Single Dose Of Rituximab Research Articles

Chronic Lymphocytic Leukemia-associated Refractory Immune Thrombocytopenia Successfully Treated with Eltrombopag

Chronic lymphocytic leukemia (CLL) may be associated with immune thrombocytopenia (ITP). The standard treatment for CLL-associated ITP is steroids. For refractory cases, various treatment strategies such as rituximab, splenectomy, and thrombopoietic mimetics are available. We report a patient with CLL who developed recurrent ITP and life-threatening pulmonary hemorrhage. Platelet counts remained extremely low despite massive platelet transfusion and treatment including steroids, immunoglobulin, and single-dose rituximab infusion. The bleeding stopped and platelet counts were increased to normal range 13 days after treatment with eltrombopag 25 mg per day. Our experience suggests that eltrombopag is an effective treatment option in CLL-associated, refractory ITP, especially during major bleeding, which requires relatively rapid improvement of thrombocytopenia.

Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety

We evaluated the efficacy and safety of rituximab as induction therapy in renal transplant patients. In a double-blind, placebo-controlled study, 280 adult renal transplant patients were randomized between a single dose of rituximab (375 mg/m(2)) or placebo during transplant surgery. Patients were stratified according to panel-reactive antibody (PRA) value and rank number of transplantation. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil and steroids. The primary endpoint was the incidence of biopsy proven acute rejection (BPAR) within 6 months after transplantation. The incidence of BPAR was comparable between rituximab-treated (23/138, 16.7%) and placebo-treated patients (30/142, 21.2%, p = 0.25). Immunologically high-risk patients (PRA >6% or re-transplant) not receiving rituximab had a significantly higher incidence of rejection (13/34, 38.2%) compared to other treatment groups (rituximab-treated immunologically high-risk patients, and rituximab- or placebo-treated immunologically low-risk (PRA ≤ 6% or first transplant) patients (17.9%, 16.4% and 15.7%, p = 0.004). Neutropenia (<1.5 × 10(9) /L) occurred more frequently in rituximab-treated patients (24.3% vs. 2.2%, p < 0.001). After 24 months, the cumulative incidence of infections and malignancies was comparable. A single dose of rituximab as induction therapy did not reduce the overall incidence of BPAR, but might be beneficial in immunologically high-risk patients. Treatment with rituximab was safe.

Single-Dose Rituximab for Recurrent Glomerulonephritis Post-Renal Transplant

Background/Aims: Post-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach. Methods: A single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) <0.3). Secondary outcomes included partial response (PR >50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence. Results: The median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16). Conclusion: Single-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.

Long-term prognosis of adult patients with steroid-dependent minimal change nephrotic syndrome following rituximab treatment.

This study was to evaluate the long-term efficacy and safety of a single-dose rituximab regimen rituximab treatment in adult patients with steroid-dependent minimal change nephrotic syndrome (MCNS).We conducted a prospective cohort study with historical controls to evaluate the effect of single-dose infusions of rituximab at 375 mg/m2 BSA per dose administered at intervals of 6 months for a period of 24 months. At the end of the 24-month period, the patients were divided into the treatment continuation (n = 20) and treatment discontinuation (n = 5) groups according to their intention to continue/discontinue the treatment.A significant reduction in the total number of relapses was observed during the 24-month period after the first rituximab infusion as compared with that during the 24-month period before the first rituximab infusion (108 vs. 8, P < 0.001). Complete remission was induced/maintained in all patients from 12 to 24 months after the first rituximab infusion. In regard to the clinical course after 24 months, 4 of the 20 patients in the treatment continuation group discontinued the rituximab treatment after the fifth infusion and 2 patients discontinued the treatment after the sixth infusion. However, complete remission was maintained in all the 20 patients of this group during the 12-month observation period after the first four single-dose rituximab infusions. On the other hand, 1 of the 5 patients in the treatment discontinuation group developed relapse during the observation period after the first four rituximab infusions, and the rituximab treatment was resumed.In our trial, rituximab therapy was associated with maintenance of complete remission. Complete remission was maintained even in most of the patients who showed B-cell repletion after discontinuation of rituximab therapy. Thus, rituximab may be considered as a radical therapeutic agent for patients with steroid-dependent MCNS.

Longitudinal analysis of T and B cell phenotype and function in renal transplant recipients with or without rituximab induction therapy.

BackgroundPrevention of rejection after renal transplantation requires treatment with immunosuppressive drugs. Data on their in vivo effects on T- and B-cell phenotype and function are limited.MethodsIn a randomized double-blind placebo-controlled study to prevent renal allograft rejection, patients were treated with tacrolimus, mycophenolate mofetil (MMF), steroids, and a single dose of rituximab or placebo during transplant surgery. In a subset of patients, we analyzed the number and phenotype of peripheral T and B cells by multiparameter flow cytometry before transplantation, and at 3, 6, 12, and 24 months after transplantation.ResultsIn patients treated with tacrolimus/MMF/steroids the proportion of central memory CD4+ and CD8+ T cells was higher at 3 months post-transplant compared to pre-transplant levels. In addition, the ratio between the percentage of central memory CD4+ and CD4+ regulatory T cells was significantly higher up to 24 months post-transplant compared to pre-transplant levels. Interestingly, treatment with tacrolimus/MMF/steroids resulted in a shift toward a more memory-like B-cell phenotype post-transplant. Addition of a single dose of rituximab resulted in a long-lasting B-cell depletion. At 12 months post-transplant, the small fraction of repopulated B cells consisted of a high percentage of transitional B cells. Rituximab treatment had no effect on the T-cell phenotype and function post-transplant.ConclusionsRenal transplant recipients treated with tacrolimus/MMF/steroids show an altered memory T and B-cell compartment post-transplant. Additional B-cell depletion by rituximab leads to a relative increase of transitional and memory-like B cells, without affecting T-cell phenotype and function.Trial RegistrationClinicalTrials.gov NCT00565331

Type of rejection and biopsy findings after induction therapy with a single dose of rituximab

Type of rejection and biopsy findings after induction therapy with a single dose of rituximab

Single-dose rituximab for remission induction and maintenance therapy in ANCA-associated vasculitis: a retrospective analysis of 17 patients

Objectives: The aim of this study was to evaluate the efficacy of a repeated single-dose rituximab (RTX) regimen for remission induction and maintenance in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).Method: We performed a retrospective analysis of all patients with an established diagnosis of AAV who were treated with single-dose RTX infusions at our institution. Clinical outcome data were assessed over a period of 24 months.Results: Sixteen patients were treated for remission induction and maintenance and one patient was treated for only maintenance therapy. Remission (absence of disease activity during the past 3 months and a prednisolone dose of ≤ 7.5 mg) was achieved in 11 patients (68%) with a mean time to remission of 9.4 (range 3–24) months. At 6 months, six patients (37.5%) were in remission and the mean prednisolone dose of all responding patients was 8.2 mg. Five patients had treatment failure due to early relapsing (n = 4) or persistently active (n = 1) disease. At 24 months, nine of the 11 responding patients (82%) were in remission. All patients still had concomitant steroid and/or disease-modifying anti-rheumatic drug (DMARD) therapy at 24 months. Overall, 11 relapses were seen in nine patients (five non-responders and four responders) with a mean time to relapse of 5.3 (range 4–24) months. No major relapses were observed in the responding patients. Severe infections were only seen in patients who had been previously treated with cyclophosphamide (CYC).Conclusions: The combination of single-dose RTX with other immunosuppressants seems less effective than the standard RTX regimen for the induction of remission of AAV.

Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402.

In low-tumor burden follicular lymphoma (FL), maintenance rituximab (MR) has been shown to improve progression-free survival when compared with observation. It is not known whether MR provides superior long-term disease control compared with re-treatment rituximab (RR) administered on an as-needed basis. E4402 (RESORT) was a randomized clinical trial designed to compare MR against RR. Eligible patients with previously untreated low-tumor burden FL received four doses of rituximab, and responding patients were randomly assigned to either RR or MR. Patients receiving RR were eligible for re-treatment at each disease progression until treatment failure. Patients assigned to MR received a single dose of rituximab every 3 months until treatment failure. The primary end point was time to treatment failure. Secondary end points included time to first cytotoxic therapy, toxicity, and health-related quality of life (HRQOL). A total of 289 patients were randomly assigned to RR or MR. With a median follow-up of 4.5 years, the estimated median time to treatment failure was 3.9 years for patients receiving RR and 4.3 years for those receiving MR (P = .54). Three-year freedom from cytotoxic therapy was 84% for those receiving RR and 95% for those receiving MR (P = .03). The median number of rituximab doses was four patients receiving RR and 18 for those receiving MR. There was no difference in HRQOL. Grade 3 to 4 toxicities were infrequent in both arms. In low-tumor burden FL, a re-treatment strategy uses less rituximab while providing disease control comparable to that achieved with a maintenance strategy.

A modified protocol with rituximab and intravenous immunoglobulin in emergent ABO-incompatible liver transplantation for acute liver failure

The established procedure for ABO-incompatible liver transplantation (ABO-I LT) was too complicated to be used in case of emergency. We developed a protocol consisting of rituximab and intravenous immunoglobulin (IVIG) for ABO-I LT in patients with acute liver failure (ALF). The data from 101 patients who had undergone liver transplantation (LT) for ALF were retrospectively analyzed. The patients were divided into two groups: ABO-compatible liver transplantation group (ABO-C LT, n=66) and ABO-I LT group (n=35). All the patients in the ABO-I LT group received a single dose of rituximab (375 mg/m2) and IVIG (0.4 g/kg per day) at the beginning of the operation. IVIG was administered for 10 consecutive days after LT. Plasma exchange, splenectomy and graft local infusion were omitted in the protocol. Quadruple immunosuppressive therapy including basiliximab, corticosteroids, tacrolimus and mycophenolatemofetil was used to reinforce immunosuppression. The 3-year cumulative patient survival rates in the ABO-I LT and ABO-C LT groups were 83.1% and 86.3%, respectively (P>0.05), and the graft survival rates were 80.0% and 86.3%, respectively (P>0.05). Two patients (5.7%) suffered from antibody-mediated rejection in the ABO-I LT group. Other complications such as acute cellular rejection, biliary complication and infection displayed no significant differences between the two groups. The simplified treatment consisting of rituximab and IVIG prevented antibody-mediated rejection for LT of blood-type incompatible patients. With this treatment, the patients did not need plasma exchange, splenectomy and graft local infusion. This treatment was safe and efficient for LT of the patients with ALF.

Type of Rejection and Biopsy Findings After Induction Therapy With a Single Dose of Rituximab.

Introduction. A variety of data indicates a role for B cells in acute renal allograft rejection. We report the type of biopsy proven acute rejection (BPAR) and biopsy findingsafter induction therapy with a single dose of the anti-B cell antibody rituximab. Patients and methods. In a single centre, double-blind, placebo-controlled study, 280 adult renal transplant patients were randomised between a single dose of rituximab (375 mg/m2) or placebo during transplant surgery. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and steroids. The primary end point was the incidence BPAR within six months after transplantation. Biopsies were scored independently by two blinded pathologists according to the updated Banff 07 criteria. Additionally biopsies were scored for CD20+, CD79a+ (B-cell markers), and CD138+ (plasma cell marker) cells and C4d. Protocol graft biopsies were not performed. Results. The incidence of BPAR was comparable between rituximab-treated (23/138, 16.7%) and placebo-treated patients (30/142, 21.2%, p=0.25 by log-rank test). Most rejections were T cell mediated according to the Banff classification. Rituximab-treated patients tended to have less antibody mediated rejections (ABMR), compared to placebo-treated patients (4/138, 2.9% vs. 11/142, 7.7% p=0.11). An additional analysis of biopsies performed during the first six months showed that biopsies of rituximab-treated patients had significantly less CD20+ cells and significantly less (clusters of) CD79a+ cells in their biopsies (CD20+ cells 18.5% vs 82.9%, p<0.01 and score for CD79a+ 0.15 vs 1.56, p<0.01), and tended to have less C4d deposition (8.2% vs. 15.8%, p=0.13) compared with biopsies from placebo-treated patients. There was no difference in the score for CD138+ cells (0.35 vs 0.48, p=0.43). Conclusion. The results of our study suggest that a single dose of rituximab may reduce the incidence of biopsy proven acute rejection in immunised patients. The incidence of ABMR tended to be lower after rituximab, especially in immunised patients. After rituximab treatment, significantly less B-cells were found in the biopsies. DISCLOSURES:Hilbrands, L.: Grant/Research Support, Hoffmann-La Roche, Astellas Pharma.

ABO-Incompatible Kidney Transplantation Outcomes: A Single Center Experience.

Background In recent years, ABO-incompatible kidney donor protocols have been developed, allowing more patients access to kidneys from a living donor. However, it is still unclear what the long-term outcomes of ABO-incompatible kidney transplantation are. Methods We conducted a single center case control study comparing 10 ABO-incompatible (ABO-i) kidney transplantations to 40 ABO-compatible (ABO-c) kidney transplantations. Controls were matched by gender, age and follow-up period. ABO-i recipients were treated with a single dose of rituximab four weeks before transplantation and started triple immunosuppressive treatment (prednisone, mycophenolate mofetil and tacrolimus) two weeks before transplantation. All ABO-incompatible recipients received IVIG preoperatively. Immunoadsorption was conducted at least four times preoperatively, with additional sessions being performed if the target anti donor blood type IgG ≤ 1:8 had not been reached. Postoperatively, 3 immunoadsorptions were conducted. Results ABO-i and ABO-c patients were followed for a median period of 2,25 vs. 2,5 years respectively. There was no significant difference in patient and graft survival. Kidney function (as measured by creatinin clearance, MDRD and proteinuria) was also not significantly different, although there was a trend toward a lower kidney function in ABO-i patients. ABO-i patients had more biopsy-proven rejection episodes (50% in ABO-i vs. 15% in ABO-c, p=0,018) for which they received additional immunosuppressive treatment. This resulted in significantly more infections (1,7 infections per ABO-i patient vs. 0,9 infections per ABO-c patient, p=0,045). The number of days in the hospital in the first year post-transplantation was also higher in the ABO-i group (24 vs. 15,5 median days). In linear regression analysis, higher baseline anti donor blood type IgG were predictive of a lower kidney function during follow-up. Conclusion ABO-i transplantations can be performed successfully, without a significant difference in patient and graft survival after a median follow-up of 2,25 years. However, patients are at increased risk of rejections and infections. Patients with high anti donor blood type IgG are not suitable candidates for ABO-i kidney transplantation.

Rituximab Does Not Prevent Graft Loss in Renal Transplant Recipients With Chronic Antibody Mediated Rejection With Significant Renal Impairment and Nephrotic Range Proteinuria.

Background: Chronic antibody mediated rejection (CAMR) is the second most common cause of graft loss in renal transplant recipients (RTR). There is limited data available for the management of CAMR. Methods: We performed a retrospective analysis of 39 RTR identified via electronic medical records transplanted between 2002-2012 who had biopsy proven CAMR.Table: No Caption available.RTR with coexisting acute rejection were excluded from analyses. Time to allograft loss was estimated using the Kaplan-Meier method. Log-rank test was used to compare the two survival curves.Results: RTR received either antithymocyte globulin or basiliximab and maintained on prednisone, tacrolimus and mycophenolate. 9/39 RTR received, a single dose of rituximab (RTX) 200 mg in addition to the standard therapy for biopsy proven CAMR. Table 1 shows baseline characteristics between the two groups. RTX group had significant renal impairment and proteinuria. The proportion of patients who had DSA was comparable between the two groups. Seventy-eight percent of patients had allograft loss in the rituximab group, compared to 30% in the non-rituximab group. The Kaplan-Meier graph shows the survival of the two different groups. Log-rank test to comparing the two curves resulted in a χ2 = 17.34, p < 0.001.Figure: No Caption available.Conclusion: RTX does not appear to decrease risk of graft loss in CAMR in RTR with significant renal impairment and proteinuria. We use one dose of RTX 200 mg, as this has been shown to effectively deplete peripheral B-cells up to one-year, but this might have been inadequate in the setting of significant nephrotic syndrome and advanced allograft disease. Its use in RTR with preserved renal function and less proteinuria needs to be further studied in a controlled study.

Long-Term Outcomes After Treatment of Chronic and Late Renal Antibody Mediated Rejection With IVIg and Rituximab.

Aim: Chronic and late antibody mediated rejection (clAMR) are the major causes of premature renal allograft loss and appear refractory to current therapies with graft loss occurring in up to 50% at 1 year. We aimed to determine long-term graft survival in patients with combined clAMR treated with IVIg and Rituximab and the predictors of graft failure. Methods: Patients >6 months post-transplant with at least 3 years follow-up since clAMR diagnosis were included if they had biopsy evidence of both late AMR defined by peritubular capillaritis (PTCitis) and chronic AMR defined by Banff criteria including presence of at least one donor specific antibody (DSAb). Patients received high dose IVIg (1gm/kg) monthly for 3 months followed by repeat biopsy. Those with persistent PTCitis received a single dose of rituximab (500mg) and further IVIg. Outcomes to 5 years are reported. Results: 24 patients were included. Their mean age was 43.5yrs, 50% were male. The median (range) time from transplant to clAMR diagnosis was 59 (7-267) months and the median (range) time from diagnosis to analysis was 60 (40.5-60) months. 22 were primary grafts. 8 were deceased donor, 14 live donor and 2 were simultaneous kidney and pancreas transplants. 13 had an early rejection episode. DSAb were class I in 5, class II in 15 and both in 4. Eight had positive C4d staining on the initial biopsy. Five-year graft survival from clAMR diagnosis was 75%. At clAMR diagnosis eGFR was significantly lower (mean difference 15ml/min, p=0.009) and urine protein to creatinine ratio significantly higher (median difference 0.12gm/mmol, p=0.008) in those who developed graft failure relative to those who did not. Individually or grouped no acute nor chronic Banff parameter was different between those with and without graft loss, nor was class or MFI of DSAb. Conclusion: Graft survival in clAMR is governed by the degree of graft dysfunction at diagnosis. The graft survival of patients in the current cohort are superior to those described in previous reports suggesting that this treatment regimen warrants randomised study to further assess efficacy.

Successful Interim Outcomes of Bortezomib Desensitization on Highly Sensitized Deceased Donor Kidney Transplant Waitlist Patients

Highly sensitized (HS) patients seldom have chance to receive kidney transplant. To increase transplantation rate among those population, previous IV immunoglobulin and rituximab desensitization protocol showed good transplant conversion rate, but also carried moderate rate of antibody mediated rejection. Bortezomib, a proteasome inhibitor can control the production of anti-HLA antibodies through plasma cell apoptosis. A single center waitlist desensitization program was employed to facilitate successful kidney transplantation in HS patients group. We prospectively enrolled 23 patients from Jul 2010 to Dec 2013. Desensitization protocol included two doses of IVIG (2 g/kg), single dose of rituximab (375 mg/m 2 , max 500 mg), and 4 days of bortezomib (1.3 mg/m 2 on days 1,3,7 and 9). Anti-HLA class I and II antibodies were determined by Luminex solid phase bead assay at baseline and M2, M3 and M6. We investigated the difference of transplant conversion rate between desensitized HS patients and non-desensitized HS waitlist patients. Also we analyzed the difference of PRA % values and mean fluorescence intensity (MFI) between pre- and post-desensitization serum. Mean age of treatment group was 48.7±11.2 years old. Male to female ratio was 12:11. O+ blood type patients were 34.8% of patients. Mean duration of previous renal replacement therapy were 153.5±65.5 months. Baseline mean class I and II PRA % values were 86±15.3 and 66±34. Baseline class I and II MFI values were 13,893±6,147 and 12,274±6,891. After desensitization, kidney transplant were successfully performed in 34.8% of patients, compared to 13.8% transplant conversion rate among non-desentized HS controls ( p =0.001 by Log-Rank). Among KT recipients, median duration of waiting after desensitization was 3 months with interquartile range 2-8.1 months. Class I PRA % had showed decreased values until 3 months after desensitization. After 6 months, there were no differences between the class I PRA values between pre-desensitization samples and post-desensitization samples. There were no other differences except class I PRA % values. Desensitization protocol were generally well tolerated, with the completion rate of 92% patients. There were no serious adverse events, but moderate adverse event were in 46%, most commonly fever and diarrhea. Highly sensitized waitlist patients are manageable by desensitization protocol including bortezomib.

Fourteen Successful Consecutive Cases of ABO-Incompatible Living Donor Liver Transplantation: New Simplified Intravenous Immunoglobulin Protocol Without Local Infusion Therapy

Since various innovative strategies including local infusion therapy and rituximab have been introduced, the survivals and outcomes of recipients in ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) have remarkably improved. Thus, ABO-I LDLT can be a feasible therapeutic option for the patient with end-stage liver disease if an ABO-compatible donor is not available. Although most ABO-I protocols are based on rituximab, plasma exchange, and local infusion therapy, treatment strategies have been changing according to a center's preference or their results. Nonetheless, the consensus of the ABO-I LDLT protocol remains undetermined. Herein, we present our experience with new simple ABO-I LDLT protocol and the excellent results for 14 patients from January 2011 to May 2013. All patients were administrated a single dose of rituximab over 7 days before transplantation followed by plasma exchange to lower anti-ABO antibody titer ≤32. The basic immunosuppression protocol consisted of tacrolimus and steroids with mycophenolate mofetil starting 3 days before transplantation. Splenectomy was not performed routinely and local infusion therapy was not applied at the postoperative period. Instead, the patients received intravenous immunoglobulin (IVIG) after LDLT on days 1, 3, and 5. Neither antibody-mediated rejection nor biliary stricture were encountered in the patients, with a mean follow-up of 16.27 ± 9.4 months. This new simplified ABO-I LDLT protocol seems to prevent antibody-mediated rejection and could be considered as the safe and effective modality to overcome the ABO blood-type barrier in LDLT.

Induction treatment of ANCA-associated vasculitis with a single dose of rituximab

Rituximab is effective in inducing remission in ANCA-associated vasculitis (AAV), with randomized evidence to support its use as four infusions of 375 mg/m(2) (the conventional lymphoma dosing schedule). As B cell depletion (BCD) appears to occur very rapidly after the first dose, we questioned the need for repeat dosing and adopted a standard single-dose protocol of 375 mg/m(2) to treat active AAV. All consecutive cases with newly diagnosed or relapsing AAV for whom conventional immunosuppression was contraindicated or ineffective were enrolled. All were rituximab naive. Circulating CD19(+) B cells and clinical and serological markers of disease activity were recorded at regular intervals. Complete remission (CR) was defined as the absence of clinical features of AAV with a prednisolone dose <10 mg/day. Nineteen patients were included, 17 (89%) with generalized disease and 2 (11%) with severe disease (creatinine level >500 μM). Eight (42%) were on additional immunosuppression at the time of rituximab treatment. Satisfactory BCD (<0.005 cells/μl) was achieved in 89% of patients after a median of 13 days. Three-month BCD probability was 89%. Median time to CR following a single dose of rituximab was 38 days and the 3-month probability of CR was 80%. Median time to B cell repopulation was 9.2 months and to disease relapse/redose was 27 months. Use of this single-dose protocol saved an estimated £4533/patient (US$7103; €5276) compared with a 4 × 375 mg/m(2) dosing schedule. Our single-centre experience suggests that a single dose of rituximab of 375 mg/m(2) is a reasonable and more cost-effective therapy for inducing remission in patients with AAV.

Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome

Calcineurin inhibitors (CIs) with/without intravenous methylprednisolone pulse therapy (MPT) constitute the standard treatment for childhood-onset, steroid-resistant nephrotic syndrome (SRNS). However, some patients fail to achieve remission. We treated SRNS patients resistant to CIs and MPT with additional rituximab combined with MPT and immunosuppressive agents. Ten patients (aged 2-14years) with CI- and MPT-resistant SRNS were enrolled. Patients were administered rituximab (1-4 doses; 375mg/m(2)) followed by MPT (30mg/kg/day of methylprednisolone for 3 consecutive days) once every 2-4weeks until complete remission (CR). We analyzed clinical outcome and safety. Six patients received a single dose of rituximab, 2 received two doses, and 2 received four doses. Seven patients achieved CR, 1 achieved partial remission, and 2 showed no response. Although 2 patients with no response progressed to end-stage renal failure, 7 patients with CR preserved normal renal function without proteinuria at the last observation. There were two serious adverse events. Additional rituximab combined with conventional MPT and immunosuppressive agents is a promising option for overcoming refractory SRNS. Aggressive B cell suppression by rituximab may ameliorate resistance to conventional treatments and a cocktail of other immunosuppressive agents, such as CIs, MMF, mizoribine, may be beneficial. However, as intense immunosuppression may cause serious adverse events, further evaluation is necessary.

Intermediate doses of rituximab used as adjuvant therapy in refractory pemphigus.

Rituximab, a monoclonal anti-CD20 antibody, has been used with encouraging results in pemphigus. We describe herein refractory cases of pemphigus vulgaris (n = 23) and pemphigus foliaceus (n = 1) treated with rituximab in addition to steroids and immunosuppressants. To assess the response to treatment, the duration of clinical remission, serology of the response and adverse effects of rituximab in pemphigus patients. We recorded observations of 24 patients with pemphigus having either refractory disease in spite of high dose of steroids and immunosuppressants, corticosteroid-dependent disease, strong contraindications to corticosteroids, or severe disease. The patients were treated with infusions of one injection per week for three consecutive weeks of 375 mg of rituximab per m ² of body-surface area. One similar infusion was repeated after 3 months of 3 rd dose. We observed the clinical outcome after 6 months of 3 rd dose of rituximab and looked for complete healing of cutaneous and mucosal lesions (complete remission). After follow-up of 7-24 months, five patients showed only partial improvement while 19 of 24 patients had a complete remission 3 months after rituximab. Of these 19 patients, 12 patients achieved complete remission and are off all systemic therapy, and the rest are continuing with no or low dose of steroids with immunosuppressants. Two patients relapsed after initial improvement; one was given moderate dose of oral steroids and immunosuppressant and the other was given repeat single dose of rituximab to control relapse. Rituximab is able to induce a prolonged clinical remission in pemphigus after a single course of four infusions. The high cost and limited knowledge of long term adverse effects are limitations to the use of this biologic agent.

Proteasome Inhibitor Based Protocol For Antibody Mediated Rejection In Kidney Transplantation

Background Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) of renal transplantation is rarely achieved with traditional antihumoral therapies. Current antihumoral therapies do not target the mature antibody producing plasma cells. Bortezomib is a first in class proteosome inhibitor for the treatment of plasma cell derived tumors like multiple myeloma. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR. Here, we report on our experience with plasma cell targeted therapy (bortezomib) as an antirejection strategy for refractory early and delayed AMR post renal transplantation. Methods Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen after failing at least 2 traditional treatments for AMR. Bortezomib therapy was administered (1.3 mg/m2 IV D1,4,8,11) with plasmapheresis performed immediately before each dose of Bortezomib and a single dose of rituximab (375 mg/m2) given with the first bortezomib dose. Methylprednisolone was administered along with Bortezomib at 100 mg IV on D1,4 and 50 mg IV on D8,11. All patients received valganciclovir prophylaxis for prevention of herpes zoster and cytomegalovirus reactivation. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels, serum creatinine levels, urine protein excretion and repeated allograft biopsies. Results Ten episodes of AMR in eight renal transplant recipients were treated with bortezomib, rituximab, methylprednisone and plasmapheresis. Post treatment reduction in immunodominant DSA was observed and this data will be available at the meeting. None of the patients experienced peripheral neuropathy from bortezomib and only one patient had GI toxicity with nausea and diarrhea, which was transient. None of the patients had reactivation of herpes zoster infection. In conclusion, bortezomib, rituximab, methylprednisone and plasma exchange therapy provided reversal of AMR rejection post renal transplantation with improvement in renal function, proteinuria and histology, at a median follow-up of 15 months. Disclosures: No relevant conflicts of interest to declare.

Intensive Immunochemotherapy In Patients With B-Cell Lymphoma, Unclassifiable (B-UCL), With Features Intermediate Between Diffuse Large B-Cell Lymphoma (DLBCL) and Burkitt Lymphoma (BL): A Comparison With BL Patients Treated With The Same Protocol In The Pethema-Burkimab-04 Trial

▪B-UCL is a new category of lymphomas that comprises a heterogeneous group of tumors from a morphological, phenotypic and genetic perspective with features intermediate between DLBCL and BL. This entity has been included as a new category in the 2008 World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues. The outcome of patients with B-UCL is generally considered very poor. However, the number of series analyzing the prognosis of B-UCL is scarce and they include small number of patients not homogeneously treated. Against this background, herein we present a series of patients diagnosed with B-UCL (WHO 2008) or Burkitt-like variant (WHO 2001) homogeneously treated according to the PETHEMA-Burkimab-04 trial. This trial was designed for the treatment of BL, including both HIV positive and negative patients. Patients with B-UCL were allowed to be treated following the same protocol and were considered separately. The main clinical characteristics and outcome were compared to those obtained from classical BL patients in the same trial (Ribera et al. Cancer 2013).Diagnosis of B-UCL was made in each center based on morphological, phenotypic and genetic characteristics and centrally reviewed by two pathologists. Patients received 6 courses of chemotherapy including continuous methotrexate infusion, cytarabine, vincristine and dexametasone among other drugs. A single dose of rituximab (375mg/m2) before each cycle was administered. Patients with non-bulky stage I-II disease received only 4 courses of treatment, whereas patients with advanced stage (II bulky-IV) received 2 additional doses of rituximab at the end of the chemotherapy.A total of 30 patients with B-UCL were included and were compared with the 118 patients with BL. Median follow-up for survivors was 24 months (range 3-93). Considering B-UCL, 8 (27%) patients were HIV positive and 10 (33%) had an ECOG performance status ≥ 2. Four (13%) and 6 (20%) patients had CNS involvement and bulky (>10 cm) disease, respectively. Serum LDH level was > UNL in 25 (83%) patients. These and other clinical characteristics were similar between patients with B-UCL and BL, except for the median age at diagnosis (57 years in B-UCL vs. 44 years in BL, p=0.001). In B-UCL patients, death during induction occurred in 5 patients (17%) and 2 patients experienced treatment failure. Twenty-three (77%) patients achieved complete remission. Relapse after CR and death in remission were observed in one patient, each. All these outcomes were comparable with BL patients except for a trend to a higher risk of death during induction in patients with B-UCL (17% in B-UCL, vs. 8% in BL, p= 0.1). A total of 104 consolidation cycles were evaluable for patients with B-UCL. Most frequent grade 3-4 toxicities were neutropenia (n=57, 54%), thrombocytopenia (n=44, 42%) and infection (n=21, 20%). Grade 3-4 gastrointestinal, renal and hepatic toxicities were seen in <5% of the cycles.Overall survival at 2 years for patients with B-UCL and BL was 68% (95% CI 59-77) vs. 78% (95% CI 74-82), p=0.2, respectively. Probability of disease-free survival from CR1 for B-UCL and BL patients was 84% (95% CI 76-92) vs. 80% (95% CI 69-91), p=0.6. In conclusion, the Burkitt-type chemotherapy included in the PETHEMA-Burkimab-04 trial was able to achieve an important number of complete and durable responses in patients with B-UCL with an acceptable toxicity. As a consequence, the outcome of patients with B-UCL treated with this intensive immunochemotherapy seems similar to that obtained in the treatment of classical BL. [Display omitted] Table 1Baseline characteristics of all patients according to definitive diagnosis.CharacteristicsBurkitt (n = 118)LDCG-B/Burkitt (n=30)pGender, male n (%)85 (72)21 (70)0.8Age, median [min -max]44 [15 - 83]57 [16-77]0.001Stage, n (%)Non bulky I – II26 (22)10 (33)0.8II (bulky), III - IV92 (78)20 (67)ECOG ≥2, n (%)55 (47)10 (33)0.3HIV infection39 (33)8 (27)0.4Extranodal involvement (≥2 sites), n (%)55 (47)11 (37)0.5CNS involvement, n (%)14 (12)4 (13)0.6Bulky disease, n (%)31 (26)6 (20)0.3LDH level above normal, n (%)106 (90)25 (83)0.5Age-adjusted IPI, n (%)Low6/116 (5)2 (7)1Low-intermediate17/116 (15)6 (20)Intermediate-high46/116 (40)11 (37)High47/116 (40)11 (37)Follow-up [all patients] (months)19 (0-92)16 (0-93)0.9 Disclosures:No relevant conflicts of interest to declare.