RESUMEN
Hairy cell leukemia (HCL) is a rare hematologic disorder characterized by pancytopenia and splenomegaly for which a single course of cladribine is highly effective in inducing complete remissions. However, there is limited real-world data on outcomes and complications among geriatric patients with HCL treated with cladribine. We conducted a retrospective review of all patients 70 years or older within the Scripps Clinic HCL Database at the time of first treatment with cladribine. Of the 45 patients meeting inclusion criteria, 32 (71%) achieved CR and 4 (9%) achieved PR. Of the 9 remaining patients, 7 achieved normalization of peripheral blood counts after a single course of cladribine (complete hematologic response, CHR) and 2 had no response. The median duration of response for all responders was 119 months. Nine (20%) patients relapsed with a median time to first relapse of 28 months. Ten patients subsequently developed 12 primary malignancies with an excess frequency (observed-to-expected ratio) of 0.85 (95% confidence interval, 0.48-1.49). Median overall survival for the entire cohort was 166 months from time of HCL diagnosis and 119 months from time of first cladribine administration. Forty patient deaths were observed; the standardized mortality ratio (observed-to-expected ratio) was 1.42 (95% confidence interval, 1.03-1.96), representing a statistically significant increase in the risk of death (P = .03). This study supports the high rate of complete and durable responses following a single course of cladribine in geriatric patients.
Asunto(s)
Antineoplásicos , Leucemia de Células Pilosas , Anciano , Antineoplásicos/uso terapéutico , Cladribina/uso terapéutico , Humanos , Leucemia de Células Pilosas/patología , Inducción de Remisión , Estudios RetrospectivosRESUMEN
Hairy cell leukemia (HCL) is a rare, indolent B-cell disorder in which single courses of cladribine induce high rates of complete responses. We report on 88 young HCL patients (≤40 years of age at diagnosis) treated with cladribine from the Scripps Clinic HCL Database, of whom 83 were evaluable for response. Seventy-three patients (88%) achieved an initial complete response and 10 (12%) a partial response, with a median response duration of 57 months. Forty-eight patients (58%) relapsed, with a median time to first relapse for all responders of 54 months. Eight patients developed 11 second primary malignancies with an excess frequency of 1.60 (95% confidence interval, 0.80-2.89). Thirteen (15%) patients died with a mortality ratio compared with age-matched normals of 1.85 (95% confidence interval, 1.07-3.18). Median overall survival for all patients following the first cladribine course was 231 months, and 251 months from diagnosis. Single courses of cladribine induce high rates of complete and durable responses in the majority of young HCL patients and are therefore recommended for HCL patients regardless of age.
Asunto(s)
Antineoplásicos/uso terapéutico , Cladribina/uso terapéutico , Leucemia de Células Pilosas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Cladribina/efectos adversos , Femenino , Humanos , Leucemia de Células Pilosas/mortalidad , Leucemia de Células Pilosas/terapia , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/etiología , Recurrencia , Inducción de Remisión , Retratamiento , Resultado del Tratamiento , Adulto JovenRESUMEN
Acute leukemia is a particularly problematic collection of hematological cancers, and, while somewhat rare, the survival rate of patients is typically abysmal without bone marrow transplantation. Furthermore, traditional chemotherapies used as standard-of-care for patients cause significant side effects. Understanding the evolution of leukemia to identify novel targets and, therefore, drug treatment regimens is a significant medical need. Genomic rearrangements and other structural variations (SVs) have long been known to be causative and pathogenic in multiple types of cancer, including leukemia. These SVs may be involved in cancer initiation, progression, clonal evolution, and drug resistance, and a better understanding of SVs from individual patients may help guide therapeutic options. Here, we show the utilization of optical genome mapping (OGM) to detect known and novel SVs in the samples of patients with leukemia. Importantly, this technology provides an unprecedented level of granularity and quantitation unavailable to other current techniques and allows for the unbiased detection of novel SVs, which may be relevant to disease pathogenesis and/or drug resistance. Coupled with the chemosensitivities of these samples to FDA-approved oncology drugs, we show how an impartial integrative analysis of these diverse datasets can be used to associate the detected genomic rearrangements with multiple drug sensitivity profiles. Indeed, an insertion in the gene MUSK is shown to be associated with increased sensitivity to the clinically relevant agent Idarubicin, while partial tandem duplication events in the KMT2A gene are related to the efficacy of another frontline treatment, Cytarabine.
RESUMEN
Cladribine induces protracted remissions in patients with hairy cell leukemia (HCL). However, many long-term responders ultimately relapse. We sought to determine whether long-term complete responders subsequent to a single 7-day course of cladribine were without minimal residual disease (MRD) and potentially cured of HCL. From the 358-person Scripps Clinic cladribine database, we identified 19 patients in continuous and complete hematologic response (median age, 75 years; median time from diagnosis, 18 years; and median time from cladribine, 16 years). Nine of 19 (47%) patient samples had no evidence of residual disease; 7 of 19 (37%) samples had MRD; and 3 of 19 (16%) had morphologic evidence of HCL in hematoxylin and eosin-stained bone marrow sections. These results indicate that HCL is potentially curable after cladribine treatment. In addition, patients with MRD and even gross morphologic disease can live many years without manifesting hematologic relapses.
Asunto(s)
Cladribina/administración & dosificación , Leucemia de Células Pilosas/tratamiento farmacológico , Leucemia de Células Pilosas/prevención & control , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Ensayos Clínicos Fase II como Asunto , Bases de Datos Factuales , Esquema de Medicación , Femenino , Humanos , Leucemia de Células Pilosas/patología , Masculino , Persona de Mediana Edad , Neoplasia Residual , Inducción de Remisión/métodos , Estudios Retrospectivos , Sobrevivientes , Factores de Tiempo , Resultado del TratamientoRESUMEN
Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we find that increased abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patient specimens correlates with poor prognosis. RNF5 inhibition decreases AML cell growth in culture, in patient-derived xenograft (PDX) samples and in vivo, and delays development of MLL-AF9-driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition causes transcriptional changes that overlap with those seen upon histone deacetylase (HDAC)1 inhibition. RNF5 induces the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment to and subsequent epigenetic regulation of genes involved in AML maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhances AML cell sensitivity to HDAC inhibitors. Notably, low expression of both RNF5 and HDAC coincides with a favorable prognosis. Our studies identify an ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML, and highlight RNF5/RBBP4 as markers useful to stratify patients for treatment with HDAC inhibitors.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Inhibidores de Histona Desacetilasas/farmacología , Leucemia Mieloide/genética , Ubiquitina-Proteína Ligasas/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Enfermedad Aguda , Animales , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Células HEK293 , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Células U937 , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
PURPOSE: Hairy cell leukemia (HCL) is an uncommon, indolent, chronic B-cell lymphoproliferative disorder involving the marrow and spleen. Therapy for HCL includes splenectomy, interferon alfa-2a and alfa-2b, pentostatin, and cladribine. The purpose of this article was to report the extended follow-up of HCL patients treated with cladribine. PATIENTS AND METHODS: Two hundred nine patients with HCL who were treated with cladribine had at least 7 years of follow-up. A course of cladribine constituted a 7-day continuous intravenous infusion at a dose of 0.1 mg/kg/d. RESULTS: Of the 207 assessable patients who had at least 7 years of follow-up, 196 (95%) achieved a complete response (CR) and 11 (5%) achieved a partial response (PR) after a single course of cladribine (overall response rate, 100%). The median first-response duration for all responders was 98 months. Seventy-six patients (37%) experienced relapse after their first course of cladribine. The median time to first relapse for all responders was 42 months. Time to treatment failure of CRs compared with PRs was statistically significant (P <.0005). The overall survival rate was 97% recorded at 108 months. Forty-seven patients developed 58 second malignancies. The observed-to-expected ratio for second malignancies was 2.03 (95% confidence interval, 1.49 to 2.71). CONCLUSION: These results confirm previous observations that single courses of cladribine administered to patients with HCL induce high response rates, the majority of which are CRs. Most patients enjoy long-lasting complete remissions, and those patients who experience relapse can be successfully re-treated with cladribine.