RESUMEN
Inotuzumab ozogamicin (IO), a novel therapeutic drug for relapsed or refractory acute lymphoblastic leukemia (RR)(ALL), is a humanized anticluster of differentiation (CD) 22 monoclonal antibody conjugated with calicheamicin that causes DNA single and doublestrand breaks. Although the efficacy of IO is significantly improved compared with that of conventional chemotherapies, the prognosis for RRALL remains poor, highlighting the need for more effective treatment strategies. The present study examined the role of DNA damage repair inhibition using the poly (ADPribose) polymerase (PARP) inhibitors olaparib or talazoparib on the enhancement of the antitumor effects of IO on BALL cells in vitro. The Reh, Philadelphia (Ph)BALL and the SUPB15 Ph+ BALL cell lines were used for experiments. Both cell lines were ~90% CD22+. The halfmaximal inhibitory concentration (IC50) values of IO were 5.3 and 49.7 ng/ml for Reh and SUPB15 cells, respectively. The IC50 values of IO combined with minimally toxic concentrations of olaparib or talazoparib were 0.8 and 2.9 ng/ml for Reh cells, respectively, and 36.1 and 39.6 ng/ml for SUPB15 cells, respectively. The combination index of IO with olaparib and talazoparib were 0.19 and 0.56 for Reh cells and 0.76 and 0.89 for SUPB15 cells, demonstrating synergistic effects in all combinations. Moreover, the addition of minimally toxic concentrations of PARP inhibitors augmented IOinduced apoptosis. The alkaline comet assay, which quantitates the amount of DNA strand breaks, was used to investigate the degree to which DNA damage observed 1 h after IO administration was repaired 6 h later, reflecting successful repair of DNA strand breaks. However, DNA strand breaks persisted 6 h after IO administration combined with olaparib or talazoparib, suggesting inhibition of the repair processes by PARP inhibitors. Adding olaparib or talazoparib thus synergized the antitumor effects of IO by inhibiting DNA strand break repair via the inhibition of PARP.
Asunto(s)
Reparación del ADN , Sinergismo Farmacológico , Inotuzumab Ozogamicina , Ftalazinas , Piperazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Piperazinas/farmacología , Piperazinas/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Línea Celular Tumoral , Reparación del ADN/efectos de los fármacos , Inotuzumab Ozogamicina/farmacología , Apoptosis/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Indoles/farmacologíaRESUMEN
The BLd regimen, which is a triplet regimen of bortezomib (Bor), lenalidomide (Len), and dexamethasone (Dex), is effective against newly diagnosed multiple myeloma (NDMM). However, non-hematological toxicities, such as peripheral neuropathy (PN), often hamper long-term continuation of the regimen, particularly in older adult patients. In this study, we examined the efficacy and safety of the modified BLd regimen with reduced-intensity Bor and standard-dose Len. The chemotherapy regimen consisted of 1.3 mg/m2 Bor administered subcutaneously on days 1 and 8, 25 mg Len administered on days 1-14, and 20 mg Dex on days 1-2 and 8-9 of a 3 week cycle for 8 cycles, followed by a 4 week cycle of Dex (40 mg weekly). Among the 30 patients enrolled, 60.0% (95% CI 40.6-77.3) had a very good partial response or better, and the best overall response rate was 96.7% (95% CI 82.8-99.9). Eight patients (26.7%) achieved a complete response. Grade 3 or higher PN was not observed and hematological toxicity was the most common adverse event. The modified BLd regimen showed favorable efficacy with a manageable safety profile, which suggests it could be a treatment option for transplant-ineligible NDMM.
Asunto(s)
Mieloma Múltiple , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib , Dexametasona , Humanos , Japón , Lenalidomida , Mieloma Múltiple/diagnóstico , Resultado del TratamientoRESUMEN
This nationwide multicentre retrospective study was performed to analyze clinical features that predict the prognosis of central nervous system invasion in multiple myeloma (CNS-MM, approximately 1% of MM). Overall, of the 77 adult patients with CNS-MM identified between 2005 and 2016, those diagnosed at MM diagnosis (n = 3) had longer overall survival (OS) than those diagnosed at relapse (n = 74; median: 48·5 vs 2·7 months). Therefore, we compared the relapsed MM with CNS-MM in patients with any treatment (n = 60). Multivariate analyses revealed that lenalidomide treatment [hazard ratio (HR) 0·27, P = 0·003], intrathecal chemotherapy (IT; HR 0·54, P = 0·05), and radiation therapy (RTx; HR 0·33, P < 0·001) for CNS-MM had a positive effect on longer OS. These factors were used to develop a scoring system combining the number of treatments with lenalidomide, IT, and RTx (0, 1, 2, 3). The OS of CNS-MM patients was stratified based on these factors, with a median OS of 1·1, 4·5, and 7·5 months for patients with zero, one, two to three favourable features, respectively (0 vs 1, P = 0·0002; 1 vs 2-3, P = 0·08). Multimodal treatment including lenalidomide in addition to conventional IT and RTx can improve OS.
Asunto(s)
Sistema Nervioso Central/patología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Invasividad Neoplásica/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Casos y Controles , Terapia Combinada , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/uso terapéutico , Inyecciones Espinales , Japón/epidemiología , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Masculino , Persona de Mediana Edad , Mieloma Múltiple/epidemiología , Pronóstico , Radioterapia/métodos , Proyectos de Investigación , Estudios Retrospectivos , Encuestas y Cuestionarios , Análisis de SupervivenciaRESUMEN
Multiple myeloma (MM) is a hematological malignancy characterized by the proliferation of abnormal plasma cells in bone marrow. Flow cytometry distinguishes between normal and abnormal plasma cells by evaluating cluster of differentiation (CD) 56 and CD19 expression patterns. Moreover, immunophenotyping of mature plasma cell 1 (MPC-1) and very late antigen-5 (CD49e) identifies the maturity of MM as mature (MPC-1+, CD49e+), intermediate (MPC-1+, CD49e-), or immature (MPC-1-, CD49e-). We retrospectively examined the effects of surface marker expression and maturity subtype on overall survival (OS) and time to next treatment (TNT) among 55 patients (25 males, 30 females) with symptomatic MM. All patients were treated with regimens containing bortezomib (BOR) (n = 39) or lenalidomide (LEN) (n = 16) as the initial treatment. Median age at diagnosis was 72 years (range: 36-88). The lack of CD56, an aberrant marker, was associated with significantly worse prognosis compared with CD56+ MM (median OS: 24 vs. 60 months, respectively; p = 0.0050). In CD49e+ MM, defined as mature type, no significant difference was seen in TNT of the initial treatment, regardless of whether it was a BOR-based regimen or LEN + dexamethasone (Ld) therapy. On the other hand, in CD49e- MM, defined as immature/intermediate type, TNT of Ld therapy was significantly longer than that of BOR-based regimens (median TNT: undefined vs. 12 months, respectively; p = 0.0043). These results suggest that Ld therapy is more effective than BOR-based therapy for CD49e- MM and thus may aid regimen-related decisions in the novel agents era.
Asunto(s)
Antineoplásicos/uso terapéutico , Antígeno CD56/metabolismo , Integrina alfa5/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bortezomib/uso terapéutico , Femenino , Humanos , Inmunofenotipificación , Lenalidomida/uso terapéutico , Masculino , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Proteínas de Neoplasias/metabolismo , Células Plasmáticas/metabolismo , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Cytarabine (ara-C) is the major drug for the treatment of acute myeloid leukemia (AML), but cellular resistance to ara-C is a major obstacle to therapeutic success. The present study examined enhanced anti-apoptosis identified in 3 newly established nucleoside analogue-resistant leukemic cell line variants and approaches to overcoming this resistance. METHODS: HL-60 human AML cells were used to develop the ara-C- or clofarabine (CAFdA)-resistant variants. The Bcl-2 inhibitor venetoclax and the Mcl-1 inhibitor alvocidib were tested to determine whether they could reverse these cells' resistance. RESULTS: A 10-fold ara-C-resistant HL-60 variant, a 4-fold CAFdA-resistant HL-60 variant, and a 30-fold CAFdA-resistant HL-60 variant were newly established. The variants demonstrated reduced deoxycytidine kinase and deoxyguanosine kinase expression, but intact expression of surface transporters (hENT1, hENT2, hCNT3). The variants exhibited lower expression of intracellular nucleoside analogue triphosphates compared with non-variant HL-60 cells. The variants also overexpressed Bcl-2 and Mcl-1. Venetoclax as a single agent was not cytotoxic to the resistant variants. Nevertheless, venetoclax with nucleoside analogs demonstrated synergistic cytotoxicity against the variants. Alvocidib as a single agent was cytotoxic to the cells. However, alvocidib induced G1 arrest and suppressed the cytotoxicity of the co-administered nucleoside analogs. CONCLUSIONS: Three new nucleoside analogue-resistant HL-60 cell variants exhibited reduced production of intracellular analogue triphosphates and enhanced Bcl-2 and Mcl-1 expressions. Venetoclax combined with nucleoside analogs showed synergistic anti-leukemic effects and overcame the drug resistance.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Clofarabina/uso terapéutico , Citarabina/uso terapéutico , Flavonoides/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Piperidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proliferación Celular , Clofarabina/farmacología , Citarabina/farmacología , Flavonoides/farmacología , Humanos , Piperidinas/farmacología , Sulfonamidas/farmacologíaRESUMEN
Relapsed acute lymphoblastic leukemia (ALL) has a poor prognosis. Inotuzumab Ozogamicin (InO) is a novel therapeutic drug for the treatment of relapsed ALL. InO has received attention as a bridging therapy before transplantation due to its high complete remission (CR) rate. However, the significance of InO in non-transplant patients remains unclear. We retrospectively evaluated four non-transplant patients treated with InO. All cases achieved CR after receiving at least two cycles of InO. Three of the four cases survived for more than 11 months without relapse. Moreover, all patients received InO as outpatients, because the adverse events were well-controlled. InO therefore appears to be a beneficial treatment even for non-transplant patients.
Asunto(s)
Inotuzumab Ozogamicina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Anciano , Femenino , Humanos , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Estudios RetrospectivosRESUMEN
Objective We retrospectively compared the clinical efficacy and toxicity of rituximab (R)-THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone) with that of R-CHOP (rituximab, adriamicin, cyclophosphamide, vincristine, and prednisolone) in previously untreated old patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients admitted to our institution between 2004 and 2013 were examined. The patients received either R (375 mg/m2, day 1)-THP-COP (pirarubicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5) or R-CHOP (adriamicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5). The doses of chemotherapeutic agents were adjusted depending on the patient's age and associated complications. The treatment was performed for 6 to 8 cycles. Results Among 74 patients with DLBCL (median 76, range 65-90 years; male 39, female 35), 29 received R-THP-COP, while 45 received R-CHOP. The overall response rates were 94.6% (complete response 86.4%, partial response 8.1%). The 2-year overall and progression-free survival rates were 77.6% and 68.5% for the R-THP-COP regimen and 79.2% and 78.9% for R-CHOP, respectively. No significant differences were found between these two regimens regarding the clinical efficacies. The most frequent adverse event was neutropenia (72.4% for the R-THP-COP regimen, 88.9% for the R-CHOP regimen). The cardiac function as evaluated by ejection fraction values was not impaired in either regimen. Conclusion R-THP-COP was effective and safe as an alternative to R-CHOP.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapéutico , Esquema de Medicación , Femenino , Humanos , Linfoma de Células B Grandes Difuso/patología , Masculino , Neutropenia/inducido químicamente , Prednisolona/uso terapéutico , Prednisona/uso terapéutico , Inducción de Remisión , Estudios Retrospectivos , Rituximab/uso terapéutico , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
BACKGROUND/AIM: Tumor lysis syndrome (TLS) is a life-threatening complication associated with cancer chemotherapy. We retrospectively evaluated the risk of developing TLS in patients with symptomatic multiple myeloma undergoing chemotherapy. PATIENTS AND METHODS: Sixty-four patients (median age=71 years, range=48-87 years, 35 males/29 females) who were treated at our Institution between April 2006 and December 2015 were evaluated. RESULTS: A total of 124 chemotherapy courses were administered, of which 63 courses were bortezomib-based regimens and 34 courses were immunomodulatory drug (IMiD)-based regimens. TLS occurred in 13 (10.5%) out of 124 chemotherapy courses with five (4.0%) cases of laboratory TLS and eight (6.5%) cases of clinical TLS. The incidences of TLS were 17.5% for bortezomib-containing regimens and 3.2% for non-bortezomib-based regimens. No TLS occurred in the patients treated with IMiD-containing regimens. TLS occurred more frequently in the patients with elevated uric acid, creatinine, or beta-2-microglobulin levels at baseline. The patients with disease classified as advanced International Staging System also developed TLS more frequently. All the patients who developed clinical TLS received bortezomib-containing regimens (8/63, 12.7%). Among them, patients with elevated values of uric acid or creatinine developed clinical TLS more often than those without such elevation. The incidence of clinical TLS was 33.3% if the patients had renal dysfunction at baseline and were subsequently treated with bortezomib-based regimens (8/24 cases). CONCLUSION: Patients with renal dysfunction or a high uric acid level receiving bortezomib-based chemotherapy have a high risk of developing TLS.