Low-dose Rituximab Research Articles

Eltrombopag, Low-Dose Rituximab, and High-Dose Dexamethasone Combination for Patients with Newly Diagnosed Immune Thrombocytopenia: A Pilot "Total Therapy" Study

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disorder that results from platelet destruction and production suppression. Frontline-therapy includes corticosteroids, intravenous immune globulin or anti-D immunoglobulin. Single-agent treatments have not been successful in inducing prolonged remission, as relapse will occur in approximately 50% of patients. Low-dose rituximab (100 mg) has been used for the treatment of ITP, showing an activity almost similar to the 375 mg/m2 standard dose. We and others have reported sustained response rates ranging from 58% to 76% using rituximab plus dexamethasone as a frontline therapy. Eltrombopag is a thrombopoietin nonpeptide mimetic that has been shown to raise platelet count in chronic ITP, and we have previously reported eltrombopag/dexamethasone as a feasible frontline therapy for ITP reaching 100% response rates.The lack of sustained response in many adult patients with newly diagnosed acute ITP has stimulated the search for a treatment that modifies the natural course of the disease.Objetive: We aim to evaluate efficacy, safety, and response duration of low-dose weekly rituximab (100 mg weekly, four doses) plus high-dose dexamethasone (40 mg PO, days 1-4) in combination with eltrombopag (50 mg, days 1-28) as frontline therapy in newly diagnosed primary ITP in an ambulatory setting.Methods: This is an ongoing open-label, single-arm study performed in patients with newly diagnosed ITP from the Hospital Universitario Dr. Jose Eleuterio Gonzalez in Monterrey, Mexico (Clinical trials.gov NCT02834286). Eligible patients are 16 years or older, with bleeding manifestations and/or a platelet count ²30×109/L, without previous treatment. Patients are excluded if they had active infection, pregnancy, or a malignant disease. A complete blood count is performed at baseline, on days 3, 5, 7 and then weekly for 28 days, monthly until month 6, and every 3 months thereafter. Partial and complete responses are defined as an increase in platelet counts ³30×109/L and ³100×109/L, respectively.Results: Ten consecutive patients have been enrolled from March 2015 until July 2016. Median age was 37 years (16-61). Six patients were women (60%) and four were men (40%). Median platelet account at diagnosis was 7 « 109/L (range 1.2-28). Median follow-up has been 7 months (range 1-13). All patients achieved at least a partial response (PR) at a median of 4 days (range 3-14). Complete response (CR) was achieved in 9 patients in a median of 7 days (7-22); all of them were still in CR at the end of treatment (Day 28). One patient lost response at 28 days and received a second high-dexamethasone course maintaining CR. No significant adverse effects have occurred during treatment, only 1 patient reported mild myalgia. No relapses have been documented until now.Currently, 8 patients remain in CR and 2 in PR.Conclusion:This is the first trial evaluating the response of low-dose rituximab in combination with eltrombopag and high-dose dexamethasone in newly diagnosed patients with ITP.Low-dose rituximab in combination with eltrombopag and high dose dexamethasone is a feasible frontline therapy for ITP. This drug combination showed high response rates achieved very rapidly, with a low incidence of side effectsand might represent an attractive option in patients with ITP and substantial bleeding. [Display omitted] DisclosuresGomez-Almaguer:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol: Consultancy, Membership on an entity's Board of Directors or advisory committees.

DI-Leu16-IL2, an Anti-CD20-Interleukin-2 Immunocytokine, Is Safe and Active in Patients with Relapsed and Refractory B-Cell Lymphoma: A Report of Maximum Tolerated Dose, Optimal Biologic Dose, and Recommended Phase 2 Dose

Background: DI-Leu16-IL2 is a recombinant fusion immunocytokine composed of interleukin-2 and a CD20-targeting monoclonal antibody that maintains the activities of both antibody and cytokine components but is also involved in tumor targeting, engagement of the immune system, and induction of an anti-cancer vaccine effect.Methods: In this multicenter open label, dose escalation trial to determine the maximum tolerated dose (MTD), optimal biological dose (OBD), and recommended phase 2 dose (RP2D), we evaluated the safety, tolerability, and efficacy of subcutaneously (SC) administered DI-Leu16-IL2 in patients (pts) with relapsed or refractory CD20+ B-cell lymphoma (NCT01874288). Following peripheral B-cell depletion with low-dose rituximab (50mg/m2), DI-Leu16-IL2 was administered SC for 3 consecutive days every 21 days for 6 cycles. A 3+3 dose escalation trial design began at 0.5 mg/m2. Responses were evaluated by PET in pts who had received at least 2 cycles of therapy. Immunologic correlates were done including peripheral blood flow cytometry and serum cytokine levels. Responding (complete or partial response, CR or PR) and stable disease (SD) pts were permitted to continue treatment for an additional year.Results: Twenty-two pts in 5 dose cohorts have been enrolled, 3 at 0.5 and 1mg/m2, 7 at 2mg/m2 and 4mg/m2, and 2 at 6mg/m2. The median age is 64 years (40-84), median prior therapies is 4 (range 1-21), with 100% having received prior rituximab and chemotherapy, and 41% with prior autologous stem cell transplant. Dose limiting toxicities (DLT) occurred in 2 pts at 6 mg/m2, both with delayed (8-10 days) grade 3 cytokine release syndrome (CRS), suggesting effector cell expansion as the cause. None of the CRS required treatment with tocilizumab, however one required dose reduction, and the other discontinued therapy.The Gr 3-4 drug-related adverse events (AEs) that required dose reduction were: QTC prolongation (Gr 3) in one patient at 4 mg/m2, tumor lysis syndrome (Gr 3) at 4mg/m2, and diarrhea (Gr 3) at 1mg/m2. Hematologic AEs were eosinophilia (Gr 1-2 = 22.7%), anemia (Gr 1-2 = 45%, Gr 3-4 = 9%), thrombocytopenia (Gr 1-2 = 36%, Gr 3-4 = 4.5%), neutropenia (Gr 1-2 = 14%, Gr 3-4 = 14%) in the 22 pts evaluable for toxicity. Other AEs were local injection site reactions (Gr 1-2 = 82%), pruritus (Gr 1-2 = 82%), edema (Gr 1-2 = 23% Gr 3-4 = 5%), fever (Gr 1-2 = 41%, Gr 3-4 = 5%), and chills (Gr 1-2 = 59%). Six pts have been enrolled at 4mg/m2 and no DLTs have been encountered. The MTD was determined to be 4mg/m2.Patients with CR or PR had higher pre-treatment absolute lymphocyte counts (>700/mcL) than pts with progressive disease (P < 0.05). Repetitive SC dosing elicited lymphocyte expansion at all dose levels. Although T-regulatory cell expansion was observed in the blood, it was not associated with a worse response. Pts achieving CR showed a trend towards lower % of granulocyte-like myeloid derived suppressor cells. Pts showed reproducible increases in cytokine levels of IL-10, MCP-1, IFNgamma, and TNFalpha. Pharmacokinetic data showed consistent drug levels between cycle 1 and 2.Therefore, the OBD and RP2D was determined to be 2mg/m2 which produced 3 CR and 3 SD.Durable tumor regression or stabilization was noted in 14 of 16 (88%) evaluable pts. There were 4 CR: 1 diffuse large B-cell lymphoma (DLBCL), 2 follicular lymphoma and 1 marginal zone lymphoma; 1 PR (DLBCL) and 9 SD, and objective response rate of 31% [Figure 1]. The median duration of disease stabilization was 8 months (4-14). Of the responders, the median duration of response was 13 months (10-15). One CR continues 11 months after stopping therapy at cycle 6.Conclusions: Promising clinical efficacy of DI-Leu16-IL2 has been observed with long-term responses in relapsed/refractory B-cell NHL pts. SC administration has permitted higher doses than could be achieved with IV treatment, however, at the higher dose range, CRS was observed. Even though the MTD was 4mg/m2, given the responses, AEs, and biologic activity in the Phase I study, the RP2D was determined to be 2mg/m2. Responses were associated with a higher starting ALC, and lymphocyte expansion was dose dependent, with reproducible serum cytokine profiles. The protocol continues to enroll pts in the expansion cohorts of this phase I/II study. DI-Leu16-IL2 given subcutaneously is safe and effective, and induces durable responses even after discontinuation of therapy, suggesting an anti-tumor vaccination effect. [Display omitted] DisclosuresLansigan:Celgene: Consultancy; Teva: Research Funding; Pharmacyclics: Consultancy; Spectrum: Consultancy, Research Funding. Vlock:Alopexx Oncology, LLC: Employment. Gillies:Provenance Bioparmaceuticals Corp: Employment.

Outcome of ABO-Incompatible Living Donor Renal Transplantations: A Single-Center Experience From Eastern India.

With the incessantly increasing number of patients on the waiting list for renal transplants, crossing the blood group barrier can substantially increase the donor pool. We started ABO-incompatible (ABOi) renal transplantation in 2013 with a relatively low-cost preconditioning protocol (additional cost, ∼$1200). This study reports the short-term outcome of ABOi renal transplantations performed at our institution. A total of 45 adult ABOi kidney transplant recipients (KTRs) were included in the study. All of them underwent a pretransplantation conditioning program, which included plasmapheresis, low-dose intravenous immunoglobulin (IVIG), and low-dose rituximab. A pretransplantation isoagglutinin titer of≤1:8 was considered acceptable for transplantation until December 2014, after which the threshold was increased to≤1:32. Overall, 50% of KTRs were of blood group O. The maximum initial antibody titer was 1:2048. All the patients achieved immediate graft function post-transplantation. The mean serum creatinine level at 370 days (median duration of follow-up) was 1.21mg%. One graft was lost due to severe antibody-mediated rejection (ABMR) with cortical necrosis. The graft survival rate was 97.78% and the patient survival rate was 97.78%. The overall result in terms of graft and patient survival, infections, and rejections were similar to ABO-compatible transplantations. ABOi renal transplantation is a cost-effective modality to increase the donor pool. Contrary to the belief that this modality is extremely expensive and requires elaborate infrastructure, we had a good short-term outcome with a relatively simple and low-cost preconditioning protocol.

Low-dose rituximab is poorly effective in patients with primary membranous nephropathy

The optimal dosing and the efficacy of rituximab for primary membranous nephropathy (PMN) has not been established. This multicentric prospective study evaluates the efficacy and safety of low-dose rituximab (RTX) therapy in patients with PMN in clinical practice. Thirty-four consecutive patients with PMN and nephrotic syndrome were included and received RTX (375 mg/m2) once (18 patients) or twice (16 patients). RTX was the first-line therapy for 19 (56%) and the second line for 15 (44%) patients. All patients were followed for 12 months after RTX and 24 for at least 18 months (mean 23.9 ± 18.6 months). At 12 months, 5 patients (14.7%) achieved complete response, 10 (29.4%) partial and 19 (55.8%) no response. Response occurred ∼6 months after RTX. At 24 months, the clinical situation was unchanged: two non-responders achieved partial response and two responders relapsed. Responders had significantly higher baseline GFR and lower anti-PLA2R antibodies compared with non-responders. Outcome was similar between one or two doses of RTX (non-responders 55.5 versus 56%, respectively) and between patients who had received previous therapy versus those receiving RTX as first-line therapy (non-responders 40 versus 68%, respectively). In the 15 patients already treated, the response to RTX was comparable to that of previous therapies. Low-dose RTX obtains remission in <50% of PMN patients. Probably, higher doses and longer treatments are needed to induce and maintain a response. The balance between the costs and benefits should guide the selection of the patient and the optimal dosage.

Could we use a lower dose of rituximab to treat rheumatoid arthritis in clinical practice: pros and cons?

The CERERRA database provides evidence that low-dose rituximab performs as well as the conventional dose in the real world, thus highlighting the possible pharmacoeconomic impact. In clinical trials, it has been shown that rituximab 500 mg twice, performs as well as 1 g twice, 2 weeks apart, in terms of the American College of Rheumatology (ACR)20 and ACR50, but not the ACR70. The choice should always be made after considering that the IMAGE trial has demonstrated similar radiographic progression after the first 6 months, but with less control, with low-dose rituximab in the first 6 months. A possible alternative can be hypothesized.

082 Comparison of the Efficacy of Standard Dose Versus Low-Dose Rituximab Infusion Regimes for the Treatment of Rheumatoid Arthritis at the Queen Elizabeth Hospital, Birmingham, UK: Experience Over a 12-Month Period

082 Comparison of the Efficacy of Standard Dose Versus Low-Dose Rituximab Infusion Regimes for the Treatment of Rheumatoid Arthritis at the Queen Elizabeth Hospital, Birmingham, UK: Experience Over a 12-Month Period

Treatment of One Case with Cryoglobulinaemia Secondary to Connective Tissue Disease with Small Doses of Rituximab.

This study aims to observe the clinical efficacy of low-dose rituximab in patients with cryoglobulinaemia secondary to connective tissue diseases. Rituximab (100 mg) was infused in patients once a week for four weeks, combined with prednisone (20 mg) once a day, and reduced regularly. Treatment effect was observed regularly. Joint pain, fever, rash and fatigue symptoms in patients eased. The serology (globulin, erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase and others) parameters returned to normal. Low-dose rituximab therapy for cryoglobulinaemia secondary to connective tissue diseases was safe and effective, and can be used as a treatment option in this condition.

Short-Term Outcomes of ABO-Incompatible Living Donor Kidney Transplantation With Uniform Protocol: Significance of Baseline Anti-ABO Titer

Antibody-mediated rejection (AMR) is one of the major causes of poor outcomes in ABO-incompatible kidney transplantation (ABOi KT). Studies investigating AMR risk factors found that anti-ABO titer is a major issue. However, the significance of antibody titer has been debated. This retrospective study analyzed AMR risk factors in 59 patients who underwent ABOi KT between August 2010 and January 2015. We also analyzed AMR risk factors in recipients with high anti-ABO baseline titers (≥1:64 on dithiothreitol at 37°C phase or ≥1:256 on antihuman globulin phase). The 2-year patient survival rate was 95.8%, and the 2-year graft survival rate was 94.9%. Nine patients (15.3%) experienced clinical (6 of 59 [10.2%]) or subclinical (3 of 59 [5.1%]) AMR. One patient experienced graft loss from hyperacute rejection. AMR risk factor analysis revealed that baseline antibody titer was associated with incidence of AMR. In patients with high baseline titers, low doses of rituximab (200-mg single-dose), an antibody against CD20, was predictive for AMR. Six patients who received pretransplant intravenous immunoglobulin did not experience AMR even when they had high baseline antibody titers. Our results indicate that a high baseline antibody titer affected the incidence of AMR. ABOi KT candidates with high baseline titers need to undergo an intensified preconditioning protocol, including high-dose rituximab (375 mg/m2) and intravenous immunoglobulin.

Single low-dose rituximab for the treatment of steroid-resistant nephrotic syndrome with acute kidney injury

The efficacy of rituximab for kidney disease, such as frequent relapsing nephrotic syndrome, has been reported recently. Herein, we report a case of a patient with acute kidney injury that was steroid-resistant nephrotic syndrome who responded to a single administration of low-dose rituximab. An 86-year-old Japanese woman with hypertension presented with severe peripheral edema within several days after onset. Due to the patient's age, renal biopsy was not performed, nephrotic syndrome was diagnosed and prednisolone was administered at 40mg/day on the day after admission. However, anuria developed and hemodialysis was inevitably initiated on the 5th hospital day. The renal function did not recover, and the general condition gradually became aggravated. On the 50th hospital day, 100mg rituximab was administered, which led to immediate depletion of CD20-positive cells. The urine volume gradually increased from 2-3weeks after the rituximab administration, and the renal function recovered slightly. After 5weeks, it became possible to wean the patient from dialysis, which had been applied for 3months. Rituximab might be an option for the treatment of acute kidney injury due to steroid-resistant nephrotic syndrome.

More about low-dose rituximab and plasma exchange as front-line therapy for patients with thrombotic thrombocytopenic purpura

Introduction: Thrombotic thrombocytopenic purpura (TTP) is characterized by a reduction in the von Willebrand cleavage protein ADAMTS-13, mainly as a consequence of autoimmunity. Plasma exchange (PEx) is standard, achieving complete remission (CR) in 77–83% of cases, but rates are variable depending on ADAMTS-13 activity and relapse is frequent in patients with <10%. Thus, an effective front-line immunosuppressive treatment is needed.Materials and methods: We administered PEx daily until CR and rituximab 100 mg/dose/week for 4 consecutive weeks to 10 patients with a first TTP episode and 1 relapsed patient (8 females (72%) and 3 males (28%)). Median age was 34 years (15–46) and laboratory parameters at diagnosis were as follows: platelets 11 × 109/l (range 7–27.4 × 109/l), lactate dehydrogenase 1822 U/l (range 705–8220 U/l, normal 70–180 U/l), and haemoglobin 6 g/dl (range 4.2–11.8 g/dl). ADAMTS-13 activity was determined in eight patients and was <10% in all. ADAMTS-13 autoantibody titre was determined in seven patients and was >15 units/ml in all (ref: negative <12, undetermined 12–15, positive >15 units/ml); Shiga toxin was negative in all patients. The median number of PEx until CR was 7 (range 4–12); prednisone 1 mg/kg was administered to six patients.Results: The median follow-up was 22 months (range 4–49) and the estimated 2-year relapse-free survival was 89%; one HIV+ patient relapsed at 8 months follow-up. No complications related to PEx or rituximab were reported.Conclusions: Our study suggests that low-dose rituximab and PEx are effective as front-line treatment for acute TTP; however, a prospective trial is needed to demonstrate whether low-dose rituximab is as effective as the conventional dose.

The effects of intrathecal rituximab on biomarkers in multiple sclerosis

ObjectivesClinical trials of IV-rituximab have proved successful. It is unclear whether intrathecal (IT)-rituximab is more efficacious at lower doses. We examine its effects on B-cell biomarkers. MethodsMS patients received IT-rituximab at 3 time-points. CSF and serum samples were obtained at up to 5 time-points (days 0, 7, 14, 56 and 112).Serum and CSF BAFF and CXCL13, and CSF kappa and lambda free light chains (FLC) were measured. Flow cytometry was performed, examining effects on lymphocytes, CD3-19+ and CD3-20+ cells. ResultsCSF BAFF fell following rituximab (p=0.0091 absolute values, p=0.0284 change from baseline) whilst serum BAFF increased across time-points 1–4 (p=0.0005 absolute values, p=0.0017 change from baseline).There were significant reductions in CD20+ and CD19+ cells in blood from baseline (p<0.0001) but not in CSF. CSF kappa FLC levels significantly increased (p=0.0480). ConclusionsBAFF levels fall in CSF but increase in serum following IT-rituximab. Rituximab appears to act peripherally with dramatic decreases in peripheral CD20+ and CD19+ cells. It is likely that CSF B-cell counts were too low to enable differences to be seen. The rapid reduction in B-cells suggests rituximab has immediate effects. The profound depletion of B-cells, despite low doses of rituximab, underlines rituximab’s efficacy.

Blood and salivary-gland BAFF-driven B-cell hyperactivity is associated to rituximab inefficacy in primary Sjögren's syndrome

ObjectivesTo determine whether B-cell markers (blood and minor salivary gland [SG] B-cell depletion [BCD], autoantibodies, B-cell-activating factor [BAFF]) are associated with clinical response to rituximab in patients with primary Sjögren's syndrome (pSS). Methods45 patients with pSS were included: in group I, 14 received low-dose rituximab (two 375-mg/m2 infusions) in an open-labelled study; in group II, 17 received full-dose rituximab (two 1000-mg infusions) and 14 received a placebo in a randomized, controlled study. The proportion of SG B cells was assessed using pixel-based software analyses of digitized double-immunostained (CD3/CD20) whole SGs. Response was defined at week-24 according to the Sjögren's Syndrome Responder Index (SSRI)-30. ResultsResponse rate was 50% in both groups of rituximab-treated patients. Duration of blood BCD was similar in both groups despite the difference in rituximab dosage, and was highly correlated with residual serum-rituximab levels at week-16. SG B-cell dynamics mirrored blood B-cell levels, with a drastic decrease in SG B-cells at week-12 (group I), but an increase in ∼50% of patients in group II by week-24, in whom blood B cells had already returned. Duration of BCD was not associated with the clinical response, but responders had lower baseline proportions of SG B cells. Baseline serum BAFF level was correlated with the proportion of SG B-cells and other B-cell-activation markers, and was associated with the clinical response with higher levels in non-responders. ConclusionsIn pSS, half of the patients display an intense BAFF-driven B-cell activation and do not respond to a single course of rituximab.

Weekly Low-Dose Rituximab As the Preemptive Management of Epstein-Barr Virus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation: A Novel Strategy?

▪Background Reactivation of Epstein-Barr Virus (EBV) frequentlyoccurs after allogeneic stem cell transplantation(allo-SCT) andEBV-induced posttransplant lymphoproliferative disease(PTLD) is a potentially fatalcomplication. Our previous study showed that the cumulative incidence of EBV viremia after allo-SCT was 21.3±1.5% ( data based on 892 evaluable patients received allo-SCT from Jun 2011 through Jun 2014 at our institution). As the preemptive treatment for EBV reactivation after allo-SCT, rituximab (anti-CD20) is commonly used, but is associated with the prolonged immunedefect. The question of over-treatment of systematic rituximab has been raised and further studies investigating the minimal doses of rituximab to resolve EBV reactivation and avoid its prolonged B cell impairment are needed. The aimof this single-center study was to evaluate the strategy of weekly low-dose rituximab as the preemptive management of EBV reactivation.Methods 52 patients received allo-SCT from Mar 2014 through Mar 2015 at our institution were enrolled in a prospective study. 38 males and 14 females, median age 25 years (range, 7-57). Patients underwent transplantation for acute leukemia (n=33), CML (n=2), NHL (n=4), MDS (n=5), or SAA(n=8). The type of donors included HLA-haploidentical donors (n=41), HLA-matched unrelated donors (n=8) and HLA-identical siblings (n=3). EBV viral loads of patients were monitored by quantitative PCR for EBV DNA performed on whole-blood samples once a week after allo-SCT. EBV reactivation was defined as a single positive EBV PCR result according to institutional thresholds (above 100 copies per millitre). Eligibility included EBV reactivation and negative hepatitis B surface antigen. Rituximabwas administered weekly at the fixed dose of 100mg after a positive PCR result (>100Cop/mL) and discontinued as soon as a negative PCR result was available. The numbers of circulating CD20+ B cellsand serum gammaglobulin levels were assessed weekly during the study.Results Weekly low-dose rituximab was well tolerated without anyserious adverse event. 52 patients receiving preemptive rituximab treatment showed an 100% cumulative complete remission (CR) rate of EBV reactivation, which resulted in cessation of treatmentas per protocol after the 1st (n=25, 48.1%), 2nd (n=24, 46.1%), or 3rd (n=3, 5.8%) dose. To date, none of the patients have developedan EBV-PTLD.There was no significant persistent B cell dysfunction following weekly low-dose rituximab treatment by assessment of the numbers of circulating CD20+ B cellsand serum gammaglobulin levels.Conclusions Our weekly low-dose rituximab-based approach is a high-efficient and safe preemptive therapy for EBV reactivation after allo-SCT. Furthermore, the use of low-dose rituximab for EBV reactivation may avoid its prolonged B cell impairment due to the over-treatment of 375mg/m2 rituxima. DisclosuresNo relevant conflicts of interest to declare.

Low Dose Rituximab and Plasma Exchange As Frontline Therapy for Patients with Thrombotic Thrombocytopenic Purpura

▪Thrombotic thombocytopenic purpura (TTP) is characterized by a reduction in the von Willebrand cleavage protein ADAMTS-13, caused mainly by autoimmunity. Plasmapheresis is the standard of care achieving complete remission (CR) in 77-83% of cases but figures are variable depending on clinical context and ADAMTS-13 activity. Relapse is frequent in patients with <10% ADAMTS-13, and has been reported in 34-41% of cases. In most of these patients, an inhibitor against ADAMS-13 is detected thus, an effective frontline immunosuppressive treatment is needed to prevent relapses. Originally rituximab was used as a 2nd line therapy in patients with relapsed and refractory TTP aiding to achieve CR and to reduce relapse rates. The assumption that B cell population may be smaller in patients with autoimmune diseases than in neoplasia supported low-dose rituximab use and therefore, we administered plasmapheresis and low-dose rituximab as frontline therapy in 11 patients with a first TTP episode.Newly diagnosed TTP Patients >15 years received plasmapheresis with 1-2 exchanges daily until CR and rituximab 100 mg/dose/week for 4 consecutive weeks, starting the 1st dose immediately after the 2nd or 3rd plasma exchange. Relapse was defined as readmission with thrombocytopenia (< 100 × 109/L), schistocytes in peripheral blood, and ADAMTS-13 <10% after discharge.Between March 2011-March 2015, eleven patients were included; three men (27%) and eight women (73%), median age was 34 years (15-46). The median follow-up is 22 months (range 4-49) and for patients evaluable for ADAMTS-13 activity (n=8) 18 months (range 4-34). Two patients had seizures and mucocutaneous bleeding, 7 numbness, confusion and petechiae and 2 severe headache. Only 2 patients had renal damage at diagnosis (creatinine>1.2). Five patients had additional comorbidities (two diabetes mellitus, two HIV positive and one hypothyroidism)Median laboratory parameters at diagnosis: platelets 11 X 10⁹/L (range 7-27.4 X 10⁹/L), LDH 1822 U/L (range 705-8220 U/L, normal 70-180 U/L), hemoglobin 6 g/dL (range 4.2-11.8 g/dL). ADAMTS-13 activity was determined in 8 patients at diagnosis and in all of them was <10% (normal 40-130%). ADAMTS-13 autoantibody titer was determined in 7 patients and in all of them was >18 units/ml (ref: negative <12, undetermined 12-15, positive > 15 units/ml), shigella toxin was negative in all patients. The median number of plasmapheresis exchanges until CR was 7 (range 4-12)andprednisone at 1 mg/kg was administered to 6 patients.The estimated two-year relapse-free survival was 90%. One HIV+ patient suffered a relapse at 8 months follow-up. A high antibody titer against ADAMTS-13 was detected at relapse with no ADAMTS-13 activity and the patient was retreated with plasmapheresis (3 exchanges) and low-dose rituximab as described and has been in CR for 4 months. There were no complications related to plasmapheresis or rituximab infusion.According to our results low-dose rituximab and plasma exchange are effective in achieving rapid and sustained response in TTP. Of note, the median of plasmapheresis needed to CR (7, range 4-12) was lower than that reported for patients with <10% ADAMTS-13 activity (19 procedures) (Kremer Hovinga JA et al Blood 2010). In our series, median follow-up for patients evaluable for severe ADAMTS-13 deficiency was 18 months, and only one HIV-positive patient relapsed at the 8th month. Our study suggest that frontline low-dose rituximab and plasmapheresis are effective as frontline treatment for TTP. This combination is associated with relatively rapid response and low relapse rate in previously untreated patients, however, a prospective clinical trial is needed to effectively demonstrate if rituximab 100 mg x 4 weekly dose is as effective as the conventional 375 mg/m2 X 4 weekly dose. DisclosuresOff Label Use: Rituximab an anti CD monoclonal antibody is used in our work to deplete B cell population therefore stop the production of autoatibodies against ADAMTS-13.

Remission Induction in a Phase I/II Study of an Anti-CD20-Interleukin-2 Immunocytokine DI-Leu16-IL2 in Patients with Relapsed B-Cell Lymphoma

DI-Leu16-IL2 immunocytokine is a recombinant fusion protein composed of interleukin 2 (IL2) and a CD20 targeting monoclonal antibody. Pre-clinical studies have shown it maintains the activities of both antibody and cytokine components but is also involved in tumor targeting, engagement of the immune system and induction of an anti-cancer vaccine effect. In a SCID mouse model,DI-Leu16-IL2 is more effective than the individual components (IL-2 and CD20) given either alone or in combination (Gillies SD; 2005). DI-Leu16-IL2 administered intravenously to 8 relapsed/refractory Non-Hodgkin's Lymphoma (NHL) patients at a maximum dose of dose of 0.5 mg/m2 resulted in 1 complete, 1 possible partial response and 4 patients with stable disease (Nakamura R; 2013).In this multicenter open label, dose escalation trial the safety, efficacy and tolerability of subcutaneously (SC) administered DI-Leu16-IL2 was evaluated as well as the maximum tolerated dose (MTD) and optimal biological dose in patients with relapsed or refractory B cell CD20 positive lymphoma (NCT01874288). DI-Leu16-IL2 was administered on three consecutive days every 21 days up to 6 cycles. Peripheral B cell depletion was achieved with low-dose rituximab (50mg/m2) on day 1 if needed to keep rituximab levels >10µg/mL. The starting dose was 0.5 mg/m2 and followed a modified accelerated titration until dose limited toxicity (DLT) occurred. To be evaluable for response patients had to receive at least 2 cycles of DI-Leu16-IL2 and were then evaluated by PET/CT imaging.To date, 13 patients in 3 cohorts have been enrolled. The median age is 63 years (range, 48-83 years). Ten patients had diffuse large B cell lymphoma, 2 follicular and 1 marginal zone NHL. All were previously treated with rituximab-containing chemotherapy - median of 3 (range 1-6) prior regimens, including radiation therapy (n=5) and autologous transplantation (n=3). All patients had relapsed or refractory disease with biopsy-confirmed tumor cells expressing CD20.DI-Leu16-IL2 dose levels were 0.5 mg/m2 (n=3), 1 mg/m2 (n=3), 2 mg/m2 (n=7). DI-Leu16-IL2 was detectable in the serum at the lowest dose level. Median number of cycles were 4 (range 1-11). No DLTs have been observed. The most common drug-related adverse events (AEs) were grade 1-2 transient skin reactions with erythema, painless induration of injection site, pruritus, edema and mild constitutional symptoms (grade 1-2 chills, low-grade fever, fatigue, low appetite) suggesting an immune stimulatory response. Lymphocyte margination occurred with nadir of 0.3x103 /mL for median 2.7 days (range 1-5). Two grade 3 non-DLT toxicities (diarrhea and QTc prolongation with pre-existing RBBB) resulted in DI-Leu16-IL2 dose reduction. Transiently prolonged QTc (grade 1-2) occurred in 3 additional patients. Routine laboratory monitoring revealed grade 1-2 transient eosinophilia, anemia and thrombocytopenia in most subjects, grade 1-2 neutropenia (n=3) without neutropenic fever, grade 1 elevation of alkaline phosphatase or bilirubin. All AEs resolved completely within one week.Twelve patients are evaluable for response. After 2 cycles, tumor regression or stabilization was noted in 10 of 12 patients with mean tumor reduction of 30% (range 0%-80%). Six had sustained disease control after 4 cycles. One patient with small tumor bulk marginal zone lymphoma achieved a complete response by PET criteria, 3 patients had a partial response (55%, 55% and 80% tumor size reduction) and continue on therapy. Stable disease (SD) response was observed in all dose cohorts; best responses occurred at the highest dose level (2mg/m2) administered thus far. Three patients have had SD for up to 1 year.In conclusion, we have observed promising clinical efficacy of the novel immunocytokine DI-Leu16-IL2 in relapsed/refractory B cell NHL. SC administration has permitted higher doses than could be achieved with IV treatment and the MTD has yet to be reached. DI-Leu16-IL2 is biologically active in doses up to 2mg/m2. Repetitive SC dosing elicits clinical immune activation associated with clinical activity. Further dose escalation of DI-Leu16-IL2 is in progress.Prior DI-Leu16-IL2 therapy After 2 cycles at dose 2mg/m2 [Display omitted] DisclosuresBachanova:Seattle Genetics Inc.: Consultancy, Research Funding.

Successful Treatment with Low-dose Rituximab in a Patient with Plasma Exchange-refractory Idiopathic Thrombotic Thrombocytopenic Purpura

í˜ˆìž¥êµí™˜ìˆ ë° ë¶€ì‹ í”¼ì§ˆìŠ¤í Œë¡œì´ë“œ ì œì œì— 반응하지 않는 성인의 특발성 TTP 환자에게 í†µìƒì ì¸ rituximab의 사용 용량인 회당 375 mg/m2 보다 ì ì€ 용량인 1회 150 mg/m2의 rituximab 주사 후 60 mg/m2/week의 3회 추가 사용만으로 ì„±ê³µì ì¸ 치료 결과를 얻었다(매주 1회씩 총 4회 주사시 ëˆ„ì ìš©ëŸ‰ 1,500 mg/m2 vs. 330 mg/m2). 이는 향후 해당 질환에서 rituximab 치료의 ì ì ˆí•œ 용량 및 용법에 대한 연구에 좋은 ì°¸ê³ ì‚¬í•­ì´ ë ìˆ˜ 있을 것이다. 중심 단어: í˜ˆì „ì„±í˜ˆì†ŒíŒê°ì†Œìžë°˜ì¦; í˜ˆì „í˜ˆê´€ë³‘ì¦; 글루코코르티코이드; í˜ˆìž¥êµí™˜ìˆ ; 리툭시맙

Modelling cost-effectiveness and value of information in clinical trials to inform stop go decisions: results from the arctic study

Methods The ARCTIC trial randomised patients with previously untreated Chronic Lymphocytic Leukaemia to receive fludarabine, cyclophosphamide, mitoxantrone and low dose rituximab (FCM-miniR) or fludarabine, cyclophosphamide and rituximab (FCR; standard care). An interim efficacy analysis was conducted after 103 patients had completed therapy. CEA and VOIA were conducted using a Markov decision model, based on subsequent data from 200 patients.

Clinical and immunological changes in patients with active moderate-to-severe Graves' orbitopathy treated with very low-dose rituximab.

Glucocorticoids represent the therapy of choice for active and moderate-to-severe Graves' orbitopathy (GO). In some patients, rituximab, a monoclonal antibody against the cluster of differentiation (CD) 20 receptor of B-lymphocytes, can serve as a second-line or an alternative treatment. The effect of very low-dose of rituximab on the clinical activity of GO and corresponding clinical or laboratory changes is reported. Changes of Clinical Activity Score (CAS) for GO, proptosis, levels of thyroid-stimulating hormone receptor antibodies, and depletion of CD19+ and CD20+ B-lymphocytes were determined in ten patients (two men and eight women) with active moderate-to-severe GO treated with a single 100-mg dose of rituximab. Correlations between differences of clinical and laboratory parameters were performed. A significant decrease of CAS was found during subsequent examinations compared to the baseline values. A significant depletion of CD19+ and CD20+ B-lymphocytes was detected after rituximab administration. Differences between follow-up and baseline levels of CD20+ positively correlated with differences in CAS after six (p < 0.05) and 12 months (p < 0.01). Differences in CD19+ levels correlated with differences in CAS after 12 months (p < 0.05) of the treatment. Two patients developed dysthyroid optic neuropathy (DON) requiring orbital decompression. No other rituximab side effects were reported during the whole study duration. A single very low-dose of rituximab appears to be very well tolerated and effective enough to reduce clinical activity in active moderate-to-severe GO patients without impending DON.

Long-term remission induced by low-dose rituximab for relapsed and refractory thrombotic thrombocytopenic purpura: A report of two cases.

Thrombotic thrombocytopenic purpura (TTP) is acquired in the majority of cases. Traditional therapy consists of plasma exchange (PEX), as well as the administration of certain immunosuppressive agents including steroids. A standard dose of rituximab (RTX) at 375 mg/m2 weekly for 4 consecutive weeks was recently demonstrated to have significant activity in patients with acquired TTP. To date, clinicians have limited experience using low-dose RTX. In the present study, 2 patients were treated with low-dose RTX at 100 mg weekly for 4 consecutive weeks as a salvage therapy following failure to respond to PEX and other immunosuppressive agents. Prior to RTX therapy, the patients had severely deficient ADAMTS13 activity and detectable anti-ADAMTS13 inhibitors. The patients achieved complete remission and presented long-term stabilization during follow-up. Repeated detection during follow-up demonstrated that the patients had 100% ADAMTS13 activity and undetectable anti-ADAMTS13 antibodies. Although further investigation in a prospective clinical trial is required, the use of low-dose RTX seems to be as effective as a standard dose for patients with relapsing or refractory acquired TTP.

A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4)

AbstractPromising reports of combination immunosuppression with high-dose dexamethasone and rituximab for the treatment of primary immune thrombocytopenia (ITP) have recently emerged. They suggest a potential to further optimize the efficacy of therapy. We investigate the use of a novel combination of conventional therapies in ITP given over 4 weeks. From 2011 to 2014, 20 patients were prospectively enrolled onto a single-arm phase 2b study to describe the safety, efficacy, and tolerability of oral dexamethasone 40 mg for days 1 to 4, oral cyclosporine 2.5 to 3 mg/kg daily for day 1 to 28, and intravenous low-dose rituximab 100 mg for days 7, 14, 21, and 28. There were no therapy-related serious adverse side effects, 6-month response rate was 60%, and treatment was well tolerated. Responders enjoyed relapse-free survivals of 92% and 76%, respectively, at 12 and 24 months. This study highlights the possibility of achieving an enduring remission from 4 weeks of therapy. This study is registered at www.anzctr.org.au (#ANZCTRN12611000015943).