RESUMEN
Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.
Asunto(s)
Adenina/análogos & derivados , Leucemia de Células Pilosas/tratamiento farmacológico , Leucemia de Células Pilosas/mortalidad , Piperidinas/administración & dosificación , Adenina/administración & dosificación , Adenina/efectos adversos , Administración Oral , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Piperidinas/efectos adversos , Tasa de SupervivenciaRESUMEN
PURPOSE OF REVIEW: This article summarizes the current state of knowledge of hairy cell leukemia (HCL) regarding presentation, diagnosis, therapy, and monitoring, including perspectives on emergent therapies. RECENT FINDINGS: Over the past decade, there has been enormous progress in the understanding of the biology of HCL which has led to the development of novel therapeutic strategies. The maturation of data regarding existing management strategies has also lent considerable insight into therapeutic outcomes and prognosis of patients treated with chemo- or chemoimmunotherapy. Purine nucleoside analogs remain the cornerstone of treatment, and the addition of rituximab has deepened and prolonged responses in the upfront and relapsed setting. Targeted therapies now have a more defined role in the management of HCL, with BRAF inhibitors now having a potential in the first-line setting in selected cases as well as in relapse. Next-generation sequencing for the identification of targetable mutations, evaluation of measurable residual disease, and risk stratification continue to be areas of active investigation. Recent advances in HCL have led to more effective therapeutics in the upfront and relapsed setting. Future efforts will focus on identifying patients with high-risk disease who require intensified regimens. Multicenter collaborations are the key to improving overall survival and quality of life in this rare disease.
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Antineoplásicos , Leucemia de Células Pilosas , Humanos , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/terapia , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Calidad de Vida , Rituximab/uso terapéutico , Pronóstico , Estudios Multicéntricos como AsuntoRESUMEN
Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis. Cytogenetic complexity (>3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV. Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation. Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p). In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002). In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (p.
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Leucemia Linfocítica Crónica de Células B , Análisis Citogenético , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , PronósticoRESUMEN
High-dose chemotherapy followed by autologous hematopoietic stem cell transplant (AHSCT) is a standard of care for patients with relapsed Hodgkin lymphoma. Different conditioning regimens before AHSCT have been used, with the 2 most common being BEAM (carmustine, etoposide, cytarabine, and melphalan) and BUCYVP16 (busulfan, cyclophosphamide, and etoposide). We retrospectively compared the outcomes of patients treated with BEAM (nâ¯=â¯128) or BUCYVP16 (nâ¯=â¯105) followed by AHSCT. After a median follow-up of 4.2 years for BEAM and 3.8 for BUCYVP16 from AHSCT, the 5-year cumulative incidence of relapse was 29% with BEAM compared with 56% with BUCYVP16 (P < .001). Median progression free survival (PFS) and overall survival (OS) were not reached with BEAM and were 2.0 and 7.8 years with BUCYVP16, respectively. Improved PFS (P < .001) and OS (Pâ¯=â¯.001) were observed with BEAM for patients who needed transplant within 24 months from diagnosis and for patients not in complete remission (non-CR; Pâ¯=â¯.001 and P < .001, respectively) at AHSCT. In this large retrospective comparison the use of BEAM conditioning before AHSCT resulted in a statistically significant improved PFS and OS and lower relapse compared with BUCYVP16. This supports the use of BEAM as a frontline conditioning regimen before AHSCT for early relapsed and non-CR Hodgkin lymphoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Busulfano/uso terapéutico , Ciclofosfamida/uso terapéutico , Etopósido/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Busulfano/farmacología , Carmustina/farmacología , Carmustina/uso terapéutico , Ciclofosfamida/farmacología , Citarabina/farmacología , Citarabina/uso terapéutico , Etopósido/farmacología , Femenino , Enfermedad de Hodgkin/patología , Humanos , Masculino , Melfalán/farmacología , Melfalán/uso terapéutico , Persona de Mediana Edad , Podofilotoxina/farmacología , Podofilotoxina/uso terapéutico , Adulto JovenRESUMEN
On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
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Testimonio de Experto , Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Antígenos CD19/inmunología , Niño , Vías Clínicas , Aprobación de Drogas , Humanos , Pautas de la Práctica en Medicina , Sociedades Médicas , Estados Unidos , Adulto JovenRESUMEN
Given the limited treatment options for relapsed lymphoma post-allogeneic hematopoietic cell transplantation (post-allo-HCT) and the success of programmed death 1 (PD-1) blockade in classical Hodgkin lymphoma (cHL) patients, anti-PD-1 monoclonal antibodies (mAbs) are increasingly being used off-label after allo-HCT. To characterize the safety and efficacy of PD-1 blockade in this setting, we conducted a multicenter retrospective analysis of 31 lymphoma patients receiving anti-PD-1 mAbs for relapse post-allo-HCT. Twenty-nine (94%) patients had cHL and 27 had ≥1 salvage therapy post-allo-HCT and prior to anti-PD-1 treatment. Median follow-up was 428 days (range, 133-833) after the first dose of anti-PD-1. Overall response rate was 77% (15 complete responses and 8 partial responses) in 30 evaluable patients. At last follow-up, 11 of 31 patients progressed and 21 of 31 (68%) remain alive, with 8 (26%) deaths related to new-onset graft-versus-host disease (GVHD) after anti-PD-1. Seventeen (55%) patients developed treatment-emergent GVHD after initiation of anti-PD-1 (6 acute, 4 overlap, and 7 chronic), with onset after a median of 1, 2, and 2 doses, respectively. GVHD severity was grade III-IV acute or severe chronic in 9 patients. Only 2 of these 17 patients achieved complete response to GVHD treatment, and 14 of 17 required ≥2 systemic therapies. In conclusion, PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment-refractory GVHD. PD-1 blockade post-allo-HCT should be studied further but cannot be recommended for routine use outside of a clinical trial.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Enfermedad Injerto contra Huésped/inducido químicamente , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/uso terapéutico , Femenino , Expresión Génica , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Nivolumab , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Inducción de Remisión , Estudios Retrospectivos , Terapia Recuperativa/métodos , Análisis de Supervivencia , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.
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Antineoplásicos/uso terapéutico , Cladribina/uso terapéutico , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/tratamiento farmacológico , Pentostatina/uso terapéutico , Manejo de la Enfermedad , Humanos , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Richter Syndrome, an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia (CLL), has a generally poor prognosis and anthracycline-based chemoimmunotherapy regimens designed to treat de novo diffuse large B-cell lymphoma achieve modest clinical benefit. R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) has demonstrated greater activity against aggressive B-cell histologies but has not been studied in Richter Syndrome. We conducted a retrospective cohort study of 46 Richter Syndrome patients treated with first-line R-EPOCH at our institution between 1 January 2006 and 31 May 2014. The median progression-free survival (PFS) was 3·5 months [95% confidence interval (CI): 2·0-7·6] and median overall survival (OS) was 5·9 months (95% CI: 3·2-10·3). Toxicity was high and 30% of patients died without progression or response. Patients with a complex CLL karyotype had significantly shorter PFS and OS (P = 0·005 and P = 0·002, respectively). Multivariable analysis identified complex CLL karyotype as the most significant predictor of decreased survival [Hazard ratio (HR) 2·72, 95% CI: 1·14-6·52, P = 0·025], adjusting for number of prior CLL treatments (P = 0·036). Richter Syndrome patients with complex CLL karyotype experience poor survival with R-EPOCH treatment and novel approaches are needed for these patients. In contrast, survival of patients without a complex CLL karyotype was similar to patients with de novo diffuse large B-cell lymphoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Progresión de la Enfermedad , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Etopósido/efectos adversos , Etopósido/uso terapéutico , Femenino , Humanos , Estimación de Kaplan-Meier , Cariotipo , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/efectos adversos , Prednisona/uso terapéutico , Pronóstico , Estudios Retrospectivos , Rituximab/administración & dosificación , Resultado del Tratamiento , Vincristina/efectos adversos , Vincristina/uso terapéuticoRESUMEN
Purpose The purpose of this study was to compare medications and potential risk factors between patients who experienced a fall during hospitalization compared to those who did not fall while admitted to the Blood and Marrow Transplant inpatient setting at The James Cancer Hospital. Secondary objectives included evaluation of transplant-related disease states and medications in the post-transplant setting that may lead to an increased risk of falls, post-fall variables, and number of tests ordered after a fall. Methods This retrospective, case-control study matched patients in a 2:1 ratio of nonfallers to fallers. Data from The Ohio State University Wexner Medical Center (OSUWMC) reported fall events and patient electronic medical records were utilized. A total of 168 adult Blood and Marrow Transplant inpatients with a hematological malignancy diagnosis were evaluated from 1 January 2010 to 30 September 2012. Results Univariable and multivariable conditional logistic regression models were used to assess the relationship between potential predictor variables of interest and falls. Variables that were found to be significant predictors of falls from the univariable models include age group, incontinence, benzodiazepines, corticosteroids, anticonvulsants and antidepressants, and number of days status-post transplant. When considered for a multivariable model age group, corticosteroids, and a cancer diagnosis of leukemia were significant in the final model. Conclusion Recent medication utilization such as benzodiazepines, anticonvulsants, corticosteroids, and antidepressants placed patients at a higher risk of experiencing a fall. Other significant factors identified from a multivariable analysis found were patients older than age 65, patients with recent corticosteroid administration and a cancer diagnosis of leukemia.
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Accidentes por Caídas/prevención & control , Trasplante de Médula Ósea/tendencias , Hospitalización/tendencias , Neoplasias/epidemiología , Corticoesteroides/efectos adversos , Adulto , Factores de Edad , Anciano , Antidepresivos/efectos adversos , Trasplante de Médula Ósea/efectos adversos , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/terapia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 10(12)) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL.
Asunto(s)
Inmunoglobulinas/química , Leucemia Linfocítica Crónica de Células B/inmunología , Análisis de Secuencia de ARN/métodos , Hipermutación Somática de Inmunoglobulina , Alelos , Secuencia de Bases , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/genética , Genoma , Humanos , Región Variable de Inmunoglobulina/genética , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Pronóstico , Homología de Secuencia de Ácido Nucleico , Transcriptoma , VDJ Recombinasas/genéticaRESUMEN
Ibrutinib has significantly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). Recent reports attribute ibrutinib resistance to acquired mutations in Bruton agammaglobulinemia tyrosine kinase (BTK), the target of ibrutinib, as well as the immediate downstream effector phospholipase C, γ2 (PLCG2). Although the C481S mutation found in BTK has been shown to disable ibrutinib's capacity to irreversibly bind this primary target, the detailed mechanisms of mutations in PLCG2 have yet to be established. Herein, we characterize the enhanced signaling competence, BTK independence, and surface immunoglobulin dependence of the PLCG2 mutation at R665W, which has been documented in ibrutinib-resistant CLL. Our data demonstrate that this missense alteration elicits BTK-independent activation after B-cell receptor engagement, implying the formation of a novel BTK-bypass pathway. Consistent with previous results, PLCG2(R665W) confers hypermorphic induction of downstream signaling events. Our studies reveal that proximal kinases SYK and LYN are critical for the activation of mutant PLCG2 and that therapeutics targeting SYK and LYN can combat molecular resistance in cell line models and primary CLL cells from ibrutinib-resistant patients. Altogether, our results engender a molecular understanding of the identified aberration at PLCG2 and explore its functional dependency on BTK, SYK, and LYN, suggesting alternative strategies to combat acquired ibrutinib resistance.
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Resistencia a Antineoplásicos/genética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Fosfolipasa C gamma/genética , Proteínas Tirosina Quinasas/fisiología , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptores de Antígenos de Linfocitos B/metabolismo , Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Células Cultivadas , Pollos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Leucemia Linfocítica Crónica de Células B/metabolismo , Mutación Missense , Piperidinas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Transducción de Señal/genética , Quinasa Syk , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter's transformation who failed ≥2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n = 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n = 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01217749.
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Anticuerpos Monoclonales/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Piperidinas , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Resultado del TratamientoRESUMEN
Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.
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Antineoplásicos/farmacología , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Supervivencia Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Immunoblotting , Ratones , Ratones Transgénicos , Transporte de Proteínas/efectos de los fármacosRESUMEN
We defined associations among immune cell subsets in granulocyte colony-stimulating factor (G-CSF)-mobilized allografts and clinical outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Fresh peripheral blood stem cell (PBSC) aliquots from 238 G-CSF-mobilized allografts were extensively characterized by immunophenotype. Subset-specific transplanted cells were correlated with acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), malignant disease relapse, nonrelapse mortality, and overall survival. Of 238 assessable alloHCT recipients, 185 patients (78%) received reduced-intensity conditioning and 152 (64%) antithymocyte globulin-based serotherapy. Incidences of aGVHD and cGVHD were 58% and 48%, respectively. Median follow-up was 21 months (range, 1.4 to 41.1). In multivariable analyses adjusted for relevant clinical factors, allograft activated natural killer (NK) cells (CD56(+)CD16(+)CD69(+)CD158b(+)) were associated with a significantly lower risk of aGVHD (P = .0016; HR, .51; 95% confidence interval, .33 to .78), whereas late-activated HLA-DR(+) CD3(+) cells were associated with significantly higher aGVHD (P < .0005; HR, 2.31; 95% confidence interval, 1.55 to 3.43). In a subgroup of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), receipt of an allograft from an older donor (≥40 years) was associated with a higher incidence of relapse (P = .0042; HR, 2.99); allograft content of early activated CD3(+) cells (CD3(+)CD69(+); P = .0024; HR, .4) and NKT cells (CD3(+)CD56(+); P = .0006; HR, .54) were associated with a lower incidence of relapse. Presence of HLA-Bw4-80Ile(+) genotype was associated with lower relapse incidence. In conclusion, activated NK cells within PBSC allografts associate with lower aGVHD risk, whereas HLA-DR(+) T cells associate with higher aGVHD and cGVHD risk. NKT cells and early activated T cells are associated with lower relapse risk in AML and MDS patients. These findings may have implications in therapeutic targeting of select populations in the allograft to minimize incidence of GVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neoplasias Hematológicas/terapia , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre de Sangre Periférica , Adolescente , Adulto , Anciano , Suero Antilinfocítico/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/patología , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Humanos , Inmunosupresores/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Embarazo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Tacrolimus/uso terapéutico , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
Statins possess potent immunomodulatory effects that may play a role in preventing acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). We performed a phase II study of atorvastatin for aGVHD prophylaxis when given to allo-HCT recipients and their HLA-matched sibling donors. Atorvastatin (40 mg/day) was administered to sibling donors, beginning 14 days before the anticipated start of stem cell collection. Allo-HCT recipients (n = 40) received atorvastatin (40 mg/day) in addition to standard aGVHD prophylaxis. The primary endpoint was cumulative incidence of grades II to IV aGVHD at day 100. Atorvastatin was well tolerated, with no attributable grades III to IV toxicities in donors or their recipients. Day 100 and 180 cumulative incidences of grades II to IV aGVHD were 30% (95% confidence interval [CI], 17% to 45%) and 40% (95% CI, 25% to 55%), respectively. One-year cumulative incidence of chronic GVHD was 43% (95% CI, 32% to 69%). One-year nonrelapse mortality and relapse incidences were 5.5% (95% CI, .9% to 16.5%) and 38% (95% CI, 18% to 47%), respectively. One-year progression-free and overall survival rates were 54% (95% CI, 38% to 71%) and 82% (95% CI, 69% to 94%). One-year GVHD-free, relapse-free survival was 27% (95% CI, 16% to 47%). These results did not differ from our historical control subjects (n = 96). Although safe and tolerable, the addition of atorvastatin did not appear to provide any benefit to standard GVHD prophylaxis alone.
Asunto(s)
Atorvastatina/administración & dosificación , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Prueba de Histocompatibilidad , Donantes de Tejidos , Enfermedad Aguda , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Otlertuzumab is a novel humanized anti-CD37 protein therapeutic. This study evaluated the safety of otlertuzumab administered intravenously to patients with chronic lymphocytic leukemia (CLL). Otlertuzumab was administered weekly for up to 8 weeks followed by 1 dose per month for 4 months ranging from 0.03 to 20 mg/kg in the dose-escalation phase and 10 to 30 mg/kg in the dose-expansion phase. Responses were determined by using the 1996 National Cancer Institute (NCI-96) and 2008 International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) criteria. Fifty-seven patients were treated in the dose-escalation phase and 26 in the dose-expansion phase. A maximum-tolerated dose was not identified. Response occurred in 19 (23%) of 83 treated patients by NCI-96 criteria. All responses were partial and occurred more commonly in patients with symptomatic untreated CLL (6/7) or 1 to 2 prior therapies (12/28) vs 3 or more therapies (1/48). Twenty percent (12/61) with serial computed tomography scan assessment had a response per IWCLL criteria. The most frequent adverse events were infusion reactions, fatigue, nausea, and diarrhea and were not dose related. Otlertuzumab was well tolerated, and modest clinical activity was observed. Otlertuzumab warrants further evaluation in combination with other agents for the treatment of CLL. This trial was registered at www.clinicaltrials.gov as #NCT00614042.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Inmunoglobulina G/efectos adversos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Proteínas Recombinantes de Fusión/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antígenos de Neoplasias/inmunología , Femenino , Humanos , Inmunoglobulina G/uso terapéutico , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Ingeniería de Proteínas , Proteínas Recombinantes de Fusión/uso terapéutico , Tetraspaninas/inmunología , Resultado del TratamientoRESUMEN
Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-ß (PKC-ß) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters ß-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-ß has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/enzimología , Proteína Quinasa C beta/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/uso terapéutico , Quinazolinas/uso terapéutico , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Receptores de Antígenos de Linfocitos B/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismoRESUMEN
Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m(2) followed by a 4-h infusion of 30 mg/m(2) once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.Registration number at ClinicalTrials.gov: NCT00377104.
Asunto(s)
Antineoplásicos/uso terapéutico , Flavonoides/uso terapéutico , Inmunoterapia/tendencias , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas/uso terapéutico , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
A jumping translocation (JT) is a rare cytogenetic aberration that can occur in haematological malignancy. It involves the translocation of the same fragment of donor chromosome onto two or more recipient chromosomes, typically in different cells. In this study, we describe the first series of chronic lymphocytic leukaemia (CLL) patients with JTs reported to date. Following a review of 878 CLL patient karyotypes, we identified 26 patients (3%) with 97 JTs. The most commonly occurring breakpoint in these translocations was 17p11.2. Loss of TP53 was identified prior to or at the same time as JT in 23 of 26 patients (88%). All patients eventually developed a complex karyotype. All but one patient has required treatment for CLL, with estimated median time to treatment of 11·5 months. This study establishes JTs as a recurrent abnormality found in CLL patients with aggressive disease. JTs contribute to complex karyotypes and, in many cases, are involved in chromosomal rearrangements that result in loss of the tumour suppressor gene TP53.