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.

Improving safety of autologous haematopoietic stem cell transplantation in patients with Crohn's disease.

OBJECTIVE: To evaluate the feasibility and toxicity of autologous haematopoietic stem cell transplantation (HSCT) for the treatment of refractory Crohn's disease (CD). DESIGN: In this prospective study, patients with refractory CD suffering an aggressive disease course despite medical treatment, impaired quality of life and in whom surgery was not an acceptable option underwent HSCT. Toxicity and complications during the procedure and within the first year following transplantation were evaluated, along with the impact of the introduction of supportive measures on safety outcomes. RESULTS: 26 patients were enrolled. During mobilisation, 16 patients (62%) presented febrile neutropaenia, including one bacteraemia and two septic shocks. Neutropaenia median time after mobilisation was 5 days. 5 patients withdrew from the study after mobilisation and 21 patients entered the conditioning phase. Haematopoietic recovery median time for neutrophils (>0.5×10(9)/L) was 11 days and for platelets (>20×10(9)/L) 4 days. Twenty patients (95%) suffered febrile neutropaenia and three patients (27%) presented worsening of the perianal CD activity during conditioning. Among non-infectious complications, 6 patients (28.5%) presented antithymocyte globulin reaction, 12 patients (57%) developed mucositis and 2 patients (9.5%) had haemorrhagic complications. Changes in supportive measures over the study, particularly antibiotic prophylaxis regimes during mobilisation and conditioning, markedly diminished the incidence of severe complications. During the first 12-month follow-up, viral infections were the most commonly observed complications, and one patient died due to systemic cytomegalovirus infection. CONCLUSIONS: Autologous HSCT for patients with refractory CD is feasible, but extraordinary supportive measures need to be implemented. We suggest that this procedure should only be performed in highly experienced centres.

Risk Factors for Mortality in Hematopoietic Stem Cell Transplantation Recipients with Bloodstream Infection: Points To Be Addressed by Future Guidelines.

In recent years, important epidemiologic changes have been described in hematopoietic stem cell transplantation (HSCT) recipients with bloodstream infection (BSI), with increases in gram-negative bacilli and multidrug resistant (MDR) gram-negative bacilli. These changes have been linked to a worrisome increase in mortality. We aimed to define the risk factors for mortality of HSCT patients experiencing BSI. All episodes of BSI in patients with HSCT between 2008 and 2017 were prospectively collected. Multivariate analyses were performed. A total of 402 BSI episodes were documented in 293 patients who had undergone HSCT (75.4% allogenic, 32.3% autologous, 19.3% second HSCT). The median time from HSCT to BSI was 62 days (interquartile range, 9 to 182 days). Gram-positive cocci accounted for 56.7% of the episodes; gram-negative bacilli, for 42%. The most common microorganisms were coagulase-negative staphylococci (30.6%) and Pseudomonas aeruginosa (15.9%). MDR gram-negative bacilli caused 11.9% of all episodes. Clinical characteristics, source of BSI, etiology, and outcomes changed depending on time since HSCT. Globally, 26.6% of episodes were treated with inappropriate empiric antibiotic therapy, more frequently in BSI episodes caused by P. aeruginosa, MDR P. aeruginosa, and MDR gram-negative bacilli. The 30-day mortality was 19.2%. Independent risk factors for mortality were BSI occurring ≥30 days after HSCT (odds ratio [OR], 11.21; 95% confidence interval [CI], 4.63 to 27.19), shock (OR, 7.10; 95% CI, 2.98 to 16.94), BSI caused by MDR P. aeruginosa (OR, 4.45; 95% CI, 1.12 to 17.72), and inappropriate empiric antibiotic therapy for gram-negative bacilli or Candida spp. (OR, 3.73; 95% CI, 1.27 to 10.89). HSCT recipients experiencing BSI have high mortality related to host and procedure factors, causative microorganism, and empiric antibiotic therapy. Strategies to identify HSCT recipients at risk of MDR P. aeruginosa and reducing inappropriate empiric antibiotic therapy are paramount to reduce mortality.

Changing epidemiology of bloodstream infection in a 25-years hematopoietic stem cell transplant program: current challenges and pitfalls on empiric antibiotic treatment impacting outcomes.

We aimed to describe epidemiology changes in bloodstream infections (BSI) episodes in hematopoietic stem cell transplant (HSCT) recipients throughout a 25-year period (1993-2017), comparing five-year time spans, and we evaluate their impact on inappropriate empirical antibiotic treatment (IEAT) and mortality. During the study period, 1164 BSI episodes were documented in patients undergoing HSCT (71.6% allogenic and 29% autologous). A significant decrease in gram-positive cocci (GPC) and increase in gram-negative bacilli (GNB) were observed (p < 0.001). Among GP, coagulase-negative staphylococci (CoNS) significantly decreased whereas rising E. faecium BSI was documented. Among GNB, E. coli, Pseudomonas aeruginosa and K. pneumoniae rates increased. Multidrug-resistant (MDR) GNB, especially ESBL-E. coli and MDR-P. aeruginosa, emerged in 2008 and has gradually increased. IEAT against MDR-P. aeruginosa, but not in other MDR-GNB, augmented throughout the study period. Overall, 30-day and related mortality rates were 12.7% and 7.7% respectively, both increasing over time (p < 0.001 and p = 0.025). In GNB, 30-day and related mortality were 18.5% and 12.8%, respectively, increasing over time (p < 0.001 and p = 0.004). To conclude, important BSI epidemiological changes were described in a 25-year period. Concerning increase in IEAT for P. aeruginosa infections and rising 30-day mortality rate were documented.

Autologous Haematopoietic Stem Cell Transplantation for Refractory Crohn's Disease: Efficacy in a Single-Centre Cohort.

BACKGROUND: Haematopoietic stem cell transplantation [HSCT] is considered a therapeutic option for patients with severe Crohn's disease [CD] unresponsive to currently available therapies. METHODS: Autologous HSCT was considered for CD patients with active disease, unresponsive or intolerant to approved medications and unsuitable for surgery. After HSCT, patients were closely followed up every 6 weeks during the first 2 years and every 6 months thereafter up to 5 years. Colonoscopy and/or magnetic resonance imaging were performed at Months 6, 12, 24, and 48 after HSCT. RESULTS: From December 1, 2007 to December 31, 2015, 37 CD patients were assessed for HSCT. Of these, 35 patients [13 within the ASTIC trial] underwent mobilisation. Six patients did not complete the transplant for various reasons and 29 patients were finally transplanted. Patients were followed up during a median of 12 months [6-60]. At 6 months, 70% of patients achieved drug-free clinical remission (Crohn's Disease Index of Severity [CDAI] < 150). The proportion of patients in drug-free remission (CDAI < 150, Simple Endoscopic activity Score [SES]-CD < 7] was 61% at 1 year, 52% at 2 years, 47% at 3 years, 39% at 4 years, and 15% at 5 years. Patients who relapsed were re-treated and 80% regained clinical remission. Six out of the 29 [21%] required surgery. One patient died due to systemic cytomegalovirus infection 2 months after transplant. CONCLUSIONS: HSCT is a salvage therapy for patients with extensive and refractory CD. Although relapse occurs in a majority of patients within 5 years after transplant, drug responsiveness is regained and clinical remission achieved in 80% of cases.

Fatal immune hemolytic anemia following allogeneic stem cell transplantation: report of 2 cases and review of literature.

Immune hemolytic anemia is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT). There are 4 possible causes for this complication. First, antibodies present in the recipient destroy donor cells. Second, donor red cell antibodies at the time of stem cell infusion are transferred to the recipient. Third, sometimes, engrafted donor lymphocytes cause active production of red cell antibodies. Fourth, another cause of hemolysis after allogeneic HSCT is autoimmune hemolytic anemia (AIHA). It is thought to be due to antibodies produced by the donor's immune system against antigens on red cells of donor origin. Autoimmune hemolytic anemia after allogeneic HSCT is rare, it is still not well characterized, and it represents a life-threatening situation. We describe 2 patients with acute myeloid leukemia treated with intensive chemotherapy and umbilical cord blood stem cell transplantation (UCBT). One patient developed AIHA at day +182 and the other at day +212 after receiving UCBT. Patients received 5 and 7 line treatment options, respectively, including continuous corticosteroids, intravenous immunoglobulin, splenectomy, cyclophosphamide, plasma exchange, rituximab, bortezomib, and eculizumab. However, both patients died because of massive hemolysis after 85 and 106 days of intensive treatment, respectively. These cases reflect the extreme difficulty in the therapeutic management of patients with AIHA following UCBT. After an extensive review of the literature, the exact physiopathologic mechanisms of AIHA after allogeneic HSCT in general, and after UCBT in particular, and therefore an effective treatment remain unknown.

[Economic evaluation of rituximab added to fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide for the treatment of chronic lymphocytic leukemia]. / Evaluación económica de rituximab en combinación con fludarabina y ciclofosfamida en comparación con fludarabina y ciclofosfamida en el tratamiento de la leucemia linfática crónica.

OBJECTIVES: We evaluated the cost-effectiveness of rituximab added to the chemotherapy regimen of fludarabine plus cyclophosphamide (R-FC) versus fludarabine plus cyclophosphamide (FC) for the treatment of patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL). METHODS: Two Markov models were built, using published results on progression-free survival (PFS) in patients receiving first- or second-line therapy with R-FC vs FC, rates of disease progression and mortality rates in Spain. Patient-elicited utilities were applied to PFS and progressed health states. The cost of drugs, supportive care, and quality-adjusted life years (QALY) were estimated over a 10-year period. Univariate and probabilistic (Monte Carlo) sensitivity analyses were performed. RESULTS: The addition of rituximab to chemotherapy in first- and second-line therapy increased life-years gained (LYG) and QALYs compared with chemotherapy. The incremental cost per LYG and QALY gained was €20,703 and €19,343 for first-line treatment and was €23,183 and €24,781 for second-line treatment. CONCLUSION: In patients with previously untreated or relapsed/refractory CLL, the addition of rituximab to the FC regimen increased life expectancy and quality-adjusted life expectancy. In both types of patient, the treatment was cost-effective.

Evaluación económica de rituximab en combinación con fludarabinay ciclofosfamida en comparación con fludarabina y ciclofosfamida enel tratamiento de la leucemia linfática crónica / Economic evaluation of rituximab added to fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide for the treatment of chronic lymphocytic leukemia

Objetivos: Evaluar el coste-efectividad del esquema de rituximab, fludarabina y ciclofosfamida (R-FC) encomparación con el de fludarabina y ciclofosfamida (FC) en dos tipos de pacientes con leucemia linfáticacrónica (LLC): no tratados previamente o bien en recidiva/resistentes al tratamiento previo.Métodos: Dos modelos de Markov, utilizando los resultados publicados de superviviencia libre de progresión(SLP) de pacientes con LLC tratados con R-FC o FC en primera o segunda línea, las tasas de progresiónde la enfermedad y las tasas de mortalidad en Espa˜na. A los estados de SLP y progresión se les asignaronutilidades obtenidas en un estudio sobre LLC. Los costes de los medicamentos y de los tratamientos desoporte, así como los a˜nos de vida ajustados por calidad (AVAC), se estimaron para un periodo de 10 a˜nos.Se efectuaron análisis de sensibilidad univariados y probabilísticos (Monte Carlo).Resultados: La adición de rituximab a la quimioterapia con FC aumentó los a˜nos de vida ganados (AVG) ylos AVAC tanto en primera como en segunda línea de tratamiento. La razón de coste-eficacia incrementalfue de 20.703 D por AVG y de 19.343 D por AVAC con la primera línea de tratamiento, y de 23.183 D porAVG y 24.781 D por AVAC con la segunda línea de tratamiento.Conclusiones: En los pacientes con LLC no tratados previamente y en aquellos en recaída o resistentes altratamiento previo, la adición de rituximab al esquema FC aumentó la esperanza de vida y los AVAC, y enambos casos resultó ser un tratamiento coste-efectivo (AU)

Objectives: We evaluated the cost-effectiveness of rituximab added to the chemotherapy regimen of fludarabineplus cyclophosphamide (R-FC) versus fludarabine plus cyclophosphamide (FC) for the treatmentof patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL).Methods: Two Markov models were built, using published results on progression-free survival (PFS) inpatients receiving first- or second-line therapy with R-FC vs FC, rates of disease progression and mortalityrates in Spain. Patient-elicited utilities were applied to PFS and progressed health states. The cost of drugs,supportive care, and quality-adjusted life years (QALY) were estimated over a 10-year period. Univariateand probabilistic (Monte Carlo) sensitivity analyses were performed.Results: The addition of rituximab to chemotherapy in first- and second-line therapy increased lifeyearsgained (LYG) and QALYs compared with chemotherapy. The incremental cost per LYG and QALYgained was D 20,703 and D 19,343 for first-line treatment and was D 23,183 and D 24,781 for second-linetreatment (AU)

Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation.

The graft-versus-host disease (GVHD) characteristics of 150 consecutive patients undergoing reduced intensity conditioning allogeneic (allo-RIC) transplants and 88 patients undergoing myeloablative conditioning regimen were analysed. All patients received the same GVHD prophylaxis and peripheral blood stem cells from a human leucocyte antigen identical sibling. The cumulative incidence of acute GVHD (aGVHD) was 67% and 44% in the myeloablative and allo-RIC regimen groups, respectively (P < 0.001), and was 39% vs. 29%, respectively (P = 0.043), for grades 2-4 aGVHD. Only conditioning type (myeloablative versus allo-RIC) significantly influenced the incidence of aGVHD in multivariate analysis: Hazard ratio (HR) = 2.16 [95% confidence interval (CI): 1.52-3.07], P < 0.0001. The cumulative incidence of chronic GVHD (cGVHD) was 63% and 71% among myeloablative and allo-RIC patients respectively (P = 0.084). This trend was because of the higher incidence of limited cGVHD, but not extensive cGVHD among allo-RIC recipients [HR = 3.3 (95% CI: 1.42-8.08), P = 0.0017]. Moreover, among patients who developed cGVHD, the cumulative incidence of limited cGVHD was significantly lower in the myeloablative group than in the allo-RIC group (7% vs. 25%, P = 0.007). Duration of immunosuppression was shorter among allo-RIC patients (35.5% vs. 68.8% required systemic immunosuppression 36 months after transplant, P = 0.028). Although prospective controlled trials are required to further evaluate the effect of the conditioning regimen on GVHD, our results suggest that RIC modifies the incidence and characteristics of both acute and cGVHD after allogeneic transplantation, and decreases the immunosuppression requirements in long-term follow up when compared with myeloablative conditioning.