RESUMEN
Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.
Asunto(s)
Anemia de Diamond-Blackfan , Benzoatos , Hidrazinas , Pirazoles , Humanos , Anemia de Diamond-Blackfan/tratamiento farmacológico , Pirazoles/uso terapéutico , Hidrazinas/uso terapéutico , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Benzoatos/uso terapéutico , Benzoatos/administración & dosificación , Benzoatos/efectos adversos , Adulto , Masculino , Femenino , Niño , Adolescente , Persona de Mediana Edad , Adulto Joven , Preescolar , Proyectos Piloto , Resultado del Tratamiento , Receptores de Trombopoyetina/agonistas , Recurrencia , Eritropoyesis/efectos de los fármacosRESUMEN
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 , VacunaciónRESUMEN
Patients with severe aplastic anaemia (SAA) are often not vaccinated against viruses due to concerns of ineffective protective antibody response and potential for pathogenic global immune system activation, leading to relapse. We evaluated the impact of COVID-19 vaccination on haematological indices and disease status and characterized the humoural and cellular responses to vaccination in 50 SAA patients, who were previously treated with immunosuppressive therapy (IST). There was no significant difference in haemoglobin (p = 0.52), platelet count (p = 0.67), absolute lymphocyte (p = 0.42) and neutrophil (p = 0.98) counts prior to and after completion of vaccination series. Relapse after vaccination, defined as a progressive decline in counts requiring treatment, occurred in three patients (6%). Humoural response was detectable in 90% (28/31) of cases by reduction in an in-vitro Angiotensin II Converting Enzyme (ACE2) binding and neutralization assay, even in patients receiving ciclosporin (10/11, 90.1%). Comparison of spike-specific T-cell responses in 27 SAA patients and 10 control subjects revealed qualitatively similar CD4+ Th1-dominant responses to vaccination. There was no difference in CD4+ (p = 0.77) or CD8+ (p = 0.74) T-cell responses between patients on or off ciclosporin therapy at the time of vaccination. Our data highlight appropriate humoural and cellular responses in SAA previously treated with IST and true relapse after vaccination is rare.
Asunto(s)
Anemia Aplásica , COVID-19 , Humanos , Anemia Aplásica/tratamiento farmacológico , Ciclosporina/uso terapéutico , Vacunas contra la COVID-19/uso terapéutico , SARS-CoV-2 , Inmunosupresores/uso terapéutico , COVID-19/prevención & control , Recurrencia , Inmunidad , VacunaciónRESUMEN
Various approaches have been developed for ex vivo T cell depletion in allogeneic stem cell transplantation to prevent graft-versus-host disease (GVHD). Direct comparisons of T cell depletion strategies have not been well studied, however. We evaluated cellular and plasma biomarkers in 2 different graft manipulation strategies, CD3+CD19+ cell depletion (CD3/19D) versus CD34+ selection (CD34S), and their associations with clinical outcomes. Identical conditions, including the myeloablative preparative regimen, HLA-identical sibling donor, GVHD prophylaxis, and graft source, were used in the 2 cohorts. Major clinical outcomes were similar in the 2 groups in terms of overall survival, nonrelapse mortality, and cumulative incidence of relapse; however, the cumulative incidence of acute GVHD trended to be higher in the CD3/19D cohort compared with the CD34S cohort. A distinct biomarker profile was noted in the CD3/19D cohort: higher levels of ST2, impaired Helios- FoxP3+Treg reconstitution, and rapid reconstitution of naïve, Th2, and Th17 CD4 cells in the early post-transplantation period. In vitro graft replication studies confirmed that CD3/19D disproportionately depleted Tregs and other CD4 subset repertoires in the graft. This study confirms the utility of biomarker monitoring, which can be directly correlated with biological consequences and possible future therapeutic indications.
Asunto(s)
Antígenos CD19/inmunología , Antígenos CD34/inmunología , Neoplasias Hematológicas , Depleción Linfocítica , Trasplante de Células Madre de Sangre Periférica , Hermanos , Linfocitos T Colaboradores-Inductores/inmunología , Donantes de Tejidos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Aloinjertos , Niño , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosAsunto(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 & derivadosRESUMEN
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 SintéticasRESUMEN
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 TratamientoRESUMEN
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 adversosRESUMEN
Patients with high risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) are commonly older with multiple co-morbidities, rendering them unsuitable for intensive induction chemotherapy or transplantation. We report preliminary cellular immune profiling of four cases receiving sequential clofarabine and lenalidomide for high risk MDS and AML in a phase I study. Our results highlight the potential of immune profiling for monitoring immune-modifying agents in high risk MDS and AML.
RESUMEN
Although there are now fewer allo-SCTs performed for CML, leukemic relapse post transplant remains a persistent problem. To better define clinical and biological parameters determining postrelapse outcome, we studied 59 patients with CML relapsing after HLA-identical sibling allo-SCT between 1993 and 2008. Eighteen (30.5%) were transplanted in advanced phase and 41 (69.5%) in chronic phase. With a median follow-up from relapse of 7.9 years, 5-year post relapse survival (PRS) was 62%. Multivariate analysis found disease status at transplant, time to diagnosis of relapse from transplant and pretransplant tyrosine kinase inhibitor (TKI) use as significant factors associated with PRS. Analysis of BCR-ABL transcript expression in the hematopoietic progenitor compartment was performed in 36 patients (22 relapsed, 8 non-relapsed and 6 TKI alone controls). Patients with BCR-ABL expression in their early hematopoietic stem cell compartment (Lineage(-)CD34(+)CD38(-)CD90(+)) had worse survival irrespective of the disease status. We conclude that disease status remains the strongest clinical prognostic factor for PRS in CML following allo-SCT. The persistence of BCR-ABL expression in the progenitor cell compartment in some patients after SCT emphasizes the need to target CML-leukemia stem cells.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adulto , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
We describe the safety and immunogenicity of a combined vaccine of 2 leukemia-associated antigenic peptides, PR1 and WT1. Eight patients with myeloid malignancies received one subcutaneous dose each of PR1 and WT1 vaccines in Montanide adjuvant, with granulocyte-macrophage colony-stimulating factor. Patients were reviewed weekly for 4 weeks to monitor toxicity and immunologic responses. Toxicity was limited to grades 1 to 2. Using peptide/HLA-A 0201 tetramers and intracellular interferon-gamma staining, CD8(+) T cells against PR1 or WT1 were detected in 8 of 8 patients after a single vaccination. To monitor the kinetics of vaccine-induced CD8(+) T-cell responses and disease regression after vaccination, absolute PR1 and WT1(+)CD8(+) T-cell numbers and WT1 expression were studied weekly after vaccination. Responses occurred as early as 1 week after vaccination. After vaccination, the emergence of PR1 or WT1(+)CD8(+) T cells was associated with a decrease in WT1 mRNA expression as a marker of minimal residual disease, suggesting a vaccine-driven antileukemia effect. Conversely, loss of response was associated with reappearance of WT1 transcripts (P < .01). This is the first demonstration that a combined PR1 and WT1 vaccine is immunogenic. These results support further studies of combination immunization strategies in leukemia patients.