High-dose rituximab in combination with autologous stem cell transplantation for relapsed or refractory diffuse large B cell lymphoma

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Kaplan–Meier estimates of progression-free survival (A) and overall survival (B) for patients with DLBCL in the HD-R group and control group." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Yi-Fen Shi, Shu-Juan Zhou, Lan Sun, Kang Yu, Yi Chen" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Yi-Fen" "apellidos" => "Shi" ] 1 => array:2 [ "nombre" => "Shu-Juan" "apellidos" => "Zhou" ] 2 => array:2 [ "nombre" => "Lan" "apellidos" => "Sun" ] 3 => array:2 [ "nombre" => "Kang" "apellidos" => "Yu" ] 4 => array:2 [ "nombre" => "Yi" "apellidos" => "Chen" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020620303855" "doi" => "10.1016/j.medcle.2019.11.013" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020620303855?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775319307213?idApp=UINPBA00004N" "url" => "/00257753/0000015500000006/v1_202009140619/S0025775319307213/v1_202009140619/en/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020620303739" "issn" => "23870206" "doi" => "10.1016/j.medcle.2019.11.012" "estado" => "S300" "fechaPublicacion" => "2020-09-25" "aid" => "5047" "copyright" => "Elsevier España, S.L.U." 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Gray's univariate cumulative incidence analysis. HR: hazard ratio; CI: confidence interval." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ana Padilla López, Manuel Alós-Almiñana, José E. Peris" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Ana" "apellidos" => "Padilla López" ] 1 => array:2 [ "nombre" => "Manuel" "apellidos" => "Alós-Almiñana" ] 2 => array:2 [ "nombre" => "José E." 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(A) Absolute numbers of B cells post-transplant in HD-R group, clearly demonstrating a fast decreased B cells post transplant (*P=0.002, #P=0.01), and a slowly recovery after auto-SCT at 6–12 months (P=0.49). (B) Absolute numbers of B cells post-auto-SCT in control group, clearly demonstrating a decreased B cells post transplant compared with pre-SCT (P=0.156) and healthy donors (P=0.07), *P<0.05, the CD19+ B cells at 1–6M vs. the CD19+ B cells in pre-SCT. #P<0.05, the CD19+ B cells 1–6M vs. the CD19+ B cells in healthy donors." ] ] ] "textoCompleto" => "IntroductionDuring the last decade, the addition of rituximab, an anti-CD20 monoclonal antibody, to various chemotherapy regimens has dramatically improved the response rates in treating diffuse large B cell lymphoma (DLBCL).<a class="elsevierStyleCrossRef" href="#bib0095">1</a> Despite improved outcomes, a proportion of patients, particularly a subgroup of patients with an International Prognostic Index (IPI) score >2, exhibit relapsed and refractory disease.High-dose chemotherapy with autologous stem cell transplantation (auto-SCT) is one of the most effective treatments for patients with chemosensitive, relapsed or refractory aggressive DLBCL.<a class="elsevierStyleCrossRef" href="#bib0100">2</a> Unfortunately, the majority of patients who undergo this procedure inevitably relapse, which usually occurs within 1–2 years after transplantation. In addition to residual disease after SCT, a major concern in autografting is that the cell harvest contains occult tumor cells that may contribute to disease relapse. Studies comparing syngeneic, allogeneic and autologous transplantation in NHL suggest that tumor-free grafts may improve outcomes.<a class="elsevierStyleCrossRefs" href="#bib0105">3,4</a> Thus, to minimize the risk of reinfusing tumor cells, a number of strategies including rituximab have been used to purge tumor cells from the autologous grafts,<a class="elsevierStyleCrossRefs" href="#bib0115">5,6</a> and accumulating evidence has shown that after purging with rituximab, 80–90% of hematopoietic stem cell collections and products are free of cancer cells.<a class="elsevierStyleCrossRef" href="#bib0125">7</a>It was recently recognized that when rituximab-containing regimens are used as first-line therapy, the response rate to salvage treatments is worse for patients with relapsed or refractory DLBCL. The overall response rate to salvage chemotherapy regimens was poor.<a class="elsevierStyleCrossRef" href="#bib0130">8</a> The reason for this poor response remains unclear but may be related to rituximab-refractory disease. However, recent studies have shown that high doses<a class="elsevierStyleCrossRef" href="#bib0135">9</a> or more frequent doses of rituximab<a class="elsevierStyleCrossRef" href="#bib0140">10</a> may help increase the response rate.<a class="elsevierStyleCrossRef" href="#bib0145">11</a> Similarly, significant dose–response relationships to rituximab have been described in murine models of NHL.<a class="elsevierStyleCrossRef" href="#bib0150">12</a>The aim of this study was to evaluate the efficacy and toxicity of HD-R in combination with auto-SCT in patients with relapsed or refractory DLBCL. Significant improvements in both PFS and OS suggest that HD-R combined with auto-SCT is a feasible and promising treatment for relapsed or refractory DLBCL patients.Materials and methodsPatient selectionThis was a prospective nonrandomized controlled study to evaluate the effectiveness of HD-R in combination with auto-SCT for relapsed or refractory B cell lymphoma compared to that of auto-SCT alone. The selection of treatment options was based on patients’ personal choice.The inclusion criteria were age of 18–65 years, histologically confirmed relapsed or refractory DLBCL following a rituximab-based standard anthracycline regimen or salvage treatment, an Eastern Cooperative Oncology Group (ECOG) status <2, and history of an auto-SCT. The exclusion criteria were CNS involvement, history of HIV infection, posttransplantation lymph proliferative disorder, inadequate organ function, previous organ transplant and pregnancy (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). From December 2011 to August 2018, 42 patients with DLBCL qualified for the study, which was approved by the Institutional Review Board of the First Affiliated Hospital of Wenzhou Medical University and performed in accordance with the principles of the Declaration of Helsinki.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Graft mobilization, graft collection, and cell processingA noncross-resistant salvage regimen was used for initial cytoreduction therapy before graft mobilization. In the control group, peripheral hematopoietic stem cells were mobilized with the CE regimen, which consisted of etoposide (100mg/m2 per day) on days 1–3 and CTX (2000mg/m2 per day) on days 1–2. After chemotherapy, patients were treated with granulocyte colony-stimulating factor (G-CSF; 10μg/kg subcutaneously) daily. Stem cells were then collected from peripheral blood according to standard techniques. The target dose was more than 4×106CD34+cells/kg. In the HD-R group, 375mg/m2 rituximab was administered one day before the CE regimen therapy and 7 days after CE therapy, and 1000mg/m2 rituximab was administered after SCT on days +1 and +8. The other procedures were the same as those in the control group.Conditioning regimen, stem cell reinfusion, and supportive carePatients were pretreated with carmustine (300mg/m2, day −7), etoposide (200mg/m2, days −6 to −3), cytarabine (400mg/m2, days −6 to −3) and melphalan (140mg/m2, day −2) (BEAM). Three days after stem cell reinfusion, G-CSF (5μg/kg/day) was administered subcutaneously until the WBC count reached >1.5×109/L. All of the patients received infection prophylaxis as follows: acyclovir to prevent viral infections, fluconazole to prevent fungal infections, sulfamethoxazole to prevent pneumocystis pneumonia, and berberine to prevent bacterial infections.OutcomesThe primary end point for the study was PFS (i.e., the time from SCT until disease progression or death by any cause). The secondary end points were OS (i.e., the time from SCT until death or last follow-up), prognostic factors, safety and tolerability. Patients were evaluated after 1, 3, 6, and 12 months and every 6 months thereafter. Patients were assessed more frequently if necessary. The response was assessed using conventional diagnostic methods, including thoracic and abdominal CT scanning. Positron emission tomography scans were not mandatory. Response to treatment was classified according to the International Workshop Criteria.<a class="elsevierStyleCrossRef" href="#bib0155">13</a> Immune reconstitution was assessed with quantitative immunoglobulins (Igs) at 1, 3, 6, 12 and 24 months from auto-SCT and lymphocyte subsets at 1, 3, 6, and 12 months from auto-SCT when possible.Statistical methodsSurvival functions were estimated using the Kaplan–Meier method and compared using the log-rank test. The Cox proportional hazards model was used to evaluate prognostic factors for disease progression in the study group. Differences in patient characteristics were evaluated by the Wilcoxon rank sum test for continuous variables and by the χ2 test for categorical variables. Igs were evaluated using a Student's t-test. Lymphocyte subset recovery was examined using the generalized Wilcoxon procedure. Statistical significance was defined at 0.05. Analyses were performed using the SPSS 17.0 statistics software package (IBM, USA).ResultsPatient characteristicsA total of 42 patients (22 in the HD-R group and 20 in the control group) were enrolled and followed in the study between December 2011 and August 2018. None of the patients were lost to follow-up. Patient characteristics are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. There were no significant differences in the characteristics of patients between the two groups.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Safety and tolerabilityPeripheral hematopoietic stem cells were the source of the autologous grafts in all patients in both groups. The cells were harvested using a blood cell separator (AS104, Fresenius Kabi AG, Bad Homburg, Germany). The median number of CD34+ cells infused in the HD-R and control groups was 9.9×106/kg and 7.3×106/kg (P>0.05), respectively, and the median number of mononuclear cells (MNCs) was 4.0×108/kg and 3.9×108/kg (P>0.05), respectively. The median time to recovery of the absolute neutrophil count (ANC) to more than 500cells/μL was 10 days (range, 7–13 days) for the HD-R group and 11 days (range, 8–19 days) for the control group, which was not significantly different (P>0.05). The median time to complete platelet recovery (more than 20000/μL) also did not differ between the HD-R group and the control group (median, 11 days; range, 7–19 days vs. median, 12 days; range, 9–27 days; P>0.05).Adverse effectsAll HBcAb-positive patients received oral lamivudine, and no HBV reactivation occurred. HD-R therapy was well tolerated. No serious adverse events or deaths related to stem cell mobilization or auto-SCT were observed, nor were any treatment-related mortalities. Overall, 16 patients experienced bacterial infections due to agranulocytosis in the HD-R group, and 14 patients experienced bacterial infections in the control group (P=0.85). Three patients had septicemia due to E. coli but recovered after antibiotic therapy. Herpes zoster was observed in 6 patients during the 9 months after transplantation in the HD-R group and 4 patients in the control group (P=0.58). Neither group demonstrated cytomegalovirus reactivation. A pulmonary fungal infection was observed in one patient in the HD-R group after transplantation, and the patient recovered at +2 months after administration of anti-fungal therapy.Immune reconstitutionSerum Ig levels were monitored prior to auto-SCT and during follow-up at +1, +3, +6, +12 and +24 months in both groups (<a class="elsevierStyleCrossRefs" href="#fig0010">Figs. 2 and 3</a>). The mean baseline Ig level in the HD-R group, although low, did not significantly differ from that in the control group before auto-SCT. After transplantation, significantly reduced IgM levels (IgM <0.46g/L) were observed at +1, +3, and +6 months in the HD-R group (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C), while the incidence of hypogammaglobulinemia (IgG <7.51g/L or IgA <0.82g/L) did not differ between the two groups (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A and B). Compared with the Ig levels of the HD-R group at different times post-auto-SCT, we found reduced IgG levels at +3, +6, and +12 months (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A), reduced IgA levels at +1 and +3 months (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>B), and reduced IgM levels at +1, +3, and +6 months (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>C).<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Lymphocyte subsets were measured during follow-up in some patients. No CD19+ B cells were detected in the peripheral blood of 4 of the 22 patients 3 months after transplantation in the HD-R group. Compared with those before auto-SCT and in healthy donors, CD19+ B cells were quickly and severely suppressed during +1 to +6 months (P=0.002 and P=0.01, respectively) and subsequently regenerated slowly after +6 months in the HD-R group (P=0.52 and P=0.49, respectively) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A). In the control group, CD19+ B cells, although also quickly suppressed, were not significantly different from those before auto-SCT and in healthy donors (P=0.156 and P=0.07, respectively) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>B). Both in the HD-R group and the control group, CD19+ B cells decreased before SCT compared with healthy donors but did not significantly differ (P=0.535 and P=0.602, respectively).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>Survival analysesThe median follow-up duration of all patients was 45 months (range, 13–94 months) in the HD-R group and 31 months (range, 3–84 months) in the control group. A comparison of the outcomes was conducted 3 years after SCT to ensure a comparable follow-up duration. The 3-year PFS was 63.8% (95% CI, 52.3–75.3%) in the HD-R group and 35.0% (95% CI, 24.3–45.7%) in the control group (P=0.028; <a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>A). The 3-year OS was 80.1% (95% CI, 71.1–89.1%) in the HD-R group and 50.0% (95% CI, 38.8–61.2%) in the control group (P=0.035; <a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>B). Disease progression was the major cause of treatment failure for both groups, and the rate of disease progression was significantly higher in the control group (65%) than in the HD-R group (32%).<elsevierMultimedia ident="fig0025"></elsevierMultimedia>Results of the univariate analysis for factors influencing OS and PFS in patients with DLBCL are reported in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. The univariate analysis revealed that time to relapse (P=0.017) and HD-R combined with auto-SCT (P=0.041) were significant for PFS, and time to relapse (P=0.006) and HD-R combined with auto-SCT (P=0.030) remained significant for OS.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The Cox proportional hazards model was used to perform multivariate analyses, which included all of the parameters significant at P<0.05 in the univariate analyses and revealed that β2-MG at SCT (P=0.03) and HD-R (P=0.03) were independent prognostic factors for PFS in patients with DLBCL. Correspondingly, β2-MG at SCT (P=0.03) and HD-R (P=0.04) were also independent prognostic factors for OS in patients with DLBCL (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>DiscussionThe main objective of the study was to determine whether HD-R combined with auto-SCT could improve PFS and OS in patients with relapsed or refractory DLBCL. Other end points included prognostic factors and safety. We found that HD-R combined with auto-SCT significantly increased 3-year PFS and OS rates compared with auto-SCT without rituximab in rituximab-refractory patients. In the current era of rituximab first-line therapy, the outcomes of salvage treatments are worse for patients with relapsed or refractory DLBCL. In our study, we can see that among all enrolled refractory or relapsed patients who had received rituximab therapy before auto-SCT, the 3-year PFS greatly improved in the HD-R group (63.8% vs. 35.0%, P=0.028), and we assumed that HD-R may overcome the refractory response to prior rituximab usage. Dayde also found that there were significant dose–response relationships with rituximab in murine models of NHL,<a class="elsevierStyleCrossRef" href="#bib0150">12</a> which supports our conclusion.Our observations are consistent with previously published reports.<a class="elsevierStyleCrossRef" href="#bib0145">11</a> However, this study is the first study involving HD-R therapy in combination with auto-SCT in rituximab refractory patients in an Asian population.PFS and OS were identified as prognostic factors. The Cox model revealed HD-R combined with auto-SCT was a positive factor for PFS. All these results suggest that HD-R combined with auto-SCT can improve the prognosis of relapsed or refractory DLBCL.Rituximab administered before stem cell collection is safe in terms of mobilization.<a class="elsevierStyleCrossRef" href="#bib0145">11</a> With regard to harvesting CD34-positive cells, rituximab did not appear to decrease the quality of harvest in our study. Rituximab was reported to affect hematologic engraftment after auto-SCT in some studies<a class="elsevierStyleCrossRef" href="#bib0160">14</a> but not in more recent ones.<a class="elsevierStyleCrossRef" href="#bib0165">15</a> In our study, HD-R was found to be well tolerated in all patients, and we did not observe any significant infusion toxicities. Hematologic recovery after transplantation did not differ between the HD-R group and the control group.With respect to nonhematologic toxicities, concerns have been raised regarding increased infection rates in rituximab-treated patients, but others have not confirmed these concerns.<a class="elsevierStyleCrossRef" href="#bib0170">16</a> In our study, the incidence of bacterial infections was as expected, and there were no significant differences between the two groups. Herpes zoster infection was more common but not significantly higher in the HD-R group.Rituximab has been found to induce profound and durable B cell depletion.<a class="elsevierStyleCrossRef" href="#bib0175">17</a> Similar to previous reports,<a class="elsevierStyleCrossRef" href="#bib0180">18</a> we found that normal B cells were eliminated from the peripheral blood for up to 6 months following HD-R use and regenerated slowly after 6 months, which resulted in reduced IgG, IgA, and IgM levels in the HD-R group compared with different time stages post-auto-SCT. In addition, serum IgM levels decreased, but the serum IgG and IgA levels remained unaffected compared with the control group, which suggests that although HD-R depressed the B cell and Ig levels compared with the control group, Ig depression is not critical and may be a synergistic effect of HD-R and SCT. The memory B cells or plasma cells in the stem cell graft were capable of reconstituting and producing normal levels of Ig without being depleted by auto-SCT infusions. Another reason may be that the Ig intravenous infusion at regular intervals (on +1 and +8 days post-auto-SCT) influences the Ig levels, although the effective half-life is 16–24 days. With infection prophylaxis, there was no significant difference in the infection rate between the two groups. We also found that in both the HD-R group and control group, CD19+ B cells decreased before SCT compared with healthy donors, although the results were not significant. We believe that reduced CD19+ B cells at baseline were caused by prior rituximab immunosuppressive therapy.In conclusion, despite the small sample size, we demonstrated that the combined treatment modality of HD-R and auto-SCT significantly improved the PFS and OS in patients with relapsed or refractory DLBCL who were refractory to standard dose rituximab therapy. Moreover, the combined treatment was not associated with an increase in adverse events after transplantation. These promising results need to be confirmed in a larger prospective randomized study.FundingThis work was supported by Natural Science Foundation of Zhejiang Province (LQ19H080002), the Public Welfare Science and Technology Project of Wenzhou (Y20190119, Y20150034) and Wujieping Medical Foundation.Conflict of interestThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1471560" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1340189" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1471559" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1340190" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patient selection" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Graft mobilization, graft collection, and cell processing" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Conditioning regimen, stem cell reinfusion, and supportive care" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Outcomes" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical methods" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Patient characteristics" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Safety and tolerability" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Adverse effects" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Immune reconstitution" ] 4 => array:2 [ "identificador" => "sec0065" "titulo" => "Survival analyses" ] ] ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflict of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-06-26" "fechaAceptado" => "2019-11-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1340189" "palabras" => array:5 [ 0 => "Rituximab" 1 => "Relapsed" 2 => "Refractory" 3 => "Diffuse large B cell lymphoma" 4 => "Autologous stem cell transplantation" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1340190" "palabras" => array:5 [ 0 => "Rituximab" 1 => "En recaída" 2 => "Refractario" 3 => "Linfoma B difuso de células grandes" 4 => "Trasplante de células madre autólogas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectivesThe aim of this study was to evaluate the efficacy and toxicity of high-dose rituximab (HD-R) in combination with autologous stem cell transplantation (auto-SCT) in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). MethodsThere were 22 patients in the HD-R group, to whom rituximab was administered during stem cell mobilization (375mg/m2 1 day before and 7 days after chemotherapy) and after transplantation (1000mg/m2 on days +1 and +8). In the control group, the procedure was the same as that in the HD-R group but without rituximab. We observed the safety, tolerability, adverse effects and immune reconstitution of HD-R therapy. The log-rank test, univariate analysis and multivariate Cox regression analysis were used to evaluate the effect of HD-R on survival. ResultsIn total, 22 relapsed or refractory DLBCL patients were treated with HD-R. No dose-limiting toxicities were observed except for CD19+ B cell reconstruction in the first 6 months after SCT. There were 20 relapsed or refractory DLBCL patients in the control group. The 3-year progression-free survival (PFS) and overall survival (OS) greatly improved in the HD-R group compared to that in the control group (63.8% vs. 35.0%, P=0.028 and 80.1% vs. 50.0%, P=0.035, respectively). The univariate and multivariate analyses demonstrated that HD-R and the time to relapse were independent prognostic factors for OS and PFS. ConclusionHD-R in combination with auto-SCT is a feasible and promising treatment for patients with relapsed or refractory DLBCL." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivosEl objetivo de este estudio fue evaluar la eficacia y la toxicidad de la combinación de altas dosis de rituximab (HD-R) y el trasplante de células madre autólogas (auto-SCT) en pacientes con linfoma B difuso de células grandes (LBDCG) en recaída o refractario. MétodosEl grupo HD-R incluyó 22 pacientes a quienes se les administró rituximab durante la movilización de células madre (375mg/m2 un día antes y 7 días después de la quimioterapia) y tras el trasplante (1000mg/m2 los días +1 y +8). En el grupo control, el procedimiento fue el mismo que en el grupo HD-R, aunque sin rituximab. Observamos la seguridad, la tolerabilidad, los efectos adversos y la reconstitución inmune de la terapia HD-R. Utilizamos la prueba log-rank, el análisis univariante y el análisis de regresión de Cox multivariante para evaluar el efecto de HD-R en la supervivencia. ResultadosEn total, 22 pacientes de LBDCG en recaída o refractario fueron tratados con HD-R. No se observaron toxicidades limitantes de dosis excepto para la reconstrucción de células CD19+ B en los primeros 6 meses tras SCT. El grupo control incluyó 20 pacientes de LBDCG en recaída o refractario. La supervivencia libre de progresión (SLP) a 3 años y la supervivencia general (SG) mejoró significativamente en el grupo HD-R en comparación con el grupo control (63,8 vs. 35%; p=0,028 y el 80,1 vs. 50%; p=0,035, respectivamente). Los análisis univariante y multivariante demostraron que HD-R y tiempo de recaída eran factores pronósticos independientes para SG y SLP. ConclusiónLa combinación de HD-R y auto-SCT es un tratamiento factible y prometedor para pacientes con LBDCG en recaída o refractario." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "multimedia" => array:8 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1328 "Ancho" => 2167 "Tamanyo" => 173305 ] ] "descripcion" => array:1 [ "en" => "Flowchart for inclusion in the study. ASCT, autologous stem-cell transplantation; HD-R, 375mg/m2 1 day before and 7 days after stem-cell mobilization, 1000mg/m2 days 1 and 8 after transplantation." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2106 "Ancho" => 2508 "Tamanyo" => 249063 ] ] "descripcion" => array:1 [ "en" => "Incidence of Igs suppression according to time post-auto-SCT. (A) IgG. (B) IgA. (C) IgM. *P<0.05, the HD-R group vs. the control group." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2081 "Ancho" => 2508 "Tamanyo" => 293386 ] ] "descripcion" => array:1 [ "en" => "Incidence of Igs suppression in HD-R group according to time post-auto-SCT. (A) IgG. (B) IgA. (C) IgM. *P<0.05, the Igs in different time stage post SCT vs. the Igs in pre-SCT." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1015 "Ancho" => 2508 "Tamanyo" => 202397 ] ] "descripcion" => array:1 [ "en" => "Reconstitution of B cells post-auto-SCT. (A) Absolute numbers of B cells post-transplant in HD-R group, clearly demonstrating a fast decreased B cells post transplant (*P=0.002, #P=0.01), and a slowly recovery after auto-SCT at 6–12 months (P=0.49). (B) Absolute numbers of B cells post-auto-SCT in control group, clearly demonstrating a decreased B cells post transplant compared with pre-SCT (P=0.156) and healthy donors (P=0.07), *P<0.05, the CD19+ B cells at 1–6M vs. the CD19+ B cells in pre-SCT. #P<0.05, the CD19+ B cells 1–6M vs. the CD19+ B cells in healthy donors." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 857 "Ancho" => 2508 "Tamanyo" => 112682 ] ] "descripcion" => array:1 [ "en" => "Survival of patients after autologous stem-cell transplantation. Kaplan–Meier estimates of progression-free survival (A) and overall survival (B) for patients with DLBCL in the HD-R group and control group." ] ] 5 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Abbreviations: β2-MG, Beta2-microglobulin; LDH, lactate dehydrogenase; NS, not significant; SCT, stem-cell transplantation; IPI, International Prognostic Index; R, rituximab." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patient characteristics \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HD-R group (22) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control group (20) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (range, median) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22–65.48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18–63.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.139 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sex male, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 (63.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (55.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.569 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Median number of regimen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.359 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Elevated β2-MG at SCT, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (36.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (40.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.808 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Elevated LDH at SCT, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 (45.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (20.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.081 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Initial bone marrow involvement, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (31.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (25.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.625 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IPI at SCT</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.241 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 (63.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (80.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (36.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (20.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">R treatment before SCT (dose) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.118 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First-line therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Salvage therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Time to relapse, months</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.827 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤12<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (31.8%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 (35.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (68.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (65.0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Disease status prior to SCT</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.724 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (73%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (80%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (27%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (20%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2532262.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Including patients not achieving CR in first-line treatment." ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of patient groups undergoing auto-SCT with or without HD-R." ] ] 6 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: HR, hazard ratio; LDH, lactate dehydrogenase; SCT, stem-cell transplantation; IPI, International Prognostic Index; β2-MG, Beta2-microglobulin; R, rituximab." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Factors \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PFS</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">OS</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HR \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HR \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.242 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.711–2.169 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.243 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.720–2.147 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.435 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.580–1.779 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.956 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.981 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.567–1.697 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.944 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bone marrow involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.928 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.462–1.864 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.833 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.838 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.420–1.675 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.618 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LDH at SCT (>ULN) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.580–1.779 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.956 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.981 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.567–1.697 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.944 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">β2-MG at SCT (>ULN) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.376 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.159–0.889 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.026 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.423 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.180–0.997 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.049 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IPI at SCT (>2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.502 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.286–0.881 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.528 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.304–0.918 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.024 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Early relapse (<12 months) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.396 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.215–0.730 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.438 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.239–0.804 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.008 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HD-R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.322 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.180–0.577 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.345 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.194–0.613 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.009 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2532263.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Univariate analysis of clinical factors for PFS and OS." ] ] 7 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: HR, hazard ratio; SCT, stem-cell transplantation; IPI, International Prognostic Index; β2-MG, Beta2-microglobulin; R, rituximab." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Factors \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PFS</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">OS</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HR \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HR \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">β2-MG at SCT (>ULN) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.379 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.102–0.678 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.438 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.209–0.794 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IPI at SCT (>2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.502 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.286–0.881 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.87 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.528 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.304–0.918 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.87 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Early relapse (<12 months) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.980 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.234–7.709 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.450 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.507–13.209 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.35 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HD-R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.398 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.098–0.906 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.228 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.102–1.089 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.04 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2532264.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Multivariate analysis of clinical factors for PFS and OS." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:18 [ 0 => array:3 [ "identificador" => "bib0095" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. 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Original article

High-dose rituximab in combination with autologous stem cell transplantation for relapsed or refractory diffuse large B cell lymphoma

Combinación de altas dosis de rituximab y autotrasplante de progenitores hematopoyéticos en pacientes de linfoma B difuso de células grandes en recaída o refractario

Yi-Fen Shi, Shu-Juan Zhou, Lan Sun, Kang Yu

Corresponding author

kangyu62@hotmail.com

Corresponding authors.

, Yi Chen

Corresponding author

20442947@qq.com

Corresponding authors.

Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, China

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relapsed or refractory aggressive DLBCL&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">2</span></a> Unfortunately&#44; the majority of patients who undergo this procedure inevitably relapse&#44; which usually occurs within 1&#8211;2 years after transplantation&#46; In addition to residual disease after SCT&#44; a major concern in autografting is that the cell harvest contains occult tumor cells that may contribute to disease relapse&#46; Studies comparing syngeneic&#44; allogeneic and autologous transplantation in NHL suggest that tumor-free grafts may improve outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">3&#44;4</span></a> Thus&#44; to minimize the risk of reinfusing tumor cells&#44; a number of strategies including rituximab have been used to purge tumor cells from the autologous grafts&#44;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">5&#44;6</span></a> and accumulating evidence has shown that after purging with rituximab&#44; 80&#8211;90&#37; of hematopoietic stem cell collections and products are free of cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">It was recently recognized that when rituximab-containing regimens are used as first-line therapy&#44; the response rate to salvage treatments is worse for patients with relapsed or refractory DLBCL&#46; The overall response rate to salvage chemotherapy regimens was poor&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">8</span></a> The reason for this poor response remains unclear but may be related to rituximab-refractory disease&#46; However&#44; recent studies have shown that high doses<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a> or more frequent doses of rituximab<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">10</span></a> may help increase the response rate&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">11</span></a> Similarly&#44; significant dose&#8211;response relationships to rituximab have been described in murine models of NHL&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">12</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this study was to evaluate the efficacy and toxicity of HD-R in combination with auto-SCT in patients with relapsed or refractory DLBCL&#46; Significant improvements in both PFS and OS suggest that HD-R combined with auto-SCT is a feasible and promising treatment for relapsed or refractory DLBCL patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patient selection</span><p id="par0025" class="elsevierStylePara elsevierViewall">This was a prospective nonrandomized controlled study to evaluate the effectiveness of HD-R in combination with auto-SCT for relapsed or refractory B cell lymphoma compared to that of auto-SCT alone&#46; The selection of treatment options was based on patients&#8217; personal choice&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The inclusion criteria were age of 18&#8211;65 years&#44; histologically confirmed relapsed or refractory DLBCL following a rituximab-based standard anthracycline regimen or salvage treatment&#44; an Eastern Cooperative Oncology Group &#40;ECOG&#41; status &#60;2&#44; and history of an auto-SCT&#46; The exclusion criteria were CNS involvement&#44; history of HIV infection&#44; posttransplantation lymph proliferative disorder&#44; inadequate organ function&#44; previous organ transplant and pregnancy &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; From December 2011 to August 2018&#44; 42 patients with DLBCL qualified for the study&#44; which was approved by the Institutional Review Board of the First Affiliated Hospital of Wenzhou Medical University and performed in accordance with the principles of the Declaration of Helsinki&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Graft mobilization&#44; graft collection&#44; and cell processing</span><p id="par0035" class="elsevierStylePara elsevierViewall">A noncross-resistant salvage regimen was used for initial cytoreduction therapy before graft mobilization&#46; In the control group&#44; peripheral hematopoietic stem cells were mobilized with the CE regimen&#44; which consisted of etoposide &#40;100<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> per day&#41; on days 1&#8211;3 and CTX &#40;2000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> per day&#41; on days 1&#8211;2&#46; After chemotherapy&#44; patients were treated with granulocyte colony-stimulating factor &#40;G-CSF&#59; 10<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg subcutaneously&#41; daily&#46; Stem cells were then collected from peripheral blood according to standard techniques&#46; The target dose was more than 4<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>CD34<span class="elsevierStyleSup">&#43;</span><span class="elsevierStyleHsp" style=""></span>cells&#47;kg&#46; In the HD-R group&#44; 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> rituximab was administered one day before the CE regimen therapy and 7 days after CE therapy&#44; and 1000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> rituximab was administered after SCT on days &#43;1 and &#43;8&#46; The other procedures were the same as those in the control group&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conditioning regimen&#44; stem cell reinfusion&#44; and supportive care</span><p id="par0040" class="elsevierStylePara elsevierViewall">Patients were pretreated with carmustine &#40;300<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#44; day &#8722;7&#41;&#44; etoposide &#40;200<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#44; days &#8722;6 to &#8722;3&#41;&#44; cytarabine &#40;400<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#44; days &#8722;6 to &#8722;3&#41; and melphalan &#40;140<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#44; day &#8722;2&#41; &#40;BEAM&#41;&#46; Three days after stem cell reinfusion&#44; G-CSF &#40;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#47;day&#41; was administered subcutaneously until the WBC count reached &#62;1&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#46; All of the patients received infection prophylaxis as follows&#58; acyclovir to prevent viral infections&#44; fluconazole to prevent fungal infections&#44; sulfamethoxazole to prevent pneumocystis pneumonia&#44; and berberine to prevent bacterial infections&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Outcomes</span><p id="par0045" class="elsevierStylePara elsevierViewall">The primary end point for the study was PFS &#40;i&#46;e&#46;&#44; the time from SCT until disease progression or death by any cause&#41;&#46; The secondary end points were OS &#40;i&#46;e&#46;&#44; the time from SCT until death or last follow-up&#41;&#44; prognostic factors&#44; safety and tolerability&#46; Patients were evaluated after 1&#44; 3&#44; 6&#44; and 12 months and every 6 months thereafter&#46; Patients were assessed more frequently if necessary&#46; The response was assessed using conventional diagnostic methods&#44; including thoracic and abdominal CT scanning&#46; Positron emission tomography scans were not mandatory&#46; Response to treatment was classified according to the International Workshop Criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">13</span></a> Immune reconstitution was assessed with quantitative immunoglobulins &#40;Igs&#41; at 1&#44; 3&#44; 6&#44; 12 and 24 months from auto-SCT and lymphocyte subsets at 1&#44; 3&#44; 6&#44; and 12 months from auto-SCT when possible&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical methods</span><p id="par0050" class="elsevierStylePara elsevierViewall">Survival functions were estimated using the Kaplan&#8211;Meier method and compared using the log-rank test&#46; The Cox proportional hazards model was used to evaluate prognostic factors for disease progression in the study group&#46; Differences in patient characteristics were evaluated by the Wilcoxon rank sum test for continuous variables and by the <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> test for categorical variables&#46; Igs were evaluated using a Student&#39;s <span class="elsevierStyleItalic">t</span>-test&#46; Lymphocyte subset recovery was examined using the generalized Wilcoxon procedure&#46; Statistical significance was defined at 0&#46;05&#46; Analyses were performed using the SPSS 17&#46;0 statistics software package &#40;IBM&#44; USA&#41;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Patient characteristics</span><p id="par0055" class="elsevierStylePara elsevierViewall">A total of 42 patients &#40;22 in the HD-R group and 20 in the control group&#41; were enrolled and followed in the study between December 2011 and August 2018&#46; None of the patients were lost to follow-up&#46; Patient characteristics are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; There were no significant differences in the characteristics of patients between the two groups&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Safety and tolerability</span><p id="par0060" class="elsevierStylePara elsevierViewall">Peripheral hematopoietic stem cells were the source of the autologous grafts in all patients in both groups&#46; The cells were harvested using a blood cell separator &#40;AS104&#44; Fresenius Kabi AG&#44; Bad Homburg&#44; Germany&#41;&#46; The median number of CD34<span class="elsevierStyleSup">&#43;</span> cells infused in the HD-R and control groups was 9&#46;9<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;kg and 7&#46;3<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span>&#47;kg &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; respectively&#44; and the median number of mononuclear cells &#40;MNCs&#41; was 4&#46;0<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">8</span>&#47;kg and 3&#46;9<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">8</span>&#47;kg &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; respectively&#46; The median time to recovery of the absolute neutrophil count &#40;ANC&#41; to more than 500<span class="elsevierStyleHsp" style=""></span>cells&#47;&#956;L was 10 days &#40;range&#44; 7&#8211;13 days&#41; for the HD-R group and 11 days &#40;range&#44; 8&#8211;19 days&#41; for the control group&#44; which was not significantly different &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; The median time to complete platelet recovery &#40;more than 20<span class="elsevierStyleHsp" style=""></span>000&#47;&#956;L&#41; also did not differ between the HD-R group and the control group &#40;median&#44; 11 days&#59; range&#44; 7&#8211;19 days vs&#46; median&#44; 12 days&#59; range&#44; 9&#8211;27 days&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Adverse effects</span><p id="par0065" class="elsevierStylePara elsevierViewall">All HBcAb-positive patients received oral lamivudine&#44; and no HBV reactivation occurred&#46; HD-R therapy was well tolerated&#46; No serious adverse events or deaths related to stem cell mobilization or auto-SCT were observed&#44; nor were any treatment-related mortalities&#46; Overall&#44; 16 patients experienced bacterial infections due to agranulocytosis in the HD-R group&#44; and 14 patients experienced bacterial infections in the control group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;85&#41;&#46; Three patients had septicemia due to <span class="elsevierStyleItalic">E&#46; coli</span> but recovered after antibiotic therapy&#46; Herpes zoster was observed in 6 patients during the 9 months after transplantation in the HD-R group and 4 patients in the control group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;58&#41;&#46; Neither group demonstrated cytomegalovirus reactivation&#46; A pulmonary fungal infection was observed in one patient in the HD-R group after transplantation&#44; and the patient recovered at &#43;2 months after administration of anti-fungal therapy&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Immune reconstitution</span><p id="par0070" class="elsevierStylePara elsevierViewall">Serum Ig levels were monitored prior to auto-SCT and during follow-up at &#43;1&#44; &#43;3&#44; &#43;6&#44; &#43;12 and &#43;24 months in both groups &#40;<a class="elsevierStyleCrossRefs" href="#fig0010">Figs&#46; 2 and 3</a>&#41;&#46; The mean baseline Ig level in the HD-R group&#44; although low&#44; did not significantly differ from that in the control group before auto-SCT&#46; After transplantation&#44; significantly reduced IgM levels &#40;IgM &#60;0&#46;46<span class="elsevierStyleHsp" style=""></span>g&#47;L&#41; were observed at &#43;1&#44; &#43;3&#44; and &#43;6 months in the HD-R group &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#41;&#44; while the incidence of hypogammaglobulinemia &#40;IgG &#60;7&#46;51<span class="elsevierStyleHsp" style=""></span>g&#47;L or IgA &#60;0&#46;82<span class="elsevierStyleHsp" style=""></span>g&#47;L&#41; did not differ between the two groups &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A and B&#41;&#46; Compared with the Ig levels of the HD-R group at different times post-auto-SCT&#44; we found reduced IgG levels at &#43;3&#44; &#43;6&#44; and &#43;12 months &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#41;&#44; reduced IgA levels at &#43;1 and &#43;3 months &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41;&#44; and reduced IgM levels at &#43;1&#44; &#43;3&#44; and &#43;6 months &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>C&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Lymphocyte subsets were measured during follow-up in some patients&#46; No CD19<span class="elsevierStyleSup">&#43;</span> B cells were detected in the peripheral blood of 4 of the 22 patients 3 months after transplantation in the HD-R group&#46; Compared with those before auto-SCT and in healthy donors&#44; CD19<span class="elsevierStyleSup">&#43;</span> B cells were quickly and severely suppressed during &#43;1 to &#43;6 months &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#44; respectively&#41; and subsequently regenerated slowly after &#43;6 months in the HD-R group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;52 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;49&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#41;&#46; In the control group&#44; CD19<span class="elsevierStyleSup">&#43;</span> B cells&#44; although also quickly suppressed&#44; were not significantly different from those before auto-SCT and in healthy donors &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;156 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;07&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B&#41;&#46; Both in the HD-R group and the control group&#44; CD19<span class="elsevierStyleSup">&#43;</span> B cells decreased before SCT compared with healthy donors but did not significantly differ &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;535 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;602&#44; respectively&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Survival analyses</span><p id="par0080" class="elsevierStylePara elsevierViewall">The median follow-up duration of all patients was 45 months &#40;range&#44; 13&#8211;94 months&#41; in the HD-R group and 31 months &#40;range&#44; 3&#8211;84 months&#41; in the control group&#46; A comparison of the outcomes was conducted 3 years after SCT to ensure a comparable follow-up duration&#46; The 3-year PFS was 63&#46;8&#37; &#40;95&#37; CI&#44; 52&#46;3&#8211;75&#46;3&#37;&#41; in the HD-R group and 35&#46;0&#37; &#40;95&#37; CI&#44; 24&#46;3&#8211;45&#46;7&#37;&#41; in the control group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028&#59; <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>A&#41;&#46; The 3-year OS was 80&#46;1&#37; &#40;95&#37; CI&#44; 71&#46;1&#8211;89&#46;1&#37;&#41; in the HD-R group and 50&#46;0&#37; &#40;95&#37; CI&#44; 38&#46;8&#8211;61&#46;2&#37;&#41; in the control group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#59; <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>B&#41;&#46; Disease progression was the major cause of treatment failure for both groups&#44; and the rate of disease progression was significantly higher in the control group &#40;65&#37;&#41; than in the HD-R group &#40;32&#37;&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Results of the univariate analysis for factors influencing OS and PFS in patients with DLBCL are reported in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; The univariate analysis revealed that time to relapse &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;017&#41; and HD-R combined with auto-SCT &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;041&#41; were significant for PFS&#44; and time to relapse &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41; and HD-R combined with auto-SCT &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;030&#41; remained significant for OS&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">The Cox proportional hazards model was used to perform multivariate analyses&#44; which included all of the parameters significant at <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 in the univariate analyses and revealed that &#946;2-MG at SCT &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41; and HD-R &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41; were independent prognostic factors for PFS in patients with DLBCL&#46; Correspondingly&#44; &#946;2-MG at SCT &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41; and HD-R &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#41; were also independent prognostic factors for OS in patients with DLBCL &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">The main objective of the study was to determine whether HD-R combined with auto-SCT could improve PFS and OS in patients with relapsed or refractory DLBCL&#46; Other end points included prognostic factors and safety&#46; We found that HD-R combined with auto-SCT significantly increased 3-year PFS and OS rates compared with auto-SCT without rituximab in rituximab-refractory patients&#46; In the current era of rituximab first-line therapy&#44; the outcomes of salvage treatments are worse for patients with relapsed or refractory DLBCL&#46; In our study&#44; we can see that among all enrolled refractory or relapsed patients who had received rituximab therapy before auto-SCT&#44; the 3-year PFS greatly improved in the HD-R group &#40;63&#46;8&#37; vs&#46; 35&#46;0&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028&#41;&#44; and we assumed that HD-R may overcome the refractory response to prior rituximab usage&#46; Dayde also found that there were significant dose&#8211;response relationships with rituximab in murine models of NHL&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">12</span></a> which supports our conclusion&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Our observations are consistent with previously published reports&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">11</span></a> However&#44; this study is the first study involving HD-R therapy in combination with auto-SCT in rituximab refractory patients in an Asian population&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">PFS and OS were identified as prognostic factors&#46; The Cox model revealed HD-R combined with auto-SCT was a positive factor for PFS&#46; All these results suggest that HD-R combined with auto-SCT can improve the prognosis of relapsed or refractory DLBCL&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Rituximab administered before stem cell collection is safe in terms of mobilization&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">11</span></a> With regard to harvesting CD34-positive cells&#44; rituximab did not appear to decrease the quality of harvest in our study&#46; Rituximab was reported to affect hematologic engraftment after auto-SCT in some studies<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">14</span></a> but not in more recent ones&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">15</span></a> In our study&#44; HD-R was found to be well tolerated in all patients&#44; and we did not observe any significant infusion toxicities&#46; Hematologic recovery after transplantation did not differ between the HD-R group and the control group&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">With respect to nonhematologic toxicities&#44; concerns have been raised regarding increased infection rates in rituximab-treated patients&#44; but others have not confirmed these concerns&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">16</span></a> In our study&#44; the incidence of bacterial infections was as expected&#44; and there were no significant differences between the two groups&#46; Herpes zoster infection was more common but not significantly higher in the HD-R group&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Rituximab has been found to induce profound and durable B cell depletion&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">17</span></a> Similar to previous reports&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">18</span></a> we found that normal B cells were eliminated from the peripheral blood for up to 6 months following HD-R use and regenerated slowly after 6 months&#44; which resulted in reduced IgG&#44; IgA&#44; and IgM levels in the HD-R group compared with different time stages post-auto-SCT&#46; In addition&#44; serum IgM levels decreased&#44; but the serum IgG and IgA levels remained unaffected compared with the control group&#44; which suggests that although HD-R depressed the B cell and Ig levels compared with the control group&#44; Ig depression is not critical and may be a synergistic effect of HD-R and SCT&#46; The memory B cells or plasma cells in the stem cell graft were capable of reconstituting and producing normal levels of Ig without being depleted by auto-SCT infusions&#46; Another reason may be that the Ig intravenous infusion at regular intervals &#40;on &#43;1 and &#43;8 days post-auto-SCT&#41; influences the Ig levels&#44; although the effective half-life is 16&#8211;24 days&#46; With infection prophylaxis&#44; there was no significant difference in the infection rate between the two groups&#46; We also found that in both the HD-R group and control group&#44; CD19<span class="elsevierStyleSup">&#43;</span> B cells decreased before SCT compared with healthy donors&#44; although the results were not significant&#46; We believe that reduced CD19<span class="elsevierStyleSup">&#43;</span> B cells at baseline were caused by prior rituximab immunosuppressive therapy&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In conclusion&#44; despite the small sample size&#44; we demonstrated that the combined treatment modality of HD-R and auto-SCT significantly improved the PFS and OS in patients with relapsed or refractory DLBCL who were refractory to standard dose rituximab therapy&#46; Moreover&#44; the combined treatment was not associated with an increase in adverse events after transplantation&#46; These promising results need to be confirmed in a larger prospective randomized study&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0130" class="elsevierStylePara elsevierViewall">This work was supported by Natural Science Foundation of Zhejiang Province &#40;LQ19H080002&#41;&#44; the Public Welfare Science and Technology Project of Wenzhou &#40;Y20190119&#44; Y20150034&#41; and Wujieping Medical Foundation&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declared no potential conflicts of interest with respect to the research&#44; authorship&#44; and&#47;or publication of this article&#46;</p></span></span>"
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              "titulo" => "Graft mobilization&#44; graft collection&#44; and cell processing"
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              "titulo" => "Conditioning regimen&#44; stem cell reinfusion&#44; and supportive care"
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    "fechaRecibido" => "2019-06-26"
    "fechaAceptado" => "2019-11-28"
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            3 => "Diffuse large B cell lymphoma"
            4 => "Autologous stem cell transplantation"
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            0 => "Rituximab"
            1 => "En reca&#237;da"
            2 => "Refractario"
            3 => "Linfoma B difuso de c&#233;lulas grandes"
            4 => "Trasplante de c&#233;lulas madre aut&#243;logas"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The aim of this study was to evaluate the efficacy and toxicity of high-dose rituximab &#40;HD-R&#41; in combination with autologous stem cell transplantation &#40;auto-SCT&#41; in patients with relapsed or refractory diffuse large B cell lymphoma &#40;DLBCL&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">There were 22 patients in the HD-R group&#44; to whom rituximab was administered during stem cell mobilization &#40;375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> 1 day before and 7 days after chemotherapy&#41; and after transplantation &#40;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> on days &#43;1 and &#43;8&#41;&#46; In the control group&#44; the procedure was the same as that in the HD-R group but without rituximab&#46; We observed the safety&#44; tolerability&#44; adverse effects and immune reconstitution of HD-R therapy&#46; The log-rank test&#44; univariate analysis and multivariate Cox regression analysis were used to evaluate the effect of HD-R on survival&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">In total&#44; 22 relapsed or refractory DLBCL patients were treated with HD-R&#46; No dose-limiting toxicities were observed except for CD19<span class="elsevierStyleSup">&#43;</span> B cell reconstruction in the first 6 months after SCT&#46; There were 20 relapsed or refractory DLBCL patients in the control group&#46; The 3-year progression-free survival &#40;PFS&#41; and overall survival &#40;OS&#41; greatly improved in the HD-R group compared to that in the control group &#40;63&#46;8&#37; vs&#46; 35&#46;0&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028 and 80&#46;1&#37; vs&#46; 50&#46;0&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#44; respectively&#41;&#46; The univariate and multivariate analyses demonstrated that HD-R and the time to relapse were independent prognostic factors for OS and PFS&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">HD-R in combination with auto-SCT is a feasible and promising treatment for patients with relapsed or refractory DLBCL&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este estudio fue evaluar la eficacia y la toxicidad de la combinaci&#243;n de altas dosis de rituximab &#40;HD-R&#41; y el trasplante de c&#233;lulas madre aut&#243;logas &#40;auto-SCT&#41; en pacientes con linfoma B difuso de c&#233;lulas grandes &#40;LBDCG&#41; en reca&#237;da o refractario&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El grupo HD-R incluy&#243; 22 pacientes a quienes se les administr&#243; rituximab durante la movilizaci&#243;n de c&#233;lulas madre &#40;375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> un d&#237;a antes y 7 d&#237;as despu&#233;s de la quimioterapia&#41; y tras el trasplante &#40;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> los d&#237;as &#43;1 y &#43;8&#41;&#46; En el grupo control&#44; el procedimiento fue el mismo que en el grupo HD-R&#44; aunque sin rituximab&#46; Observamos la seguridad&#44; la tolerabilidad&#44; los efectos adversos y la reconstituci&#243;n inmune de la terapia HD-R&#46; Utilizamos la prueba <span class="elsevierStyleItalic">log-rank</span>&#44; el an&#225;lisis univariante y el an&#225;lisis de regresi&#243;n de Cox multivariante para evaluar el efecto de HD-R en la supervivencia&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">En total&#44; 22 pacientes de LBDCG en reca&#237;da o refractario fueron tratados con HD-R&#46; No se observaron toxicidades limitantes de dosis excepto para la reconstrucci&#243;n de c&#233;lulas CD19&#43; B en los primeros 6 meses tras SCT&#46; El grupo control incluy&#243; 20 pacientes de LBDCG en reca&#237;da o refractario&#46; La supervivencia libre de progresi&#243;n &#40;SLP&#41; a 3 a&#241;os y la supervivencia general &#40;SG&#41; mejor&#243; significativamente en el grupo HD-R en comparaci&#243;n con el grupo control &#40;63&#44;8 vs&#46; 35&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;028 y el 80&#44;1 vs&#46; 50&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;035&#44; respectivamente&#41;&#46; Los an&#225;lisis univariante y multivariante demostraron que HD-R y tiempo de reca&#237;da eran factores pron&#243;sticos independientes para SG y SLP&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La combinaci&#243;n de HD-R y auto-SCT es un tratamiento factible y prometedor para pacientes con LBDCG en reca&#237;da o refractario&#46;</p></span>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flowchart for inclusion in the study&#46; ASCT&#44; autologous stem-cell transplantation&#59; HD-R&#44; 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> 1 day before and 7 days after stem-cell mobilization&#44; 1000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> days 1 and 8 after transplantation&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Incidence of Igs suppression according to time post-auto-SCT&#46; &#40;A&#41; IgG&#46; &#40;B&#41; IgA&#46; &#40;C&#41; IgM&#46; &#42;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; the HD-R group vs&#46; the control group&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Reconstitution of B cells post-auto-SCT&#46; &#40;A&#41; Absolute numbers of B cells post-transplant in HD-R group&#44; clearly demonstrating a fast decreased B cells post transplant &#40;&#42;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#44; <span class="elsevierStyleSup">&#35;</span><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#44; and a slowly recovery after auto-SCT at 6&#8211;12 months &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;49&#41;&#46; &#40;B&#41; Absolute numbers of B cells post-auto-SCT in control group&#44; clearly demonstrating a decreased B cells post transplant compared with pre-SCT &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;156&#41; and healthy donors &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;07&#41;&#44; &#42;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; the CD19<span class="elsevierStyleSup">&#43;</span> B cells at 1&#8211;6<span class="elsevierStyleHsp" style=""></span>M vs&#46; the CD19<span class="elsevierStyleSup">&#43;</span> B cells in pre-SCT&#46; <span class="elsevierStyleSup">&#35;</span><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; the CD19<span class="elsevierStyleSup">&#43;</span> B cells 1&#8211;6<span class="elsevierStyleHsp" style=""></span>M vs&#46; the CD19<span class="elsevierStyleSup">&#43;</span> B cells in healthy donors&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Survival of patients after autologous stem-cell transplantation&#46; Kaplan&#8211;Meier estimates of progression-free survival &#40;A&#41; and overall survival &#40;B&#41; for patients with DLBCL in the HD-R group and control group&#46;</p>"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; &#946;2-MG&#44; Beta2-microglobulin&#59; LDH&#44; lactate dehydrogenase&#59; NS&#44; not significant&#59; SCT&#44; stem-cell transplantation&#59; IPI&#44; International Prognostic Index&#59; R&#44; rituximab&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleItalic">Age &#40;range&#44; median&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Sex male&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11 &#40;55&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Median number of regimen</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Elevated &#946;2-MG at SCT&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;808&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Elevated LDH at SCT&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Initial bone marrow involvement&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">IPI at SCT</span></td><td class="td" title="\n
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                  \t\t\t\t">14 &#40;63&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8 &#40;36&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">R treatment before SCT &#40;dose&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">22&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>First-line therapy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Salvage therapy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Time to relapse&#44; months</span></td><td class="td" title="\n
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                  \t\t\t\t">0&#46;827&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804;12<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7 &#40;31&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7 &#40;35&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;12&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">15 &#40;68&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">13 &#40;65&#46;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Disease status prior to SCT</span></td><td class="td" title="\n
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                  \t\t\t\t">0&#46;724&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CR&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">16 &#40;73&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">16 &#40;80&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PR&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">6 &#40;27&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  """
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t" scope="col">Factors&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Sex&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Bone marrow involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;462&#8211;1&#46;864&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;833&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;838&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;420&#8211;1&#46;675&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;618&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LDH at SCT &#40;&#62;ULN&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">1&#46;016&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;580&#8211;1&#46;779&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;956&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;981&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;567&#8211;1&#46;697&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">0&#46;944&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;2-MG at SCT &#40;&#62;ULN&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;376&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;159&#8211;0&#46;889&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;423&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;180&#8211;0&#46;997&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;049&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IPI at SCT &#40;&#62;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;502&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;286&#8211;0&#46;881&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;528&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;304&#8211;0&#46;918&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;024&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early relapse &#40;&#60;12 months&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;396&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;215&#8211;0&#46;730&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;438&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;239&#8211;0&#46;804&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">HD-R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;322&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;180&#8211;0&#46;577&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;345&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Early relapse &#40;&#60;12 months&#41;&nbsp;\t\t\t\t\t\t\n
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                            4 => "M&#46; Mohren"
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                      "doi" => "10.1016/S1470-2045(08)70002-0"
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                        "tituloSerie" => "Lancet Oncol"
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                        "volumen" => "9"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18226581"
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