Boas Práticas na Administração do Rituximab: Revisão Integrativa da Literatura / Good practices in Rituximab Administration: Integrative Literature Review / Buenas Prácticas en la Administración de Rituximab: Revisión Integradora de la Literatura

Introdução: O rituximab é um anticorpo monoclonal quimérico camundongo/humano, amplamente utilizado no cenário terapêutico de vários diagnósticos. Por apresentar diferentes protocolos de administração, manejo e efeitos adversos, seu uso requer atenção da equipe de saúde. Objetivo: Descrever os protocolos infusionais do rituximab na primeira infusão, nas subsequentes e na dessensibilização, e caracterizar a sua segurança. Método: Revisão integrativa da literatura. A busca pelos periódicos foi realizada nas bases de dados e bibliotecas eletrônicas: LILACS, PubMed, MEDLINE, SciELO e BDEnf. Resultados: O cruzamento dos descritores proporcionou a identificação de 413 artigos. Destes, 113 foram lidos na íntegra e, ao final, 16 artigos foram aplicáveis ao desenho do estudo. Os artigos foram publicados entre os anos de 2016 e 2020, com predomínio da língua inglesa (87,5%). Quanto às principais formas de administração do medicamento, nove estudos abordaram a infusão por via intravenosa (em variadas modalidades de tempo) e sete por via subcutânea. Conclusão: De acordo com a literatura científica, todas as modalidades de infusão intravenosa e subcutânea demostram ser seguras e eficazes se os protocolos forem adequadamente indicados e corretamente aplicados

Introduction: Rituximab is a mouse/human chimeric monoclonal antibody, widely used in the therapeutic setting of various diagnoses, due to its different administration, management and adverse effects protocols; its use requires attention by the healthcare team. Objective: Describe the infusion protocols for rituximab in the first, subsequent and desensitization infusions, and characterize their safety. Method: Integrative literature review. The search was performed in databases and electronic libraries: LILACS, PubMed, MEDLINE, SciELO and BDEnf. Results: In all, 413 articles were eligible after crossing the descriptors. Of these, 113 were read in full and eventually, 16 articles matched the study design. The articles were published from 2016 to 2020, predominantly in English (87.5%). Concerning the main routes of administration in the studies included, nine addressed the intravenous infusion (in different modalities of time) and seven, subcutaneously. Conclusion: According to the scientific literature, all intravenous and subcutaneous infusion modalities are shown to be safe and effective if the protocols are correctly selected and applied

Introducción: Rituximab es un anticuerpo monoclonal quimérico de ratón/humano, ampliamente utilizado em el ámbito terapéutico de diversos diagnósticos. Debido a sus diferentes protocolos de administración, manejo y efectos adversos, su uso requiere la atención del equipo de salud. Objetivo: Describirlos protocolos de infusión de rituximab em la primera, subsiguiente y desensibilización, y caracterizar su seguridad. Método: Es una revisión integradora de la literatura. La búsqueda de revistas se realizó en bases de datos y bibliotecas electrónicas: LILACS, PubMed, MEDLINE, SciELO y BDEnf. Resultados: Cruzar los descriptores proporciono la elegibilidad de 413 artículos. De estos, 113 fueron leí dos íntegramente y al final, 16 artículos fueron aplicables al diseño del estudio. Los artículos fueron publicados entre 2016 y 2020, con predominio del inglés (87,5%). En cuanto a las principales formas de administración del fármaco, entre los estudios incluidos, nueve abordaron la infusión intravenosa (en diferentes modalidades de tiempo) y siete la vía subcutánea. Conclusión: Según la literatura científica, todas las modalidades de infusión intravenosa y subcutánea se muestran seguras y efectivas si los protocolos están debidamente indicados y correctamente aplicados

Novel Therapies for Follicular Lymphoma and Other Indolent Non-Hodgkin Lymphomas.

OPINION STATEMENT: When selecting therapy for patients with indolent non-Hodgkin lymphoma (iNHL) including follicular (FL), marginal zone (MZL), small lymphocytic (SLL), and lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM), there are several factors to consider. With a median age around 70 at diagnosis, many patients have accumulated comorbid conditions that may limit treatment options. Although incurable for most, iNHL is a chronic disease with a median overall survival measured in years to decades. This long natural history changes the risk-to-benefit balance with a lower acceptance of toxicity early in the treatment course compared to that of aggressive lymphomas. Despite a recent rapid increase in available therapies, overall progress in iNHL has been slow for several reasons. Initial trials grouped iNHLs together making it challenging to appreciate the differential activity among subtypes. We have not been able to develop prognostic models that maintain validity in the era of chemotherapy-free options. Predictive markers have been elusive and without identified molecular signatures, it is challenging to select and sequence therapy. With these clinical factors in mind, in addition to the heterogeneity among and within iNHLs, I do not have a standard treatment algorithm and feel each patient should have an individualized treatment approach. This review focuses on recent updates and controversies in the management of iNHL with a focus on FL and MZL.

Prognostic nutritional index, a novel biomarker which predicts worse prognosis in diffuse large B cell lymphoma.

The prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is associated with survival in several types of lymphoma. The purpose of this study was to investigate the prognostic value of PNI in diffuse large B cell lymphoma (DLBCL). With three hundred and ten patients were enrolled, the median level of PNI was 45.90 (range 25.30-139.70). According to the receiver operating characteristic (ROC) curve, 44.85 was determined to be the best cutoff value to divide patients into two different groups. With a median follow-up of 33.3 months (range 3.5-118.5), compared with the high PNI group, the 3-year and adjusted 3-year progression-free survival (PFS) and overall survival (OS) were worse in the low PNI group (all P < 0.050). Multivariate Cox analysis suggested that low PNI was an independent risk factor for PFS (hazard ratio (HR) 2.196, 95 % CI 1.197-4.030, P = 0.011) and showed a tendency to predict inferior OS (HR 1.918, 95 % CI 0.932-3.948, P = 0.077). Furthermore, PNI combined with other significant prognostic factors to build a novel prognostic index, namely NPI, was more accurate than the National Comprehensive Cancer Network international prognostic index (NCCN-IPI) to predict worse PFS and had a similar effect on predicting OS. All these findings suggested that PNI, as a novel available biomarker, was of prognostic significance in DLBCL patients.

MiR-22, a serum predictor of poor outcome and therapy response in diffuse large B-cell lymphoma patients.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive, heterogeneous neoplasm where prognostication and therapeutic decision are challenging. The available prognostic tools are not able to identify all patients refractory to treatment. MicroRNAs, small RNAs frequently deregulated in cancer, stably circulate in biofluids, representing interesting candidates for non-invasive biomarkers. Here we validated serum miR-22, an evolutionarily conserved microRNA, as a prognostic/predictive biomarker in DLBCL. Moreover, we found that its expression and release from DLBCL cells are related to therapy response and adversely affect cell proliferation. These results suggest that miR-22 is a promising complementary or even independent non-invasive biomarker for DLBCL management.

The first biological choice in patients with rheumatoid arthritis: data from the Moroccan register of biotherapies.

INTRODUCTION: the aim of our study is to determine, from data of the Moroccan register of biotherapies, the factors influencing the choice of the first prescribed biological treatment. METHODS: cross-sectional multicenter study including rheumatoid arthritis patients who were initiated the first biological treatment either: Rituximab, an anti-TNF, or Tocilizumab. The determinants related to the patient and disease have been gathered. A univariate and then multivariate analysis to determine the factors associated with the choice of the first bDMARDs was realized. RESULTS: a total of 225 rheumatoid arthritis patients were included in the Moroccan registry. The mean age was 52 ± 11 years, with female predominance 88% (n = 197). The first prescribed biological treatment was Rituximab 74% (n = 166), the second one was Tocilizumab, 13.6% (n = 31) then comes the anti-TNF in 3rd position with 12.4% (n = 28). The factors associated with the choice of Rituximab as the first line bDMARDs prescribed in univariate analysis were: the insurance type, the positivity of the rheumatoid factor. In multivariate analysis, only the insurance type that remains associated with the choice of Rituximab as the first biological drugs. The Tocilizumab was associated with shorter disease duration and was more prescribed as mono-therapy compared to non Tocilizumab group. TNFi was associated with the insurance type. CONCLUSION: our study suggests that Rituximab and TNFi are associated with the type of insurance and Tocilizumab is the most prescribed biologic mono-therapy in RA patients. Further studies are needed to confirm these results.

Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma.

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.

Watch-and-wait or immediate immunotherapy/immunochemotherapy in patients with phase IE primary pulmonary MALT lymphoma? A multicenter retrospective study.

Primary pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is rare, and the optimal frontline treatment has not taken shape so far. It is still debatable whether the watch-and-wait (W&W) policy is beneficial to patients, especially in the early stage. This study was to compare the efficacy of W&W with rituximab single agent or combined chemotherapy (R/R-Chemo) on primary pulmonary MALT patients with localized disease. Clinical characters and effect on 28 patients with primary pulmonary MALT (IE phase) were analyzed. Among the 28 patients, 14 were grouped into W&W cohort, and 14 were immediately treated with R/R-Chemo. The median follow-up duration was 62 months. The estimated median time to treatment failure (TTF) in the W&W cohort and immediate R/R-Chemo cohort was 29 months and 59 months, which were not significantly different (P = 0.667). The estimated median time of overall survival (OS) in the W&W cohort and immediate R/R-Chemo cohort was 78 months and 76 months, which were also not statistically significant (P = 0.696). Concerning prognosis, there is no difference between patients with primary pulmonary MALT (IE phase) treated with W&W and with timely R/R-Chemo.

Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and front line therapies have not improved overall outcomes since the advent of immunochemotherapy. By pairing DNA and gene expression data with clinical response data, we identified a high-risk subset of non-GCB DLBCL patients characterized by genomic alterations and expression signatures capable of sustaining an inflammatory environment. These mutational alterations (PIM1, SPEN, and MYD88 [L265P]) and expression signatures (NF-κB, IRF4, and JAK-STAT engagement) were associated with proliferative signaling, and were found to be enriched in patients treated with RCHOP that experienced unfavorable outcomes. However, patients with these high-risk mutations had more favorable outcomes when the immunomodulatory agent lenalidomide was added to RCHOP (R2CHOP). We are the first to report the genomic validation of a high-risk phenotype with a preferential response towards R2CHOP therapy in non-GCB DLBCL patients. These conclusions could be translated to a clinical setting to identify the ~38% of non-GCB patients that could be considered high-risk, and would benefit from alternative therapies to standard RCHOP based on personalized genomic data.

Low-dose radiotherapy (2×2 g) versus low doses and rituximab in the treatment of marginal zone b-cell lymphoma previously untreated.

Radiotherapy (RT)is considered the treatment of choice in patients with Extra-nodal marginal zone lymphoma (EMZL) at early stage, but the presence of late toxicities has been limited the acceptance. Recently, low doses of RT LDR) (2 x 2 Gy) and the use of limited fields has been observed that retain the efficacy but eliminate toxicities; rituximab is considered as a single agent useful in these setting of patients. Thus, we conducted a open label study to evaluate the use of LDR compared with LDR and rituximab, in a large number of patients without previous treatment. METHODS: Patients with pathological diagnosis or(EMZL)), stage I, without previous treatment, were allocated in a proportion 1:1 to received LDR) that were compared with a group that received LDR and rituximab. RESULTS: One hundred and fourteen patients were recruit ; overall response rate and complete response were : 58(98.3%) and 54 (96.4 %)in patients whose respectively in LDR that were no statistical different to the observed in the LDR + R arm: 53 (96.3%) and 51 (92.75 %) respectively. Actuarial curves at 5-years show that progression-free survival in LDR arm were: 98.4% (95% Confidence interval (CI): 93%-108%) and OS were 97.2% (95%CI: 92%-110%), that did no show statistical difference with the LDR-R arm: 96.4% (95%CI: 90%-110%), and 98.5%(95%CI:92%-107%) respectively. Univariate analysis did not show any statistical differences in the analysis of prognostic factors. Acute and late toxicities were not observed. CONCLUSION: We conclude that LDR will be considered as the treatment of choice in patients with EMZL, in early stage, localized in head and neck anatomical sites; because response and outcome were excellent, without any toxicity, addition of rituximab did not improve results and outcome.

Maintenance rituximab in Veterans with follicular lymphoma.

Real-world practice patterns and clinical outcomes in patients with follicular lymphoma (FL), including the adoption of maintenance rituximab (MR) therapy in the United States (US), have been reported in few studies since the release of the National LymphoCare Study almost a decade ago. We analyzed data from the largest integrated healthcare system in the United States, the Veterans Health Administration (VHA), to identify rates of adoption and effectiveness of MR in FL patients after first-line (1L) treatment. We identified previously untreated patients with FL in the VHA between 2006 and 2014 who achieved at least stable disease after chemoimmunotherapy or immunotherapy. Among these patients, those who initiated MR within 238 days of 1L composed the MR group, whereas those who did not were classified as the non-MR group. We examined the effect of MR on progression-free survival (PFS) and overall survival (OS). A total of 676 patients met our inclusion criteria, of whom 300 received MR. MR was associated with significant PFS (hazard ratio [HR]=0.55, P < .001) and OS (HR = 0.53, P = .005) compared to the non-MR group, after adjusting by age, sex, ethnicity, geographic region, diagnosis period, stage, grade at diagnosis, hemoglobin, lactate dehydrogenase (LDH), Charlson comorbidity index (CCI), 1L treatment regimen, and response to 1L treatment. These results suggest that in FL patients who do not experience disease progression after 1L treatment in real-world settings, MR is associated with a significant improvement in both PFS and OS. Maintenance therapy should be considered in FL patients who successfully complete and respond to 1L therapy.

Risk adapted approach: How to treat splenic marginal zone lymphoma in resource-poor settings? - The real-life experience of a Brazilian cancer treatment center.

BACKGROUND: Splenic marginal zone lymphoma (SMZL) is a rare lymphoid B-cell malignant neoplasm with primary involvement of the spleen. It is a chronic disease, of indolent behavior and prolonged survival. However, 25% of cases have higher biological aggressiveness, propensity for histological transformation to high grade B-cell non-Hodgkin lymphoma and shortened survival. Recognition of these cases of reserved outcome is important for selecting a risk-adapted therapeutic approach in a resource-poor settings. METHODS: We described clinical and epidemiological characteristics, survival analysis and prognostic factors in a retrospective cohort of 39 SMZL patients, treated in Latin America. RESULTS: We observed a predominance of female (71.8%), median age of 63 years and higher incidence of B symptoms (56.4%) and extra-splenic involvement (87.1%) than in European and North-American series. With a median follow-up of 8.7 years (0.6-20.2 years), estimated 5-year overall survival (OS) and progression-free survival (PFS) were 76.9% and 63.7%, respectively. Factors with adverse prognostic impact on OS and PFS were Hb < 100 g/L, platelet count < 100 x 109/L, albumin < 3.5 g/dL, LDH > 480 U/L and high-risk Arcaini and SMZL/WG scores. Despite a relative low number of patients, no superiority was observed among the therapeutic regimens used including rituximab monotherapy, splenectomy and cytotoxic chemotherapy. CONCLUSION: Therefore, in resource-poor settings, where access to immunotherapy is not universal for all SMZL patients, we suggest that first-line should consist on rituximab therapy for elderly patients or with high surgical risk or with at least 1 risk factor identified in our study. Remainders can be safely managed with splenectomy.

Safety and efficacy of temsirolimus in combination with three different immuno-chemotherapy regimens in relapse and refractory mantle cell lymphoma, final results of the T3 phase IB trial of the LYSA.

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1-3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.

Indications for Rituximab Use in an Integrated Health Care Delivery System.

BACKGROUND: Rituximab is a top-selling biologic that was first approved by the FDA in 1997 for a non-Hodgkin lymphoma orphan indication. It has since been approved for additional orphan indications, with rheumatoid arthritis as the only FDA-approved, nonorphan indication. Evidence suggests that rituximab is frequently used off-label, but information on its use over time and indications for use in the United States is limited. OBJECTIVE: To assess incident rituximab use over time in an integrated health care delivery system. METHODS: This was a cross-sectional, retrospective study. Data were collected from administrative databases and manual chart reviews. Patients who received their first rituximab infusion between October 1, 2009, and December 31, 2017, and who were not a part of a clinical trial were included. Indication for use (FDA-approved orphan/nonorphan, off-label) was determined. Proportions of use were assessed over time. Multivariable logistic regression modeling was performed to assess factors associated with receiving rituximab for an FDA-approved indication. RESULTS: A total of 1,674 patients were included. The majority (66.4%) of patients had an FDA-approved indication, with lymphoma being the most common approved indication (66.4%). The most common indication for off-label use was neurologic conditions (72.7%), predominantly demyelinating diseases. Off-label indication use increased from 1.2% in 2009 to 55.6% in 2017. Factors associated with rituximab use for an FDA-approved indication included increased age (adjusted odds ratio [AOR] = 1.05, 95% CI = 1.04-1.07) and increased burden of chronic disease (chronic disease score: AOR = 1.07, 95% CI = 1.02-1.12; Charlson Comorbidity Index score: AOR = 3.52, 95% CI = 3.03-4.10). CONCLUSIONS: Off-label use of rituximab grew dramatically over the course of the study. With the recent FDA approval of the rituximab biosimilar and its expected lower price, off-label use will likely continue to rise. Opportunities for cost savings and to ensure appropriate use of these medications should be evaluated. DISCLOSURES: This study was funded by Kaiser Permanente. All authors except Hansen are employed by Kaiser Permanente. Hansen has nothing to disclose. Preliminary results were presented at the Mountain States Conference for Residents and Preceptors in May 2019 in Salt Lake City, UT, and at an encore presentation October 2019 at the American College of Clinical Pharmacy Annual Meeting in New York, NY.

The simplified follicular lymphoma PRIMA-prognostic index is useful in patients with first-line chemo-free rituximab-based therapy.

Follicular lymphoma (FL) is a heterogeneous disease; therefore, reliable prognostic tools are needed to plan treatment strategies. The FL International Prognostic Index (FLIPI) was developed before the rituximab era, while the PRIMA-PI was built on rituximab chemotherapy. Our objective was to evaluate these two prognostic tools in a cohort of 291 patients with FL treated in two prospective randomised Nordic Lymphoma Group trials with rituximab ± interferon. All patients had symptomatic/progressive disease and were previously untreated. The PRIMA-PI was prognostic for both time to treatment failure (TTF) and overall survival (OS) (log-rank P = 0·003 and P < 0·001, respectively). The PRIMA-PI high-risk identified a small group of patients with a very short TTF and OS compared to the low-risk group, with a hazard ratio (HR) of 1·90 (95% confidence interval [CI] 1·30-2·78, P = 0·001) and HR of 3·19 (95% CI 1·75-5·83, P < 0·001), respectively. The FLIPI risk groups were prognostic only for OS (log-rank P = 0·018). The simplified PRIMA-PI was valid in our FL cohort with first-line rituximab-containing chemo-free therapy and shows an improved risk stratification compared to the FLIPI, especially in patients aged >60 years. Patients in the PRIMA-PI high-risk group should be considered for alternative therapies.

Prognostic model based on the geriatric nutritional risk index and sarcopenia in patients with diffuse large B-cell lymphoma.

BACKGROUND: Systemic inflammation and cachexia are associated with adverse clinical outcomes in diffuse large B-cell lymphoma (DLBCL). The Geriatric Nutritional Risk Index (GNRI) is one of the main parameters used to assess these conditions, but its efficacy in DLBCL is inconclusive. METHODS: We retrospectively reviewed 228 DLBCL patients who were treated with R-CHOP immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The patients were stratified according to GNRI score (> 98, 92 to 98, 82 to < 92, and < 82) as defined in previous studies. Additionally, the extent of sarcopenia was categorized as sarcopenia-both, sarcopenia-L3/PM alone, and non-sarcopenia-both according to skeletal muscle index. RESULTS: Survival curves plotted against a combination of GNRI and sarcopenia scores revealed two clear groups as follows: high cachexia risk (HCR) group (GNRI < 82, sarcopenia-both, or GNRI 82-92 with sarcopenia-L3/PM alone) and low cachexia risk (LCR) group (others). The HCR group had a lower complete response rate (46.5% vs. 86.6%) and higher frequency of treatment-related mortality (19.7% vs. 3.8%) and early treatment discontinuation (43.7% vs. 8.3%) compared with the LCR group. The median progression-free survival (PFS) (not reached vs. 10.3 months, p <  0.001) and overall survival (OS) (not reached vs. 12.9 months, p <  0.001) were much shorter in the HCR group than in the LCR group. On multivariable analyses, the HCR group was shown to be an independent negative prognostic factor for PFS and OS after adjusting the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI). CONCLUSIONS: A combined model of GNRI and sarcopenia may provide prognostic information independently of the NCCN-IPI in DLBCL.

R-DHA-oxaliplatin (R-DHAOx) versus R-DHA-cisplatin (R-DHAP) regimen in B-cell lymphoma treatment: A eight-year trajectory study.

BACKGROUND: The R-DHAP regimen (rituximab, cisplatin, dexamethasone, and high-dose cytarabine) is standardly used to treat relapsed Non-Hodgkin lymphoma (NHL). Despite scarce data, cisplatin is frequently substituted with oxaliplatin (R-DHAOx) to avoid nephrotoxicity. We compared nephrotoxicity of cisplatin and oxaliplatin based on creatinine-based trajectory modeling. METHODS: All patients with NHL treated by R-DHAP or R-DHAOx in Angers hospital between January 01, 2007, and December 31, 2014, were included. Patients received cisplatin 100 mg/m2 or oxaliplatin 130 mg/m2 (d1) with cytarabine (2000 mg/m2 , two doses, d2), dexamethasone (40 mg, d1-4), and rituximab (375 mg/m2 , d1). Creatinine levels were recorded before each cycle. Individual profiles of trajectories were clustered to detect homogeneous patterns of evolution. RESULTS: Twenty-two patients received R-DHAP, 35 R-DHAOx, 6 switched from R-DHAP to R-DHAOx due to nephrotoxicity. Characteristics of patients were similar between two groups. Patients receiving R-DHAP experienced more severe renal injury than patients receiving R-DHAOx (68% vs. 7.7%, P < .001). Two homogeneous clusters appeared: cluster A, with a majority of R-DHAOx (32, 91.4%), was less nephrotoxic than B, with a majority of R-DHAP (19, 86.4%), with a decreased average serum creatinine level (P < .0001). There were no other differences between clusters. CONCLUSIONS: Our study confirms that R-DHAOx regimen causes less nephrotoxicity than R-DHAP regimen.

International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI.

Great heterogeneity in survival exists for patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL). Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We evaluated 2124 DLBCL patients treated from 1998 to 2009 with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; or variant) across 7 multicenter randomized clinical trials to determine which scoring system best discriminates overall survival (OS). Median age was 63 years, and 56% of patients were male. Five-year OS estimates ranged from 54% to 88%, from 61% to 93%, and from 49% to 92% using the IPI, R-IPI, and NCCN-IPI, respectively. The NCCN-IPI had the greatest absolute difference in OS estimates between the highest- and lowest-risk groups and best discriminated OS (concordance index = 0.632 vs 0.626 [IPI] vs 0.590 [R-IPI]). For each given IPI risk category, NCCN-IPI risk categories were significantly associated with OS (P ≤ .01); the reverse was not true, and the IPI did not provide additional significant prognostic information within all NCCN-IPI risk categories. Collectively, the NCCN-IPI outperformed the IPI and R-IPI. Patients with low-risk NCCN-IPI had favorable survival outcomes with little room for further improvement. In the rituximab era, none of the clinical risk scores identified a patient subgroup with long-term survival clearly <50%. Integrating molecular features of the tumor and microenvironment into the NCCN-IPI or IPI might better characterize a high-risk group for which novel treatment approaches are most needed.

Clinical impact of controlling nutritional status score on the prognosis of patients with diffuse large B-cell lymphoma.

The controlling nutritional status (CONUT) score is a nutritional index calculated from serum albumin and total cholesterol levels and lymphocyte counts. Its role in predicting clinical outcomes of diffuse large B-cell lymphoma (DLBCL) has not been evaluated. In this retrospective study, data from 476 patients with DLBCL were analyzed. The cutoff value of the CONUT score was set as 4. CONUT score significantly stratified the overall survival (OS) and the progression-free-survival (PFS) (5-year OS, 49.0% vs 83.2%, P < .001; 5-year PFS, 46.1% vs 73.1%, P < .001) of the patients. Among patients at high-intermediate or high risk, as per the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), 5-year OS was lower in patients with high CONUT scores than in those with low CONUT scores (high-intermediate risk, 51.2% vs 75.5%, P < .001; high risk, 29.9% vs 63.3%, P = .007). Additionally, in patients with high CONUT scores, maintenance of relative dose intensity (RDI) of chemotherapy did not affect the 5-year OS (RDI > 80% vs RDI ≤ 80%: 59.8% vs 50.9%, P = .73). In the present study, we have demonstrated that the CONUT score is an independent prognostic factor in patients with DLBCL.

Evaluation of the MD Anderson tumor score for diffuse large B-cell lymphoma in the rituximab era.

OBJECTIVES: Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. METHODS: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327). RESULTS: Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. CONCLUSIONS: (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets.

Scientific rationale underpinning the development of biosimilar rituximab in hematological cancers and inflammatory diseases.

Sandoz rituximab (SDZ-RTX; Rixathon®; GP2013), a rituximab biosimilar, was approved in June 2017 in Europe in all indications of reference rituximab. The stepwise SDZ-RTX development program generated extensive physicochemical, structural, functional, and biological data demonstrating a match with reference rituximab on all clinically relevant attributes. A focused clinical development program followed, in two indications selected for sensitivity to detect potential differences versus reference rituximab: rheumatoid arthritis (pivotal pharmacokinetics and efficacy evaluation) and follicular lymphoma (pivotal efficacy/safety evaluation). These trials demonstrated highly similar pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity profiles. The totality of evidence for biosimilarity for SDZ-RTX, combined with knowledge that B-cell depletion is common to each approved indication, allowed SDZ-RTX approval for use in all indications of reference rituximab.