Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Results of a phase 1/2 study of cemdisiran in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria.

Complement dysregulation underpins the physiopathology of paroxysmal nocturnal hemoglobinuria (PNH). Cemdisiran, an RNA interference investigational treatment, silences complement component 5 (C5) expression in the liver. Previously reported results showed sustained reduction in C5 levels following cemdisiran monotherapy, with >90% reduction in patients with PNH. This phase 1/2 study evaluated single (Part A, n = 32; 50-900 mg) or multiple (Part B, n = 24; 100-600 mg) ascending doses of cemdisiran or placebo (double-blind, randomized 3:1) in healthy adults, or cemdisiran in patients with PNH who were naive to, or receiving, eculizumab (Part C, n = 6; 200 or 400 mg weekly; open-label). The primary objective was to assess the safety and tolerability of cemdisiran. Other assessments included change in complement activity, lactate dehydrogenase levels, and inhibition of hemolysis following cemdisiran treatment. Cemdisiran was generally well tolerated in this study. Overall, 75%, 89%, and 100% of subjects in Parts A, B, and C, respectively, experienced ≥1 non-serious adverse event (AE). Most events were Grade 1 or 2 in severity and the most common AEs included nasopharyngitis and headache. Cemdisiran elicited robust, sustained reductions in the complement activity in healthy adults and patients with PNH. In Part C, exploratory analyses showed that cemdisiran monotherapy was insufficient to prevent hemolysis in patients with PNH as measured by serum lactate dehydrogenase levels. Cemdisiran and eculizumab combination therapy reduced the dose of eculizumab required to provide adequate control of intravascular hemolysis. These results demonstrate a potential benefit of cemdisiran coadministration in patients who are inadequate responders to eculizumab alone.

Cloudy fluid, cloudy diagnosis.

Here, we report a case of a patient with cloudy effluent that was initially diagnosed as bacterial peritonitis. The persistence of a cloudy effluent despite antibiotic therapy led to an extensive peritoneal dialysis (PD) effluent analysis, with the final diagnosis being high-grade B-cell lymphoma. This case will increase the awareness of this rare presentation of a lymphoproliferative disorder reminding clinicians to consider this diagnosis as a part of the differential diagnosis PD effluent.

One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab.

Ravulizumab every 8 weeks showed non-inferiority to eculizumab every 2 weeks in a 26-week, phase 3, randomized controlled trial in adults with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on eculizumab (NCT03056040). We report results from the first 26 weeks of the extension period in which patients continued ravulizumab (n = 96) or switched from eculizumab to ravulizumab (n = 95). At week 52, mean (SD) lactate dehydrogenase levels increased 8.8% (29%) with ravulizumab-ravulizumab and 5.8% (27%) with eculizumab-ravulizumab from primary evaluation period baseline. During the extension period, four patients (ravulizumab-ravulizumab, n = 3; eculizumab-ravulizumab, n = 1) experienced breakthrough hemolysis, but none associated with serum free C5 ≥ 0.5 µg/mL. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores remained stable through week 52. During the extension period, proportions of patients avoiding transfusion remained stable (ravulizumab-ravulizumab, 86.5%; eculizumab-ravulizumab, 83.2%); 81.2% and 81.1%, respectively, had stabilized hemoglobin. All patients maintained serum free C5 levels < 0.5 µg/mL. Adverse events were generally similar between groups, and rates were lower in the extension period. Adults with PNH on stable eculizumab therapy who received ravulizumab over 52 weeks experienced durable efficacy, with consistent efficacy in patients who received eculizumab during the primary evaluation period and then switched to ravulizumab. Ravulizumab was well tolerated.

Persistent replication of SARS-CoV-2 in a severely immunocompromised patient treated with several courses of remdesivir.

Microbiological response of SARS-CoV-2 to remdesivir in immunocompromised patients has not been evaluated. We present the case of a severely immunocompromised patient with persistent replication of SARS-CoV-2, who required different courses of remdesivir. Short courses of remdesivir might be insufficient in immunocompromised patients due to prolonged viral clearance.

Comparison of one-catheter strategy versus conventional two-catheter strategy on the volume of radiological contrast and diagnostic coronary catheterization performance by transradial access: A systematic review and meta-analysis of randomized clinical trials.

Background: One-catheter strategy, based in multipurpose catheters, allows exploring both coronary arteries with a single catheter. This strategy could simplify coronary catheterization and reduce the volume of contrast administration, by reducing radial spasm. To date, observational studies showed greater benefits regarding contrast consumption and catheterization performance than controlled trials. The aim of this work is to perform the first systematic review and meta-analysis of randomized clinical trials (RCT) to adequately quantify the benefits of one-catheter strategy, with multipurpose catheters, over conventional two-catheter strategy on contrast consumption, and catheterization performance. Methods: A search in PubMed, CINALH, and CENTRAL databases was conducted to identify randomized trials comparing one-catheter and two-catheter strategies. The primary outcome was volume of iodinated contrast administrated. Secondary endpoints, evaluating coronary catheterization performance included: arterial spasm, fluoroscopy time, and procedural time. Results: Five RCT were included for the final analysis, with a total of 1599 patients (802 patients with one-catheter strategy and 797 patients with two-catheter strategy). One-catheter strategy required less administration of radiological contrast (difference in means [DiM] [95% confidence interval (CI)]; -3.831 mL [-6.165 mL to -1.496 mL], p = 0.001) as compared to two-catheter strategy. Furthermore, less radial spasm (odds ratio [95% CI], 0.484 [0.363 to 0.644], p < 0.001) and less procedural time (DiM [95% CI], -72.471 s [-99.694 s to -45.249 s], p < 0.001) were observed in one-catheter strategy. No differences on fluoroscopy time were observed. Conclusions: One-catheter strategy induces a minimal reduction on radiological contrast administration but improves coronary catheterization performance by reducing arterial spasm and procedural time as compared to conventional two-catheter strategy.

Antecedentes: La estrategia de catéter único permite explorar ambas coronarias con un solo catéter. Nuestro objetivo es realizar la primera revisión sistemática y meta-análisis de ensayos clínicos aleatorizados para cuantificar adecuadamente los beneficios de la estrategia de catéter único, con catéteres multipropósito, sobre la estrategia convencional de dos catéteres. Métodos: Se realizó una búsqueda en PubMed, CINALH y CENTRAL, identificando ensayos aleatorizados que compararan estrategias de un catéter y dos catéteres. El resultado primario fue volumen de contraste administrado. Los secundarios, que evaluaron el rendimiento del cateterismo, incluyeron: espasmo radial, tiempo de fluoroscopia y de procedimiento. Resultados: Se incluyeron cinco ensayos, totalizando 1,599 pacientes (802 con estrategia de un catéter y 797 con estrategia de dos catéteres). La estrategia de catéter único requirió menos contraste (diferencia-de-medias; −3.831 mL [−6.165 mL a −1.496 mL], p = 0.001), presentando menos espasmo radial (odds ratio, 0.484 [0.363 a 0.644], p < 0.001) y menos tiempo de procedimiento (diferencia-de-medias; −72.471 s [−99.694 s a −45.249 s], p < 0.001). No hubo diferencias en el tiempo de fluoroscopia. Conclusiones: La estrategia de catéter único induce una reducción mínima en la administración de contraste, pero mejora el rendimiento del cateterismo al reducir el espasmo radial y el tiempo de procedimiento en comparación con la estrategia convencional.

Comparison of one-catheter strategy versus conventional two-catheter strategy on the volume of radiological contrast and diagnostic coronary catheterization performance by transradial access: A systematic review and meta-analysis of randomized clinical trials / Comparación de la estrategia de catéter único versus la estrategia convencional de dos catéteres sobre el volumen de contraste radiológico y el rendimiento del cateterismo coronario diagnóstico por acceso transradial: una revisión sistemática y meta-análisis de ensayos clínicos aleatorizados

Abstract Background: One-catheter strategy, based in multipurpose catheters, allows exploring both coronary arteries with a single catheter. This strategy could simplify coronary catheterization and reduce the volume of contrast administration, by reducing radial spasm. To date, observational studies showed greater benefits regarding contrast consumption and catheterization performance than controlled trials. The aim of this work is to perform the first systematic review and meta-analysis of randomized clinical trials (RCT) to adequately quantify the benefits of one-catheter strategy, with multipurpose catheters, over conventional two-catheter strategy on contrast consumption, and catheterization performance. Methods: A search in PubMed, CINALH, and CENTRAL databases was conducted to identify randomized trials comparing one-catheter and two-catheter strategies. The primary outcome was volume of iodinated contrast administrated. Secondary endpoints, evaluating coronary catheterization performance included: arterial spasm, fluoroscopy time, and procedural time. Results: Five RCT were included for the final analysis, with a total of 1599 patients (802 patients with one-catheter strategy and 797 patients with two-catheter strategy). One-catheter strategy required less administration of radiological contrast (difference in means [DiM] [95% confidence interval (CI)]; −3.831 mL [−6.165 mL to −1.496 mL], p = 0.001) as compared to two-catheter strategy. Furthermore, less radial spasm (odds ratio [95% CI], 0.484 [0.363 to 0.644], p < 0.001) and less procedural time (DiM [95% CI], −72.471 s [−99.694 s to −45.249 s], p < 0.001) were observed in one-catheter strategy. No differences on fluoroscopy time were observed. Conclusions: One-catheter strategy induces a minimal reduction on radiological contrast administration but improves coronary catheterization performance by reducing arterial spasm and procedural time as compared to conventional two-catheter strategy.

Resumen Antecedentes: La estrategia de catéter único permite explorar ambas coronarias con un solo catéter. Nuestro objetivo es realizar la primera revisión sistemática y meta-análisis de ensayos clínicos aleatorizados para cuantificar adecuadamente los beneficios de la estrategia de catéter único, con catéteres multipropósito, sobre la estrategia convencional de dos catéteres. Métodos: Se realizó una búsqueda en PubMed, CINALH y CENTRAL, identificando ensayos aleatorizados que compararan estrategias de un catéter y dos catéteres. El resultado primario fue volumen de contraste administrado. Los secundarios, que evaluaron el rendimiento del cateterismo, incluyeron: espasmo radial, tiempo de fluoroscopia y de procedimiento. Resultados: Se incluyeron cinco ensayos, totalizando 1,599 pacientes (802 con estrategia de un catéter y 797 con estrategia de dos catéteres). La estrategia de catéter único requirió menos contraste (diferencia-de-medias; −3.831 mL [−6.165 mL a −1.496 mL], p = 0.001), presentando menos espasmo radial (odds ratio, 0.484 [0.363 a 0.644], p < 0.001) y menos tiempo de procedimiento (diferencia-de-medias; −72.471 s [−99.694 s a −45.249 s], p < 0.001). No hubo diferencias en el tiempo de fluoroscopia. Conclusiones: La estrategia de catéter único induce una reducción mínima en la administración de contraste, pero mejora el rendimiento del cateterismo al reducir el espasmo radial y el tiempo de procedimiento en comparación con la estrategia convencional.

Patient preferences and quality of life implications of ravulizumab (every 8 weeks) and eculizumab (every 2 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Eculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference. OBJECTIVE: The aim of this study was to assess patient preference for ravulizumab or eculizumab. METHODS: Study 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis. RESULTS: Overall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%). CONCLUSION: This study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study.

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.

Presence of acute and chronic renal failure in patients with paroxysmal nocturnal hemoglobinuria: results of a retrospective analysis from the Spanish PNH Registry.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disease. With the advent of eculizumab treatment, renal function has substantially improved, although no data from real-world clinical practice are available. An observational, retrospective, multicenter study was conducted in Spain on clinical data obtained from outpatient visits of patients with PNH (Spanish PNH Registry) who had experienced acute (ARF) or chronic (CRF) renal failure. Of the 128 patients registered (April 2014), 60 were diagnosed with classic PNH. Twenty-seven (45.0%) patients with a mean age of 48.5 (±16.2) years had renal failure, ARF or CRF, and were included in this study. Near half of the patients (n = 13; 48.1%) presented with ARF alone, 33.3% (n = 9) had CRF with episodes of ARF, while 18.5% (n = 5) were diagnosed with CRF alone. For patients with diagnosis of PNH and renal failure (n = 27), the median time to the first ARF episode was 6.5 (CI 95%; 2.2, 14.9) years, whereas the median to the diagnosis of CRF was 14.5 (CI 95%; 3.8, 19.2) years after the diagnosis of PNH. Patients with ARF (n = 22) were treated with eculizumab and did not experience new episodes of ARF, except for one patient with sepsis. Of the patients with CRF, two received treatment without experiencing further episodes of ARF. Sixteen patients who completed treatment (11 with ARF and 5 with ARF + CRF) recovered from the episode of ARF or from CRF. Of the remaining patients treated with eculizumab, one patient improved from stages III to II, three patients stabilized without showing disease progression, and one patient progressed from stages III to IV. Treatment with eculizumab in PNH patients has beneficial effects on renal function, preventing ARF and progression to CRF.

Rol de la resonancia magnética renal en la monitorización del aclaramiento de los depósitos de hemosiderina en la hemoglobinuria paroxística nocturna / Role of kidney MRI to monitoring clearance of hemosiderin deposits in paroxysmal nocturnal hemoglobinuria

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PiwiRNA-651 as marker of treatment response and survival in classical Hodgkin lymphoma.

PiwiRNAs, small non-coding RNAs processed by Piwi proteins, are involved in maintaining genome stability in germline cells. Recently, piwiRNA expression has been identified in some tumors. We have examined the potential reactivation of the Piwi/piwiRNA pathway in classical Hodgkin lymphoma (cHL). We found that Piwi proteins and three selected piwiRNAs, including piR-651, were expressed in cHL patients and cell lines, indicating that the Piwi/piwiRNA pathway is active in cHL. Interestingly, low levels of piR-651 were associated with lack of complete response to first-line treatment, as well as shorter disease-free and overall survival in a cohort of 94 cHL patients. At diagnosis, piR-651 was underexpressed in cHL serum samples compared to healthy controls, while after complete remission, piR-651 levels increased to levels similar to healthy controls. This is the first evidence that piwiRNAs are active in tumor and serum samples and impact prognosis in cHL.

Consenso español para el diagnóstico y tratamiento de la hemoglobinuria paroxística nocturna / Spanish consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria

La hemoglobinuria paroxística nocturna (HPN) es una enfermedad clonal de las células progenitoras hematopoyéticas originada por la mutación adquirida del gen fosfatidil-inositol-glicano del grupo A, situado en el brazo corto del cromosoma X. Se caracteriza por anemia hemolítica intravascular, tendencia a la trombosis y un componente variable de insuficiencia medular. Otras complicaciones derivadas de la hemólisis son disfagia, disfunción eréctil, dolores abdominales, astenia e insuficiencia renal crónica (un 65% de los pacientes). La enfermedad afecta por igual a ambos sexos y puede aparecer a cualquier edad, con una mayor incidencia en la tercera década de la vida. Actualmente, el diagnóstico se basa en la detección de poblaciones celulares con marcadores asociados al déficit de glucosil-fosfatidil-inositol mediante citometría de flujo. Durante años, el pilar terapéutico de la HPN hemolítica era el soporte transfusional. Un gran avance en el tratamiento ha sido la aprobación del anticuerpo monoclonal humanizado eculizumab, que bloquea la proteína C5 del complemento impidiendo su activación, y por tanto, la hemólisis. Diversos estudios han confirmado que el tratamiento con eculizumab evita o disminuye el requerimiento transfusional, reduce la probabilidad de trombosis, mejora la sintomatología asociada y la calidad de vida de los pacientes con HPN, mostrando un aumento de la supervivencia. Este rápido avance en el conocimiento de la enfermedad y su tratamiento hace necesario adaptar y homogeneizar las directrices de actuación clínica en el manejo de pacientes con HPN (AU)

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of the haematopoietic progenitor cells due to a somatic mutation in theX-linked phosphatidylinositol glycan class A gene. The disease is characterized by intravascular haemolytic anaemia, propensity to thromboembolic events and bone marrow failure. Other direct complications of haemolysis include dysphagia, erectile dysfunction, abdominal pain, asthenia and chronic renal failure (65% of patients). The disease appears more often in the third decade of life and there is no sex or age preference. Detection of markers associated with glucosyl phosphatidyl inositol deficit by flow cytometry is currently used in the diagnosis of PNH. For years, transfusions have been the mainstay of therapy for PNH. A breakthrough in treatment has been the approval of the humanized monoclonal antibody eculizumab, which works by blocking the C5 complement protein, preventing its activation and therefore haemolysis. Several studies have confirmed that treatment with eculizumab avoids or decreases the need for transfusions, decreases the probability of thrombosis, improves the associated symptomatology and the quality of life in patients with PNH, showing an increase in survival. Because of rapid advances in the knowledge of the disease and its treatment, it may become necessary to adapt and standardize clinical guidelines for the management of patients with PNH (AU)

[Spanish consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria]. / Consenso español para el diagnóstico y tratamiento de la hemoglobinuria paroxística nocturna.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of the haematopoietic progenitor cells due to a somatic mutation in theX-linked phosphatidylinositol glycan class A gene. The disease is characterized by intravascular haemolytic anaemia, propensity to thromboembolic events and bone marrow failure. Other direct complications of haemolysis include dysphagia, erectile dysfunction, abdominal pain, asthenia and chronic renal failure (65% of patients). The disease appears more often in the third decade of life and there is no sex or age preference. Detection of markers associated with glucosyl phosphatidyl inositol deficit by flow cytometry is currently used in the diagnosis of PNH. For years, transfusions have been the mainstay of therapy for PNH. A breakthrough in treatment has been the approval of the humanized monoclonal antibody eculizumab, which works by blocking the C5 complement protein, preventing its activation and therefore haemolysis. Several studies have confirmed that treatment with eculizumab avoids or decreases the need for transfusions, decreases the probability of thrombosis, improves the associated symptomatology and the quality of life in patients with PNH, showing an increase in survival. Because of rapid advances in the knowledge of the disease and its treatment, it may become necessary to adapt and standardize clinical guidelines for the management of patients with PNH.

Prognosis of patients with diffuse large B cell lymphoma not reaching complete response or relapsing after frontline chemotherapy or immunochemotherapy.

A retrospective study was performed to assess the outcome of patients with diffuse large B cell lymphoma (DLBCL) who did not achieve complete response or who relapsed before and after the use of rituximab. Clinical features and outcome of 816 (425 M/391 F; median age 63 years) patients diagnosed from 1991 to 2001 (pre-rituximab era, N = 348) and from 2002 to 2012 (rituximab era, N = 468) in a single institution were evaluated. Five hundred fifty-three patients achieved complete remission (CR), 57 partial response (PR), and 206 were refractory with a median overall survival of 15, 1.5, and 0.4 years, respectively. Patients receiving rituximab had lower risk of refractoriness or relapse. In primarily refractory and PR patients, there was not a difference in survival depending on whether patients received or not rituximab-containing frontline treatment. Early death rate was 11%, including 3.6% due to infectious complications. Rituximab did not modify these figures. In the relapse setting, 5-year survival from relapse was 25% for patients who never received rituximab, 54% for those who received rituximab only at relapse, and 48% for those treated with immunochemotherapy both as frontline and at relapse. In conclusion, relapsed/refractory patients with DLBCL show poor prognosis despite the use of frontline immunochemotherapy. New therapeutic approaches are needed in this group of patients.

MiR-SNPs as markers of toxicity and clinical outcome in Hodgkin lymphoma patients.

BACKGROUND: In recent years, microRNA (miRNA) pathways have emerged as a crucial system for the regulation of tumorogenesis. miR-SNPs are a novel class of single nucleotide polymorphisms that can affect miRNA pathways. DESIGN AND METHODS: We analyzed eight miR-SNPs by allelic discrimination in 141 patients with Hodgkin lymphoma and correlated the results with treatment-related toxicity, response, disease-free survival (DFS) and overall survival (OS). RESULTS: The KRT81 (rs3660) GG genotype was associated with an increased risk of neurological toxicity (P = 0.016), while patients with XPO5 (rs11077) AA or CC genotypes had a higher rate of bleomycin-associated pulmonary toxicity (P = 0.048). Both miR-SNPs emerged as independent factors in the multivariate analysis. The XPO5 AA and CC genotypes were also associated with a lower response rate (P = 0.036). XPO5 (P = 0.039) and TRBP (rs784567) (P = 0.022) genotypes emerged as prognostic markers for DFS, and XPO5 was also associated with OS (P = 0.033). In the multivariate analysis, only XPO5 emerged as an independent prognostic factor for DFS (HR: 2.622; 95%CI 1.039-6.620; P = 0.041). Given the influence of XPO5 and TRBP as individual markers, we then investigated the combined effect of these miR-SNPs. Patients with both the XPO5 AA/CC and TRBP TT/TC genotypes had the shortest DFS (P = 0.008) and OS (P = 0.008). CONCLUSION: miR-SNPs can add useful prognostic information on treatment-related toxicity and clinical outcome in Hodgkin lymphoma and can be used to identify patients likely to be chemoresistant or to relapse.