RESUMEN

B-cell targeted therapies, including anti-CD20 monoclonal antibodies (mAb) and Bruton's tyrosine kinase inhibitors (BTKi), further suppress antibody (Ab) response to vaccines in patients with chronic lymphocytic leukemia (CLL). We conducted a prospective cohort study of SARS-CoV-2 vaccination in 81 CLL patients receiving BTKi (n = 54), venetoclax (VEN, n = 9), or who were treatment naïve (TN, n = 18). Anti-spike Ab were detected in 53% of patients on BTKi post-primary series and 84% post-booster, 57% of patients on VEN post-primary series and 50% post-booster, and 67% of TN patients post-primary series and 87% post-booster. T-cell response to the primary series was independent of Ab response. At the time of booster, 12 patients interrupted BTKi (median 21 d, range 8-22) and 33 continued BTKi. Among patients with detectable Ab post-booster, those who interrupted BTKi (n = 10) had significantly higher Ab titers (median 7149 units/mL) compared with patients who continued BTKi (n = 27, median 2071 units/mL, p = .04).

Asunto(s)

Vacunas contra la COVID-19 , COVID-19 , Leucemia Linfocítica Crónica de Células B , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , SARS-CoV-2 , Vacunación , Interrupción del Tratamiento

RESUMEN

Vaccinations effectively prevent infections; however, patients with chronic lymphocytic leukemia (CLL) have reduced antibody responses following vaccinations. Combined humoral and cellular immune responses to novel adjuvanted vaccines are not well characterized in CLL. In an open-label, single-arm clinical trial, we measured the humoral and cellular immunogenicity of the recombinant zoster vaccine (RZV) in CLL patients who were treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitor (BTKi) therapy. The primary endpoint was antibody response to RZV (≥fourfold increase in anti-glycoprotein E [anti-gE]). Cellular response of gE-specific CD4+ T cells was assessed by flow cytometry for upregulation of ≥2 effector molecules. The antibody response rate was significantly higher in the TN cohort (76.8%; 95% confidence interval [CI], 65.7-87.8) compared with patients receiving a BTKi (40.0%; 95% CI, 26.4-53.6; P = .0002). The cellular response rate was also significantly higher in the TN cohort (70.0%; 95% CI, 57.3-82.7) compared with the BTKi group (41.3%; 95% CI, 27.1-55.5; P = .0072). A concordant positive humoral and cellular immune response was observed in 69.1% (95% CI, 56.9-81.3) of subjects with a humoral response, whereas 39.0% (95% CI, 24.1-54.0) of subjects without a humoral response attained a cellular immune response (P = .0033). Antibody titers and T-cell responses were not correlated with age, absolute B- and T-cell counts, or serum immunoglobulin levels (all P > .05). RZV induced both humoral and cellular immune responses in treated and untreated CLL patients, albeit with lower response rates in patients on BTKi therapy compared with TN patients. This trial was registered at www.clinicaltrials.gov as #NCT03702231.

Asunto(s)

Vacuna contra el Herpes Zóster , Herpes Zóster , Leucemia Linfocítica Crónica de Células B , Herpes Zóster/inducido químicamente , Herpes Zóster/tratamiento farmacológico , Herpes Zóster/prevención & control , Vacuna contra el Herpes Zóster/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Vacunas Sintéticas

Asunto(s)

Vacunas contra la COVID-19/uso terapéutico , COVID-19/complicaciones , COVID-19/prevención & control , Enfermedades Hematológicas/complicaciones , COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Enfermedades Hematológicas/inmunología , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/inmunología , Humanos , Inmunogenicidad Vacunal , SARS-CoV-2/inmunología

RESUMEN

High-risk cytogenetics and minimal residual disease (MRD) after chemoimmunotherapy (CIT) predict unfavorable outcome in chronic lymphocytic leukemia (CLL). This phase 2 study investigated risk-adapted CIT in treatment-naïve CLL (NCT01145209). Patients with high-risk cytogenetics received induction with fludarabine, cyclophosphamide, and ofatumumab. Those without high-risk cytogenetics received fludarabine and ofatumumab. After induction, MRD positive (MRD+) patients received 4 doses of ofatumumab consolidation. MRD negative (MRD-) patients had no intervention. Of 28 evaluable for response, all responded to induction and 10 (36%) achieved MRD-. Two-year progression-free survival (PFS) was 71.4% (CI95, 56.5-90.3%). There was no significant difference in median PFS between the high-risk and the standard-risk groups. Ofatumumab consolidation didn't convert MRD + to MRD-. In the MRD + group, we saw selective loss of CD20 antigens during therapy. In conclusion, risk-adapted CIT is feasible in treatment-naïve CLL. Ofatumumab consolidation didn't improve depth of response in MRD + patients. Loss of targetable CD20 likely reduces efficacy of consolidation therapy.

Asunto(s)

Leucemia Linfocítica Crónica de Células B , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Inmunoterapia , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Resultado del Tratamiento

RESUMEN

Vaccinations are effective in preventing infections; however, it is unknown if patients with chronic lymphocytic leukemia (CLL) who are treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitors (BTKi's) respond to novel adjuvanted vaccines. Understanding the effect of BTKi's on humoral immunity is timely because BTKi's are widely used and vaccination against coronavirus disease 2019 is urgently needed. In 2 open-label, single-arm clinical trials, we measured the effect of BTKi's on de novo immune response against recombinant hepatitis B vaccine (HepB-CpG) and recall response against recombinant zoster vaccine (RZV) in CLL patients who were TN or on BTKi. The primary end point was serologic response to HepB-CpG (anti-hepatitis B surface antibodies ≥10 mIU/mL) and RZV (≥fourfold increase in anti-glycoprotein E). The response rate to HepB-CpG was lower in patients on BTKi (3.8%; 95% confidence interval [CI], 0.7-18.9) than patients who were TN (28.1%; 95% CI, 15.6-45.4; P = .017). In contrast, the response rate to RZV did not differ significantly between the BTKi (41.5%; 95% CI, 27.8-56.6) and TN cohorts (59.1%; 95% CI, 38.7-76.7; P = .2). BTKi's were associated with a decreased de novo immune response following HepB-CpG, whereas recall immune response following RZV was not significantly affected by BTKi therapy. These trials were registered at www.clinicaltrials.gov as #NCT03685708 (Hep-CpG) and #NCT03702231 (RZV).

Asunto(s)

Vacunas contra Hepatitis B/inmunología , Vacuna contra el Herpes Zóster/inmunología , Inmunidad , Leucemia Linfocítica Crónica de Células B/inmunología , Inhibidores de Proteínas Quinasas/efectos adversos , Vacunas Sintéticas/inmunología , Adyuvantes Inmunológicos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Anciano , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Evaluación del Resultado de la Atención al Paciente , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Vacunación

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Linfocítica Crónica de Células B , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/análogos & derivados , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados

RESUMEN

Immune dysregulation in chronic lymphocytic leukemia (CLL) contributes to a high rate of infections and morbidity. The Bruton tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib mark major breakthroughs in the treatment of CLL, however many patients require long-term therapy with these agents. Despite receiving effective therapy for CLL, patients on BTK inhibitors remain immunocompromised and at risk of infectious complications. We previously reported that treatment of CLL with ibrutinib leads to partial reconstitution of humoral immunity and fewer infections during the first two years of therapy. It is currently unclear whether the positive effects of ibrutinib on the immune system are sustained during long-term therapy. Acalabrutinib is a newer, more selective BTK inhibitor than ibrutinib; however a detailed evaluation of the immunologic impact of acalabrutinib therapy is lacking. Herein, utilizing two independent trials, we assessed the immunological effects and infectious risk of ibrutinib and acalabrutinib treatment in patients with CLL.

Asunto(s)

Leucemia Linfocítica Crónica de Células B , Humanos , Inmunidad Humoral , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Pirimidinas/efectos adversos

RESUMEN

Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval [CI], 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. This trial was registered at www.clinicaltrials.gov as #NCT02337829.

Asunto(s)

Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/biosíntesis , Agammaglobulinemia Tirosina Quinasa/genética , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Esquema de Medicación , Inducción Enzimática , Femenino , Cefalea/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Dolor/inducido químicamente , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , RNA-Seq , Transcriptoma , Resultado del Tratamiento

RESUMEN

Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Inmunosupresores/farmacología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Microambiente Tumoral/efectos de los fármacos , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/inmunología , Autoinmunidad/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Comunicación Celular/efectos de los fármacos , Humanos , Inmunosupresores/uso terapéutico , Infecciones/inducido químicamente , Infecciones/epidemiología , Infecciones/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Piperidinas , Inhibidores de Proteínas Quinasas/uso terapéutico , Purinas/farmacología , Purinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Quinazolinonas/farmacología , Quinazolinonas/uso terapéutico , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Resultado del Tratamiento , Microambiente Tumoral/inmunología

Asunto(s)

Bloqueo del Plexo Braquial/efectos adversos , Parálisis/etiología , Enfermedades del Sistema Nervioso Periférico/etiología , Nervio Frénico , Anciano , Humanos , Masculino

RESUMEN

Lysozyme amyloidosis is an exceedingly rare hereditary autosomal dominant amyloidosis, which is characterized by the precipitation of lysozyme protein within the body, leading to multi-organ dysfunction. Herein, we present the case of a U.S. family affected by lysozyme amyloidosis. In particular, we report pericardial disease involvement leading to recurrent pericardial effusion, which to our knowledge has not been described yet. To our knowledge, we have also for the first time identified the amyloidogenic component of lysozyme amyloidosis via laser microdissection and mass spectrometry from a bone marrow biopsy. The diagnosis of this disease remains challenging as it can be easily mistaken for primary amyloidosis, which also presents with similar symptoms. Immunohistochemical staining of tissue for specific amyloidogenic proteins allows for an accurate diagnosis and should be performed in all amyloidosis patients in order to spare patients from potentially futile or harmful therapy. The widespread systemic involvement of lysozyme amyloidosis currently provides limited options for treatment, although kidney and/or liver transplantation appear to be promising palliative treatments. Practicing clinicians and researchers need to collect more information about this rare entity to further characterize the behavior of this disease and develop new potential treatment strategies.