEER , Humanos , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/mortalidade , Idoso , Masculino , Feminino , Idoso de 80 Anos ou mais , Estados Unidos/epidemiologia , Modelos de Riscos Proporcionais , Prognóstico , Estudos de Coortes , Estimativa de Kaplan-Meier , MedicareRESUMO
ABSTRACT: Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and 52%/38%, respectively. The median progression-free and overall survival estimates for the same treatment groups were 4.9/14.3 months, 14.9 months/not reached, and 3.3/9 months, respectively. CLL with del(17p) was associated with a lower complete response rate in the total cohort (odds ratio [OR] 0.15; 95% confidence interval [CI] 0.04-0.6; p=0.01) and venetoclax-naïve subgroup (OR 0.13; 95%CI 0.02-0.66; p=0.01). TP53 mutated CLL was associated with a lower complete response rate (OR 0.15; 95%CI 0.03-0.74; p=0.02) and shorter progression-free survival (hazard ratio 3.1; 95%CI 1.21-7.95; p=0.02) only in venetoclax-naïve subgroup. No other clinical or baseline characteristics, including prior venetoclax treatment for CLL, showed statistically significant association with outcomes. Grade 3-4 neutropenia and thrombocytopenia events were most frequent with intensive chemoimmunotherapy + venetoclax; grade 3-4 infection rates were similar across treatment groups. In this difficult-to-treat RT patient population, venetoclax-based combination regimens achieved high response rates, with durable remission and survival observed in a subset of patients.
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Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Linfocítica Crônica de Células B , Sulfonamidas , Humanos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Idoso , Feminino , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Adulto , Resultado do Tratamento , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Rituximab/uso terapêutico , Rituximab/administração & dosagem , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Vincristina/uso terapêuticoRESUMO
PURPOSE: This pilot study of a diet and physical activity intervention (HEALTH4CLL) was conducted to reduce fatigue and improve physical function (PF) in patients with chronic lymphocytic leukemia (CLL). METHODS: The HEALTH4CLL study used a randomized factorial design based on the multiphase optimization strategy (MOST). Patients received diet, exercise, and body weight management instructional materials plus a Fitbit and were randomized to undergo one of 16 combinations of 4 evidence-based mHealth intervention strategies over 16 weeks. Patients' fatigue, PF, health-related quality of life, behavior changes, and program satisfaction and retention were assessed. Paired t-tests were used to examine changes in outcomes from baseline to follow-up among patients. Factorial analysis of variance examined effective intervention components and their combinations regarding improvement in fatigue and PF scores. RESULTS: Among 31 patients, we observed significant improvements in fatigue (+ 11.8; t = 4.08, p = 0.001) and PF (+ 2.6; t = 2.75, p = 0.01) scores. The combination of resistance and aerobic exercise with daily self-monitoring was associated with improved fatigue scores (ß = 3.857, SE = 1.617, p = 0.027). Analysis of the individual components of the MOST design demonstrated greater improvement in the PF score with resistance plus aerobic exercise than with aerobic exercise alone (ß = 2.257, SE = 1.071, p = 0.048). CONCLUSIONS: Combined aerobic and resistance exercise and daily self-monitoring improved PF and reduced fatigue in patients with CLL. IMPLICATIONS FOR CANCER SURVIVORS: This pilot study supported the feasibility of a low-touch mHealth intervention for survivors of CLL and provided preliminary evidence that exercising, particularly resistance exercise, can improve their symptoms and quality of life.
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BACKGROUND: While the efficacy and safety of zanubrutinib have been established in relapsed or refractory chronic lymphocytic leukemia, the evidence on cost effectiveness is still lacking. OBJECTIVE: We aimed to evaluate the cost effectiveness of zanubrutinib versus ibrutinib in relapsed or refractory chronic lymphocytic leukemia from the commercial payer perspective in the USA. METHODS: A partitioned survival model was developed based on survival curves from the phase III ALPINE trial. We reconstructed patient-level data for each curve and conducted a parametric estimation to incorporate long-term clinical outcomes and treatment costs into the model. Medical costs and utilities were obtained from public data and previous cost-effectiveness studies. A discount rate of 3.0% per annum was applied and costs were adjusted to 2023 US dollars. The incremental cost-effectiveness ratio was calculated by dividing the incremental costs of zanubrutinib over ibrutinib by the incremental life-years or quality-adjusted life-years. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of the results. RESULTS: Over a 10-year analysis period, the incremental cost-effectiveness ratio of zanubrutinib versus ibrutinib was $91,260 per life-year gained and $120,634 per quality-adjusted life-year gained, making it cost effective within a threshold of $150,000 per quality-adjusted life-year gained. The incremental cost-effectiveness ratio was most sensitive to drug acquisition costs and progression-free survival distributions, and the probability of zanubrutinib being cost effective was approximately 52.8%, with a 30.0% likelihood of dominance. CONCLUSIONS: Zanubrutinib is likely to be cost effective versus ibrutinib in relapsed or refractory chronic lymphocytic leukemia in the USA, but the high threshold should be noted. Our findings may provide a basis for pricing strategy and reimbursement decisions for zanubrutinib.
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Adenina/análogos & derivados , Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Piperidinas , Pirazóis , Pirimidinas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Análise de Custo-Efetividade , Análise Custo-Benefício , Anos de Vida Ajustados por Qualidade de VidaRESUMO
WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck. HOW WAS THE RESEARCH DONE?: The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL. WHAT WERE THE RESULTS?: After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).
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Adenina/análogos & derivados , Leucemia Linfocítica Crônica de Células B , Linfoma de Células B , Pirimidinas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Piperidinas/uso terapêutico , Pirazóis/efeitos adversos , Linfoma de Células B/tratamento farmacológicoRESUMO
The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival.
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Idarubicina , Leucemia Mieloide Aguda , Humanos , Pessoa de Meia-Idade , Sorafenibe/uso terapêutico , Cladribina/uso terapêutico , Citarabina/uso terapêutico , Indução de Remissão , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMO
Chronic lymphocytic leukemia (CLL), is a hematologic malignancy characterized by the uncontrolled proliferation of mature B lymphocytes. CLL is the most prevalent leukemia in Western countries. Its presentation can range from asymptomatic with the incidental finding of absolute lymphocytosis on a routine blood test, to symptomatic disease requiring immediate intervention. Prognosis of the disease is defined by the presence or absence of specific mutations such as TP53, chromosomal abnormalities such as del(17p), a type of IGHV mutational status, and elevation of B2M and LDH. Treatment of CLL in the United States and Europe has evolved over the recent years thanks to the development of targeted therapies. The standard of care has shifted from traditional chemoimmunotherapy approaches to targeted therapies including Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors, administered either as monotherapy or in combination with CD20 monoclonal antibodies. Several clinical trials have also recently evaluated combinations of BTKi and venetoclax and showed the combination to be well tolerated and able to induce deep remissions. Targeted therapies have a good safety profile overall; however, they also have unique toxicities that are important to recognize. Diarrhea, fatigue, arthralgia, infections, cytopenias, bleeding, and cardiovascular toxicities (including atrial fibrillation, ventricular arrhythmias, and hypertension) are the adverse events (AEs) commonly associated with BTKis. Initiation of therapy with venetoclax requires close monitoring because of the risk for tumor lysis syndrome associated with this agent, particularly in patients with a high disease burden. Development of newer target therapies is ongoing and the therapeutic landscape in CLL is expanding rapidly.
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Increased rates of clinically significant bleeding have been reported with ibrutinib, however, limited data is available on the risk when given with concomitant therapeutic anticoagulation. We analyzed the incidence of major bleeding in 64 patient exposures that received ibrutinib with concomitant therapeutic anticoagulation. Major bleeding was observed in 5/64 (8%) patient exposures. The highest incidence was observed with rivaroxaban (3/17, 18%), followed by apixaban (2/35, 6%). No major bleeding events were seen with enoxaparin (n = 10). A total of 38% of patient exposures received a concomitant antiplatelet agent along with therapeutic anticoagulation. Among these patients, one (4%) experienced a fatal hemorrhage while taking ibrutinib, apixaban, and clopidogrel concomitantly. Our retrospective study observed a higher rate of major hemorrhage with combined DOAC with ibrutinib than historically reported with ibrutinib alone. This combination may be associated with increased risk of major bleeding and further prospective studies evaluating this risk are necessary.
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Anticoagulantes , Leucemia Linfocítica Crônica de Células B , Humanos , Anticoagulantes/efeitos adversos , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Incidência , Estudos Prospectivos , Estudos Retrospectivos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologiaRESUMO
Patients receiving ibrutinib for CLL rarely achieve undetectable measurable residual disease (U-MRD), necessitating indefinite therapy, with cumulative risks of treatment discontinuation due to progression or adverse events. This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥12 months (mo) and had ≥1 high risk feature (TP53 mutation and/or deletion, ATM deletion, complex karyotype or persistently elevated ß2-microglobulin). The primary endpoint was U-MRD with 10-4 sensitivity (U-MRD4) in bone marrow (BM) at 12mo. Forty-five patients were treated. On intention-to-treat analysis, 23/42 (55%) patients improved their response to CR (2 pts were in MRD + CR at venetoclax initiation). U-MRD4 at 12mo was 57%. 32/45 (71%) had U-MRD at the completion of venetoclax: 22/32 stopped ibrutinib; 10 continued ibrutinib. At a median of 41 months from venetoclax initiation, 5/45 patients have progressed; none have died from CLL or Richter Transformation. In 32 patients with BM U-MRD4, peripheral blood (PB) MRD4 was analyzed every 6 months; 10/32 have had PB MRD re-emergence at a median of 13 months post-venetoclax. In summary, the addition of venetoclax in patients treated with ≥12mo of ibrutinib achieved high rate of BM U-MRD4 and may achieve durable treatment-free remission.
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Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Adenina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes , Neoplasia Residual/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Continuous ibrutinib administration is needed to maintain efficacy in patients with chronic lymphocytic leukemia (CLL) and, as such, long-term toxicity is a concern. The authors report the 5-year follow-up of patients with CLL who received treatment with ibrutinib with a focus on hypertension and cardiovascular toxicities. METHODS: Patient characteristics were assessed, including blood pressure, cardiovascular disease, disease progression, and death. Univariate logistic regression analysis assessed the relation of patient characteristics and the development of new or worsened hypertension. The incidence of hypertensive outcomes was evaluated using competing risk. Survival was estimated using the Kaplan-Meier method. RESULTS: Three hundred patients with CLL who were treated with ibrutinib on clinical trials were included. The median patient age at study enrollment was 65 years (range, 29-83 years). Seventy percent of patients were men, and 88% were Caucasian. Sixty-nine percent of patients had hypertension at baseline, and 47% were on antihypertensive medication. Eighty-eight percent had relapsed or refractory CLL. New-onset and worsening hypertension were common, occurring in 68.5% and 38% of patients, respectively. Systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg was observed in 16.9% of patients. Hypertension was reversible after ibrutinib discontinuation. Older age, male sex, tobacco use, and chronic kidney disease were associated with ibrutinib-related hypertension. Baseline hypertension was not associated with major adverse cardiovascular events in ibrutinib-treated patients nor with event-free or overall survival. CONCLUSIONS: Hypertension is a common toxicity in patients with CLL who receive ibrutinib but is manageable in most patients. Other than chronic kidney disease, baseline cardiovascular disease did not affect ibrutinib-related hypertension nor was hypertension associated with major adverse cardiovascular events or survival. PLAIN LANGUAGE SUMMARY: Ibrutinib is an effective treatment for patients with chronic lymphocytic leukemia. Ibrutinib is a well tolerated therapy, however hypertension can develop or worsen in patients receiving ibrutinib and other cardiovascular events are significant challenges to the use of this drug. This may be particularly true in patients with heart disease. Short-term side effects may worsen heart disease, but the long-term impact is unknown. The long-term results of ibrutinib on heart disease and hypertension are described.
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Doenças Cardiovasculares , Cardiopatias , Hipertensão , Leucemia Linfocítica Crônica de Células B , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Resultado do Tratamento , Hipertensão/induzido quimicamente , Hipertensão/epidemiologia , Hipertensão/tratamento farmacológico , Cardiopatias/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
OBJECTIVE: Examine physical function and T-cell phenotype in patients with chronic lymphocytic leukemia (CLL) before and after a physical activity (PA) intervention. METHODS: Physical function measures and blood samples were collected from CLL patients (Rai stage 0-4, 50% receiving targeted therapy, N = 24) enrolled in a 16-week intervention of at-home aerobic and/or resistance exercise. Flow cytometry characterized T-cells in cryopreserved peripheral blood cells. Wilcoxon signed-rank test compared physical function and T-cell phenotype at baseline and 16-weeks; Kendall's Tau assessed associations between variables. RESULTS: Godin leisure-time PA score increased from baseline to 16-weeks (mean difference: 14.61, p < .01) and fatigue decreased (mean difference: 6.71, p < .001). At baseline, lower fatigue correlated with a lower proportion of CD8+ T-cells (τ = 0.32, p = .03) and cardiorespiratory fitness (CRF) inversely correlated with the percentage of PD-1+CD8+ T-cells (τ -0.31, p = .03). At 16-weeks, CRF inversely correlated with the proportion of PD-1+CD4+ T-cells (τ -0.34, p = .02). Reduced fatigue at 16-weeks correlated with an increased CD4:CD8 ratio (τ = 0.36, p = .02) and lower percentage of HLA-DR+PD-1+CD4+ T-cells (τ = -0.37, p = .01). CONCLUSIONS: This intervention increased leisure-time PA and decreased fatigue in CLL patients. These changes correlated with an increased CD4:CD8 T-cell ratio and reduced proportion of T-cells subsets previously associated with poor outcomes in CLL patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02194387.
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Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/terapia , Projetos Piloto , Receptor de Morte Celular Programada 1 , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Fadiga/etiologiaRESUMO
Integrated clinicopathological and molecular analyses of Richter transformation of diffuse large B-cell lymphoma subtype (RT-DLBCL) cases remain limited. This study group included 142 patients with RT-DLBCL. Morphological evaluation and immunophenotyping, using immunohistochemistry and/or multicolour flow cytometry, were performed. The results of conventional karyotyping, fluorescence in situ hybridisation analysis and mutation profiling performed using next generation sequencing were reviewed. Patients included 91 (64.1%) men and 51 (35.9%) women with a median age of 65.4 years (range 25.4-84.9 years) at the time of RT-DLBCL diagnosis. Patients had CLL for a median of 49.5 months (range 0-330 months) before onset of RT-DLBCL. Most cases (97.2%) of RT-DLBCL had immunoblastic (IB) morphology, the remainder had a high grade morphology. The most commonly expressed markers included: CD19 (100%), PAX5 (100%), BCL2 (97.5%), LEF1 (94.7%), CD22 (90.2%), CD5 (88.6%), CD20 (85.7%), CD38 (83.5%), MUM1 (83.3%), CD23 (77%) and MYC (46.3%). Most (51/65, 78.4%) cases had a non-germinal centre B-cell immunophenotype. MYC rearrangement was detected in 9/47 (19.1%) cases, BCL2 rearrangement was detected in 5/22 (22.7%) cases, and BCL6 rearrangement was detected in 2/15 (13.3%) cases. In comparison to CLL, RT-DLBCL had higher numbers of alterations involving chromosomes 6, 17, 21, and 22. The most common mutations detected in RT-DLBCL involved TP53 (9/14, 64.3%), NOTCH1 (4/14, 28.6%) and ATM (3/14, 21.4%). Among RT-DLBCL cases with mutant TP53, 5/8 (62.5%) had TP53 copy number loss, and among those, such loss was detected in the CLL phase of the disease in 4/8 (50%) cases. There was no significant difference in overall survival (OS) between patients with germinal centre B-cell (GCB) and non-GCB RT-DLBCL. Only CD5 expression correlated significantly with OS (HR=2.732; 95% CI 1.397-5.345; p=0.0374). RT-DLBCL has distinctive morphological and immunophenotypic features, characterised by IB morphology and common expression of CD5, MUM1 and LEF1. Cell-of-origin does not seem to have prognostic implications in RT-DLBCL.
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Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Masculino , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Imunofenotipagem , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , GenômicaAssuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas Tirosina Quinases , Benzamidas/efeitos adversos , Pirazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
For patients with non-Hodgkin lymphoma (NHL), formal comorbidity assessment is recommended but is rarely conducted in routine practice. A simple, validated measure of comorbidities that standardizes their assessment could improve adherence to guidelines. We previously constructed the 3-factor risk estimate scale (TRES) among patients with chronic lymphocytic leukemia (CLL). Here, we investigated TRES in multiple NHL subtypes. In the surveillance, epidemiology, and end results-Medicare database, patients with NHL diagnosed from 2008 to 2017 were included. Upper gastrointestinal, endocrine, and vascular comorbidities were identified using ICD-9/ICD-10 codes to assign TRES scores. Patient characteristic distributions were compared using χ2 or t test. Association of mortality and TRES score was assessed using Kaplan-Meier and multivariable Cox regression model for competing risk. A total of 40 486 patients were included in the study. Median age was 77 years (interquartile range [IQR], 71-83 years). The most frequent NHL subtypes were CLL (28.2%), diffuse large B-cell (27.6%), and follicular lymphoma (12.6%). Median follow-up was 33 months (IQR, 13-60 months). TRES was low, intermediate, and high in 40.8%, 37.0%, and 22.2% of patients, corresponding to median overall survival (OS) of 8.2, 5.3, and 2.9 years (P < .001), respectively. TRES was associated with OS in all NHL subtypes. In multivariable models, TRES was associated with inferior OS and NHL-specific survival. TRES is clinically translatable and associated with OS and lymphoma-specific survival in older adults with NHL.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma Folicular , Linfoma não Hodgkin , Humanos , Idoso , Estados Unidos/epidemiologia , Idoso de 80 Anos ou mais , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/epidemiologia , Medicare , Linfoma não Hodgkin/epidemiologia , ComorbidadeAssuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Humanos , Crise Blástica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/diagnóstico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
PURPOSE: Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities. PATIENTS AND METHODS: ALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled. RESULTS: Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib. CONCLUSION: Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.