RESUMEN
Objective To investigate the pathogenesis of Philadelphia (Ph)-positive acute lymphocytic leukemia (ALL), we established a lymphoblastoid cell line. Methods Bone marrow cells from a patient with Ph-positive ALL were enriched by Ficoll-Hypaque centrifugation and cultured in medium with fetal calf serum. Materials The mononuclear cells of bone marrow aspirate were obtained from an adult man with ALL after he experienced relapse following induction therapy including imatinib mesylate. Results The cell line termed TNA-M was established, carrying a three-way Ph translocation involving two chromosome 9s and one chromosome 22 as a sole karyotypic abnormality. Furthermore, the cells were positive for CD13 and CD33 in addition to CD19, CD22 and CD79a antigens. Conclusion This unique cell line is expected to be a valuable tool for understanding the pathogenesis of Ph-positive ALL.
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Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Masculino , Humanos , Línea Celular , Mesilato de Imatinib , Lectina 3 Similar a Ig de Unión al Ácido SiálicoRESUMEN
The patient, a 56-year-old lady, also exhibited numerous lymphadenopathy, hepatosplenomegaly, hyperleukocytosis (167,200/µl, aberrant lymphocytes 91.5%), and fever. A lymph node biopsy revealed follicular lymphoma (FL), grade 1. Peripheral blood tumor cells did not express CD10, which was a distinctive characteristic of the lymph node specimen. To prevent tumor lysis syndrome (TLI), CHOP was delivered without an anti-CD20 antibody, but afterward, residual lymphoma cells were found in peripheral blood (>80%). As a result, obinutuzumab (Obi) was given on day 8 following the second round of CHOP, and the tumor cells in the peripheral blood vanished without any major side effects like TLI. She underwent six chemotherapy sessions before receiving maintenance therapy with Obi and achieving a full metabolic response. According to reports, leukemic FL exhibits negative CD10 expression in peripheral blood lymphoma cells, while leukemic mantle cell lymphoma also shows this trait. Therefore, it is important not to confuse the two types in diagnosis. Leukemic FL with significant leukocytosis is reportedly uncommon and has a bad prognosis. Our case indicates that CHOP with Obi would be a good alternative for cases like yours, however, there have been a few cases recorded. Further case accumulation or investigation is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Folicular , Femenino , Humanos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Prednisolona/uso terapéutico , Prednisona/uso terapéutico , Rituximab/uso terapéutico , Vincristina/uso terapéuticoRESUMEN
To elucidate the relevance of genetic alterations, we analysed 17 genes known to be involved in haematological neoplasms in patients with chronic leucocytosis and patients with persistent thrombocytosis. Mutations of the JAK2, SETBP1 and ASXL1 genes were found in 1/13, 1/13, and 2/13 patients with leucocytosis, respectively. Mutations of the JAK2, CALR, SETBP1 and ASXL1 genes were found in 1/5, 1/5, 1/5 and 2/5 patients with thrombocytosis, respectively. One leucocytosis patient with a JAK2 V617F mutation developed polycythaemia vera. Another leucocytosis patient developed Philadelphia chromosome-negative chronic myeloid leukaemia (Ph(-) CML) accompanied by t(9;12)(q34.1;p13.?3) (Mori et al. 2016). Another leucocytosis patient with mutations of the SETBP1 and ASXL1 genes progressed to blast crisis of Ph(-) CML accompanied by i(17)(q10). Chronic leucocytosis patients who had genetic alterations tended to develop haematological neoplasms, while thrombocytosis unexpectedly resolved in two persistent thrombocytosis patients with genetic alterations.
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Trombocitosis , Humanos , Mutación , Trombocitosis/genéticaRESUMEN
To evaluate the long-term efficacy of high-dose dexamethasone (HD-DXM) treatment for immune thrombocytopenia (ITP), we retrospectively analysed 36 newly diagnosed ITP patients treated with HD-DXM as a first-line treatment. An initial response was obtained in 23 (63.9%) patients, including 11 with a complete response (CR) and 12 with a partial response (PR). Six months after HD-DXM treatment, 26 of 33 (78.8%) evaluable patients achieved objective responses, including 18 CR and 8 PR. Among 13 patients without initial response, very early increased platelet count within a week (VEIP) was observed in 7 patients, 5 (71.4%) of whom achieved a response at 6 months. In 29 patients who had available platelet count within a week, patients showing VEIP revealed longer survival than those who did not (p = 0.026). HD-DXM was an effective treatment for newly diagnosed ITP patients. VEIP after HD-DXM treatment initiation was associated with a long-term objective response in newly diagnosed ITP patients.
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Púrpura Trombocitopénica Idiopática , Dexametasona/uso terapéutico , Humanos , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
We investigated the clinical implications of preferentially expressed antigen in melanoma (PRAME) expression in bone marrow cells of 116 patients with myelodysplastic syndromes (MDS). Quantitative RT-PCR was carried out to examine the PRAME expression level. High PRAME expression was observed in MDS patients classified into higher revised International Prognostic Scoring System (IPSS-R) risk categories (Very high and High) with a high bone marrow blast percentage (5% or higher). Kaplan-Meier analysis demonstrated that high PRAME expression is significantly associated with a poorer overall survival (OS) in MDS patients with a low bone marrow blast percentage (less than 5%) (log-rank test p = .0014) and those classified into lower IPSS-R risk categories (Very Low, Low, and Intermediate) (log-rank test, p = .0035). In contrast, there was no significant association between PRAME expression and OS in MDS patients with a high bone marrow blast percentage or those classified into higher IPSS-R risk categories. In addition, high PRAME expression was associated with early disease progression in MDS patients with a low bone marrow blast percentage. This study suggested PRAME expression to be a prognostic factor in MDS.
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Médula Ósea , Síndromes Mielodisplásicos , Antígenos de Neoplasias/genética , Progresión de la Enfermedad , Humanos , Estimación de Kaplan-Meier , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , PronósticoRESUMEN
We herein report two cases of thrombotic thrombocytopenic purpura (TTP) complicated by other autoimmune disorders, autoimmune hepatitis and immune thrombocytopenia, respectively. In both cases, corticosteroids were continuously administered for the treatment of preceding autoimmune disorders. However, a sufficient objective response for TTP was not obtained by plasma exchange and corticosteroid treatment. Once a week rituximab (375 mg/m2) treatment for 4 times was initiated within 2 weeks from the diagnosis. Both patients achieved a sufficient response, and have never had any recurrence as of the last follow-up dates. The early introduction of rituximab could be an effective treatment option in TTP patients complicated with other autoimmune disorders.
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Púrpura Trombocitopénica Idiopática , Púrpura Trombocitopénica Trombótica , Humanos , Intercambio Plasmático , Púrpura Trombocitopénica Idiopática/complicaciones , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Trombótica/complicaciones , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Recurrencia , Rituximab/uso terapéuticoRESUMEN
In the published online paper, the data "p = 0.144" was not deleted from the line "Median and mean number of prior treatments (range)" in Table 4.
RESUMEN
Although treatment outcomes for diffuse large B cell lymphoma (DLBCL) have improved with the introduction of rituximab, approximately half of patients experience relapsed/refractory (r/r) disease. Furthermore, no standard salvage therapy has yet been established to date, while limitations in treatment options exist due to toxicity and restricted tolerability among elderly patients and/or those with comorbidities. The ICE (ifosfamide, cyclophosphamide, and etoposide) regimen is often used as salvage therapy for r/r DLBCL. Several modified ICE regimens not requiring continuous ifosfamide infusion are available, which can be used in outpatient clinics. This study analyzed the efficacy and toxicity of fractionated ICE with rituximab (f-R-ICE) as a salvage regimen among 47 patients with relapsed/refractory DLBCL (median age upon f-R-ICE initiation, 71 years). The whole cohort had an overall (ORR) and complete response rate of 53.1% (n = 25) and 25.5% (n = 12), respectively, and an estimated 1-year overall survival after f-R-ICE initiation of 57%. Comorbidities were evaluated using the Charlson Comorbidity Index (CCI) upon f-R-ICE initiation. Patients with low CCI scores (68%) had a higher ORR than those with high CCI scores (36.4%) upon f-R-ICE initiation (P = 0.042). In contrast, no significant differences in overall survival (OS) were observed between the low and high CCI groups (1-year OS 56.6% vs. 52.2%; median OS 24 vs. 22.8 months) after initiating f-R-ICE. Our results suggest that f-R-ICE is a safe and effective salvage therapy for r/r DLBCL and can be used for older patients and/or those with high CCI scores in outpatient clinics.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Comorbilidad , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Masculino , Persona de Mediana Edad , Rituximab/administración & dosificación , Tasa de SupervivenciaRESUMEN
The PLCG1 gene, which encodes the phospholipase C γ1 isoform, is located within the commonly deleted region of the long arm of chromosome 20 (del(20q)) observed in myelodysplastic syndromes (MDS). Phospholipase C is involved in diverse physiological and pathological cellular processes through inositide signaling. We hypothesized that reduced PLCG1 expression because of haploinsufficiency by del(20q) plays a role in the molecular pathogenesis of MDS. Therefore, we analyzed PLCG1 expression in bone marrow mononuclear cells at diagnosis in 116 MDS patients with or without del(20q) by quantitative RT-PCR to evaluate its clinical significance. The expression level of PLCG1 was significantly lower not only in MDS patients with del(20q) but also in those without del(20q) compared to that of the controls, which suggests that reduced PLCG1 expression is a common molecular event in MDS. Patients in the lowest quartile (Q4) group for PLCG1 expression had lower overall survival (OS) compared to that of other patients (Q1-Q3) (log-rank test, P = .0004) with estimated median OS times of 22 in the Q4 group and 106 months in the Q1-3 group. Univariate and multivariate analysis indicated reduced PLCG1 expression (Q4) was associated with lower OS (hazard ratio 2.58, 95% CI 1.35-4.84, P = .0049), which suggests that reduced PLCG1 expression is an independent prognostic factor for OS. In addition, patients were well-stratified for OS by combining PLCG1 expression level (Q4 vs Q1-3) and bone marrow blast percentage (5% or more vs less than 5%). Thus, the level of PLCG1 expression at time of diagnosis is a prognostic biomarker for MDS.
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Biomarcadores de Tumor/metabolismo , Médula Ósea/patología , Síndromes Mielodisplásicos/mortalidad , Fosfolipasa C gamma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/metabolismo , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
Deletion of the long arm of chromosome 20 (del(20q)) is observed in 5-10% of patients with myelodysplastic syndromes (MDS). We examined the expression of 28 genes within the common deleted region (CDR) of del(20q), which we previously determined by a CGH array using clinical samples, in 48 MDS patients with (nâ¯=â¯28) or without (nâ¯=â¯20) chromosome 20 abnormalities and control subjects (nâ¯=â¯10). The expression level of 8 of 28 genes was significantly reduced in MDS patients with chromosome 20 abnormalities compared to that of control subjects. In addition, the expression of BCAS4, ADA, and YWHAB genes was significantly reduced in MDS patients without chromosome 20 abnormalities, which suggests that these three genes were commonly involved in the molecular pathogenesis of MDS. To evaluate the clinical significance, we analyzed the impact of the expression level of each gene on overall survival (OS). According to the Cox proportional hazard model, multivariate analysis indicated that reduced BCAS4 expression was associated with inferior OS, but the difference was not significant (HR, 3.77; 95% CI, 0.995-17.17; Pâ¯=â¯0.0509). Functional analyses are needed to understand the biological significance of reduced expression of these genes in the pathogenesis of MDS.
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Biomarcadores , Deleción Cromosómica , Cromosomas Humanos Par 20 , Regulación de la Expresión Génica , Síndromes Mielodisplásicos/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Bandeo Cromosómico , Femenino , Perfilación de la Expresión Génica , Humanos , Cariotipo , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapiaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Herpes Zóster/mortalidad , Anciano , Autoinjertos , Carmustina/administración & dosificación , Citarabina/administración & dosificación , Femenino , Estudios de Seguimiento , Herpes Zóster/etiología , Herpes Zóster/prevención & control , Humanos , Melfalán/administración & dosificación , Persona de Mediana Edad , Podofilotoxina/administración & dosificaciónRESUMEN
Multidrug resistance (MDR) is a major obstacle to leukemia treatment. The Frizzled-1 (FZD1) Wnt receptor is involved in MDR in some solid cancers, but has rarely been reported to act in acute myeloid leukemia (AML). We investigated whether the knockdown of FZD1 affects MDR1 expression and P-glycoprotein (P-gp) function in multidrug resistant leukemic cell lines, as well as FZD1 and MDR1/P-gp expression in leukemic cells taken from patients with AML (nâ¯=â¯112). FZD1 knockdown significantly reduced MDR1 expression through the Wnt/ß-catenin pathway, disrupted the P-gp efflux function, induced the recovery of sensitivity to chemotherapeutic agents, and hindered cell proliferation in cell lines. FZD1 expression in leukemic cells was significantly higher in patients experiencing relapse (nâ¯=â¯34) than in those with no relapse (nâ¯=â¯44, Pâ¯=â¯.003). Leukemic cells unable to achieve complete response (CR) showed an increased expression of MDR1 and P-gp, compared to patients who achieved CR. Obtaining CR in patients with higher FZD1 expression at diagnosis is difficult. Moreover, they tend to present instances of relapse, suggesting that AML cells with increased FZD1 expression are resistant to chemotherapy. We conclude that the activated FZD1 observed in leukemic cells likely confers acquired drug resistance, whereas FZD1 silencing may be more effective in reversing MDR.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Receptores Frizzled/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Técnicas de Silenciamiento del Gen , Humanos , Leucemia Mieloide Aguda/patología , Transporte de Proteínas , Interferencia de ARN , ARN Interferente Pequeño/genética , Inducción de Remisión , Transducción de Señal , Vía de Señalización Wnt , beta Catenina/metabolismoRESUMEN
BACKGROUND: With the introduction of imatinib, a first-generation tyrosine kinase inhibitor (TKI) to inhibit BCR-ABL1 kinase, the outcome of chronic-phase chronic myeloid leukemia (CP-CML) has improved dramatically. However, only a small proportion of CP-CML patients subsequently achieve a deep molecular response (DMR) with imatinib. Dasatinib, a second-generation TKI, is more potent than imatinib in the inhibition of BCR-ABL1 tyrosine kinase in vitro and more effective in CP-CML patients who do not achieve an optimal response with imatinib treatment. METHODS: In the present study, we attempted to investigate whether switching the treatment from imatinib to dasatinib can induce DMR in 16 CP-CML patients treated with imatinib for at least two years who achieved a major molecular response (MMR) with detectable levels of BCR-ABL1 transcripts. RESULTS: The rates of achievement of DMR at 1, 3, 6 and 12 months after switching to dasatinib treatment in the 16 patients were 44% (7/16), 56% (9/16), 63% (10/16) and 75% (12/16), respectively. The cumulative rate of achieving DMR at 12 months from initiation of dasatinib therapy was 93.8% (15/16). The proportion of natural killer cells and cytotoxic T cells in peripheral lymphocytes increased after switching to dasatinib. In contrast, the proportion of regulatory T cells decreased during treatment. The safety profile of dasatinib was consistent with previous studies. CONCLUSION: Switching to dasatinib would be a therapeutic option for CP-CML patients who achieved MMR but not DMR by imatinib, especially for patients who wish to discontinue TKI therapy.
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Dasatinib/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Células Asesinas Naturales/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Crónica/genética , Masculino , Persona de Mediana Edad , Mutación , Resultado del TratamientoRESUMEN
OBJECTIVES: We previously reported loss of heterozygosity on 1p in chronic myelogenous leukemia (CML). We analyzed promoter methylation and mutation of tumor suppressor genes on 1p36 in CML. METHODS: We performed methylation-specific PCR (MS-PCR) analysis of the PRDM2, RUNX3, and TP73 genes in 61 patients with CML (43 chronic phase, CP; two accelerated phase; and 16 blast crisis, BC). Oxidative MS-PCR, PCR-single-strand conformation polymorphism, and real-time reverse transcriptase PCR were also analyzed. K-562 cells were grown in the presence of 5-Aza-dC and trichostatin A. RESULTS: Methylation of the PRDM2, RUNX3, and TP73 genes was detected in 24/60 (40%), 21/61 (34%), and 28/60 (47%) patients, respectively. Methylation of all three genes was detected in 19/59 (32%) patients. Methylation was more frequent in BC than in CP. Oxidative MS-PCR analysis detected 5-mC in the PRDM2, RUNX3, and TP73 genes in 10/22 (45%), 15/21 (71%), and 16/26 (62%) samples with methylation detected by MS-PCR, respectively. Decreased expression was observed in several samples with methylation, while no mutations were found in the genes. Treatment of K-562 cells induced growth suppression, demethylation, and reexpression of the PRDM2 and RUNX3 genes. CONCLUSION: Multiple tumor suppressor genes on 1p were inactivated in CML by methylation.
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Cromosomas Humanos Par 1 , Metilación de ADN , Genes Supresores de Tumor , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adulto , Anciano , Línea Celular Tumoral , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Proteínas de Unión al ADN/genética , Femenino , Predisposición Genética a la Enfermedad , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Proteínas Nucleares/genética , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , Análisis de Secuencia de ADN , Factores de Transcripción/genética , Proteína Tumoral p73/genéticaAsunto(s)
Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 9/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Anciano , Humanos , Masculino , Cromosoma FiladelfiaAsunto(s)
Antígenos CD20/metabolismo , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/mortalidad , Antígenos CD20/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Citometría de Flujo , Expresión Génica , Humanos , Estimación de Kaplan-Meier , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/tratamiento farmacológico , Prednisona/uso terapéutico , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
Chromosome translocations involving the immunoglobulin heavy chain (IGH) gene locus at chromosome region 14q32 are often observed in B-cell lymphoid neoplasms. Of these, t(14;18)(q32;q21) results in juxtaposition of the IGH gene on chromosome 14 and the BCL2 gene on chromosome 18, leading to the overexpression of BCL2 anti-apoptotic protein, which plays a critical role in the development of follicular lymphoma (FL). However, BCL2 overexpression is not observed in approximately 10 % of FL, and the molecular pathogenesis of BCL2-negative FL has not been elucidated. Here, we identify the SRY-related high-morbidity-group (HMG) box 5 (SOX5) gene on chromosome 12p12 as a novel IGH-involved translocation partner in the case of BCL2-negative follicular lymphoma (FL) with a complex karyotype including t(12;14)(p12.2;q32) by long-distance inverse PCR. As a result of this translocation, the SOX5 gene is juxtaposed to the enhancer of the IGH gene; SOX5 overexpression in neoplastic cells was demonstrated by immunohistochemistry. The results of the present study suggest a role for SOX5 in the molecular pathogenesis of FL.
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Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 14/genética , Linfoma Folicular , Proteínas Proto-Oncogénicas c-bcl-2 , Factores de Transcripción SOXD , Translocación Genética , Anciano , Femenino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Folicular/patología , Factores de Transcripción SOXD/biosíntesis , Factores de Transcripción SOXD/genéticaRESUMEN
The preferentially expressed antigen of melanoma (PRAME), a tumor-associated antigen, is considered a prognostic marker for various human malignancies. The prognostic significance of PRAME expression for diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab-containing chemotherapy has not been evaluated to date, and the ability of immunohistochemistry (IHC) to detect PRAME expression in these patients has not yet been studied, although IHC is simple to perform in clinical practice. We evaluated the prognostic significance of PRAME expression based on IHC analysis in 160 DLBCL patients treated with R-CHOP therapy. There was a significant association between higher PRAME expression and shorter progression-free survival (PFS), and a trend toward shorter overall survival (OS) in patients with higher PRAME expression than that in patients with lower PRAME expression (5-year PFS, 48.1 vs. 61.1 %; 5-year OS, 65.6 vs. 79.1 %). Patients with high PRAME expression tended to have lower chemotherapeutic responses. Thus, IHC is useful for detecting and assessing PRAME expression in DLBCL. Further, we found a positive correlation between IHC and quantitative real-time RT-PCR measurements of PRAME expression. Our findings indicate that IHC results of PRAME expression can be a novel prognostic maker in DLBCL patients treated with R-CHOP therapy.