Rituximab Combination Therapy Research Articles

The risk of hepatitis B virus reactivation and the role of antiviral prophylaxis in hepatitis B surface antigen negative/hepatitis B core antibody positive patients with diffuse large B-cell lymphoma receiving rituximab-based chemotherapy

The risk factors and the role of prophylactic antiviral therapy of hepatitis B virus (HBV) reactivation in patients with hepatitis B surface antigen (HBsAg) negative/hepatitis B core antibody (HBcAb) positive disease remain controversial. We reviewed 629 patients with diffuse large B-cell lymphoma (DLBCL). Among 629 patients, 150 of 246 patients with resolved HBV (HBsAg negative and HBcAb positive) were treated with rituximab-combined therapy. Among these 150 patients, none of 104 patients (0.0%) who were hepatitis B surface antibody (HBsAb) positive experienced HBV reactivation versus four of 46 patients (8.7%) who were HBsAb negative (p = 0.008). One of 113 patients (0.9%) with International Prognostic Index (IPI) 0–2 suffered HBV reactivation versus three of the remaining 37 patients (8.1%) with IPI 3–5 (p = 0.047). HBsAb and IPI are potential risk factors for HBV reactivation. The use of prophylactic agents may not be recommended for these patients until the occurrence of HBV reactivation.

Therapeutic Effect of Combination Therapy with Rituximab and Intravenous Immunoglobulin on the Progression of Chronic Antibody Mediated Rejection

Background While combination therapy of Rituximab (RTX) and intravenous immunoglobulin (IVIg) (RIT) has been proposed as therapeutic strategy for the treatment of chronic active antibody-mediated rejection (CAMR), its efficacy has not been established. In this study, we compared clinical outcome between the treatment group and historic control group to ascertain the efficacy of combination therapy for CAMR. Methods Fifty-four patients diagnosed as CAMR from 2003 to 2013 were included in this study, among whom twenty-five were treated with RTX (375 mg/m2) and IVIg (0.4 g/kg) for 4 days (RIT group) and the remaining twenty-nine patients were regarded as historic control group. We assessed the change of allograft function before and after the diagnosis of CAMR in terms of the amount of decline in estimated glomerular filtration rate per month (ΔeGFR) and also investigated allograft survival rate after diagnosis of CAMR. Results Neither of the two groups showed any significant differences with respect to clinical, historical and baseline characteristics including age at biopsy and gender. Nor did they show any remarkable differences on ΔeGFR and eGFR prior to and at the time of biopsy. However, ΔeGFR improved significantly to 0.02±1.3 mL min-1 1.73m-2 per month 6 months after biopsy compared to that observed 6 months before RIT (1.33±1.21, p Conclusion In CAMR, RIT could be proposed as a promising regimen in terms of delaying the progression of CAMR and better allograft survival rate compared to HC group.

An evaluation of the potential for drug-drug interactions between bendamustine and rituximab in indolent non-Hodgkin lymphoma and mantle cell lymphoma.

PurposeBendamustine plus rituximab has been reported to be effective in treating lymphoid malignancies. This analysis investigated the potential for drug–drug interactions between the drugs in patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma.MethodsData were derived from a bendamustine–rituximab combination therapy study, a bendamustine monotherapy study, and published literature on rituximab monotherapy and combination therapy. Analysis of the potential for rituximab to affect bendamustine systemic exposure included comparing bendamustine concentration–time profile following monotherapy to that following combination therapy and comparing model-predicted Bayesian bendamustine clearance in the presence and absence of rituximab. Analysis of the potential for bendamustine to affect rituximab systemic exposure included plotting observed minimum, median, and maximum serum rituximab concentrations at the end of rituximab infusion (EOI) and 24 h and 7 days post-infusion in patients receiving combination therapy versus concentrations reported in literature following rituximab monotherapy.ResultsThe established population pharmacokinetic model following bendamustine monotherapy was evaluated to determine its applicability to combination therapy for the purpose of confirming lack of pharmacokinetic interaction. The model adequately described the bendamustine concentration–time profile following monotherapy and combination therapy in adults. There was no statistically significant difference in estimated bendamustine clearance either alone or in combination. Also, rituximab concentrations from EOI to 24 h and 7 days demonstrated a pattern of decline similar to that seen in rituximab studies without bendamustine, suggesting that bendamustine does not affect the rituximab clearance rate.ConclusionsNeither bendamustine nor rituximab appears to affect systemic exposure of the other drug when coadministered.

Chemoimmunotherapy resistant follicular lymphoma: predictors of resistance, association with transformation and prognosis

Follicular lymphoma (FL) is characterized by an initial response to treatment with inevitable relapse. We evaluated chemoimmunotherapy resistance (CIR resistance) including transformation. We identified patients who received rituximab combination therapy for symptomatic FL. CIR resistance was defined as disease progression during rituximab-based chemoimmunotherapy, rituximab maintenance or within 6 months of treatment completion. Our primary outcome was time to early progression (CIR resistance). Between July 2006 and April 2010, 132 patients met the inclusion criteria and 22 (16.7%) demonstrated CIR resistance with a median follow-up of 33 months. High-risk Follicular Lymphoma International Prognostic Index (FLIPI) score was predictive of CIR resistance (hazard ratio [HR] 2.43; 95% confidence interval [CI], 1.4–4.1; p = 0.001). Overall, eight patients (36.3%) transformed (biopsy-proven), with no transformation in the chemoimmunotherapy responder group. Median overall survival in the CIR resistant group was 47 months. Patients with CIR resistance had high rates of histologic transformation and shorter survival with poor response to next therapy.

Current Issues in the Treatment of Chronic Antibody-Mediated Rejection in Kidney Transplantation

Circulating alloantibodies are found in a substantial number of renal allograft recipients, and can induce chronic allograft injury, which is represented microscopically as transplant glomerulopathy and diffuse C4d deposition in peritubular capillaries (PTCs). Development of these injuries is significantly correlated with late allograft loss, and in this regard, it was included as a new disease entity named chronic antibody-mediated rejection (cAMR) in the updated Banff 05 classification. Usually, the prognosis of cAMR is poor and conventional immunosuppressants mainly targeting T cell-mediated immunity cannot prevent or reverse it. Therefore, some researchers have suggested that therapies directed at the humoral response may be required for the treatment of cAMR. Recently, some reports have suggested that the combined use of rituximab and intravenous immunoglobulin (IVIg) therapy may be useful for the treatment of cAMR. Our previous study also showed that rituximab and IVIg combination therapy effectively delayed the progression of cAMR. We administered rituximab and IVIg combination therapy to 18 biopsy-proven cAMR patients and found that it significantly slowed the decline of the estimated glomerular filtration rate. However, this effect was limited in patients with heavy proteinuria, and dissipated in all patients by 1 year post-treatment. Recently, new drugs targeting the humoral immune system, such as bortezomib and eculizumab, have been tested for the treatment of cAMR. However, the studies still lack definitive data in terms of successful treatment of cAMR. We speculate that those therapies will compensate for the limitation of previous anti-humoral therapies for cAMR.

Efficacy Of Bendamustine and Rituximab In Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia

The objective of the study was to assess the efficacy and safety of the Bendamustine (B) and Rituximab (R) combination therapy in pre-treated patients with relapsed/refractory chronic lymphocytic leukaemia (CLL). Patients and Methods13 patients with CLL were examined, out of which 9 were men and 4 women. The average age of the enrolled patients was 62 years (52-77). 5 CLL patients had RAI stage II, 1-III and 7 patients had stage IV. FISH test detected del (17p) in 4 patients (30.8%), del (11q) in 3 patients (13.1%) the immunophenotype test of peripheral blood lymphocytes identified 5 patients (38.5%) with CD38+positive (cut off over 20%).The patients received prior therapy with COP, CHOP, RFC, FC, RCHOP, FluCam, Alemtuzumab and R courses. The treatment lasted for 23.7 months (12-36). 10.4 (7-20) treatment courses were made on average. Median of Chemotherapy lines in each patient was 4 (2-5). All the patients were resistant to the previous treatment and relapsed. The patients received R through intravenous infusions at a dose of 500 mg/m2 on day 1 of the therapy course and B through intravenous infusions at a dose of 100 mg/m2 on days 2 and 3 of the therapy course, and the course was repeated every 28 days. 4.6 (3-9) therapy courses were administered. ResultsAll the patients (100%) responded to the administered therapy by achieving partial remission. Progression-free survival within 6 months is 67%. Median of the examination was 12.3 months (4-33) and 9 patients (69%) are alive. 3 patients (21%) had hematologic toxicity of levels 3 and 4. At the same time 2 patients (14%) had neutropenia, and 1 patient (7%) had thrombocytopenia respectively. 3 patients (23%) had non-haematological toxicity of level III in the form of infections (pneumonia) and 3 patients (27%) had gastroenterological toxicity. Conclusionthus, the BR combination has a high anticancer activity in heavily pre-treated patients with relapsed/refractory CLL. It should be noted that the examined patients had pejorative prognostic characters such as del (17p) and del 11(q), and high CD 38+ expression (82.4%). At the same time the toxicity profile was low.Good anticancer effect and moderate toxicity indicate strict selectivity of the BR program. Disclosures:No relevant conflicts of interest to declare.

THE IMPACT OF ANTI B-CELL THERAPY ON ARTERIAL STIFFNESS IN SYSTEMIC SCLERODERMA

Background.Arterial wall stiffness is an independent predictor of cardiovascular mortality in different patient populations. Currently, there are several studies that show an increase of arterial wall stiffness in systemic sclerosis (SSc). The effect of immunosuppressive therapy on vascular wall stiffness in SSc patients is not investigated. The authors of this paper attempted to study the effect of rituximab and cyclophosphamide combination therapy on vascular stiffness in 5 patients with diffuse form of SSc.Design and methods.We assessed arterial stiffness in 5 patients with diffuse form of SSc before and after 6 months after combined immunosuppressive therapy.Conclusion.The parameters of arterial stiffness decreased in all patients with the moderate effect of the therapy.

AB0368 Systematic review of efficacy and safety of biological therapies in lupus nephritis

ObjectivesThe aim of this study is to analyze the efficacy and safety of 10 biological therapies (BT) for lupus nephritis. These therapies are infliximab (IFX), etanercerpt (ETN), adalimumab (ADA), golimumab...

Abstract LB-140: Combined epigenetic and immunotherapy produces dramatic responses in 100% of newly diagnosed mantle cell lymphoma patients.

Abstract Background: Mantle cell lymphoma (MCL) is an incurable disease in which there is no accepted standard of care. While dose intensive approaches are effective, we and others have shown that cladribine and rituximab (RTX) combination therapy is well tolerated and can induce durable remissions. The synergistic effect observed with the combination of cladribine, a purine analogue with known but cryptic epigenetic activity as a hypomethylating agent, and a monoclonal antibody, RTX, prompted us to add a histone deacetylase inhibitor, vorinostat (SAHA), to this combination. We describe a phase II study that uses SAHA and a unique hypomethlating agent, cladribine, that potentially can inhibit both DNA and histone methylation through SAM. In combination with RTX, dramatic durable responses are observed in newly diagnosed MCL (ORR 100%, CR rate 70%) as well as in relapsed MCL and other B cell malignancies. Objectives: The primary objective is overall response rate (ORR). Secondary objectives include progression free survival (PFS) and overall survival (OS) as well as correlative epigenetic, transcriptional and pharmacogenomic studies. Methods: Dosing is as follows: starting dose was vorinostat 400 mg po (days 1-14) combined with cladribine 5mg/m2 IV (days 1-5), and RTX 375 mg/m2 IV (weekly x 4 for cycle 1 and 1x/month) every 28 days for up to 6 cycles. Responses were evaluated after 2 and 6 cycles. The majority of complete responders have received maintenance RTX. Phase II eligibility includes relapsed NHL and previously untreated MCL. Scientific correlatives included epigenetic and gene expression assays. Results: 32 previously untreated MCL patients have been enrolled on the phase II portion of the study. 2 have not yet completed the planned 6 cycles; however, 30 patients have completed ≥ 2 cycles and are evaluable for response. The ORR is 100% (30/30) with 70% (21/30) achieving CR. Of those patients not attaining CR, 3 had blastic MCL and 2 have died, 2 have not yet completed treatment, and 1 withdrew consent after two cycles. At a median follow up of 14.7 months (.07 - 25 months) 4 patients have relapsed and 3 have died. Of the relapsing patients, two had blastic MCL. No patient achieving a CR has relapsed. The estimated PFS curve did not reach the 0.5 level. Toxicities using CTCAE 4 included neutropenia, thrombocytopenia, fatigue, anorexia, and dehydration. We found that cladribine hypomethylates DNA in vivo (6/6 pts) and inhibits histone methylation in MCL cell lines. Upregulated genes after treatment included DUSP2 (3 pts), FOXO3 (2 pts), NOXA1 (2 pts), CEBPβ (2 pts) and p53 (3 pts). Dramatic responses and CRs were also seen in fewer patients with low grade NHLs, but not in DLBCL. Conclusion: Combined epigenetic and immunotherapy (SCR) is nontoxic and effective in the treatment of newly diagnosed mantle cell lymphoma. This therapeutic approach potentially has broader applications in other malignancies. Citation Format: Zainul Hasanali, Kamal Sharma, Stephen Spurgeon, Craig Okada, August Stuart, Sara Shimko, Violetta Leshchenko, Samir Parekh, Yiyi Chen, Mark Kirschbaum, Elliot M. Epner. Combined epigenetic and immunotherapy produces dramatic responses in 100% of newly diagnosed mantle cell lymphoma patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-140. doi:10.1158/1538-7445.AM2013-LB-140

Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study

Bendamustine is a unique cytotoxic agent active against various human malignancies, including chronic lymphocytic leukemia (CLL). In vitro studies suggest that cytotoxic activity of bendamustine on CLL-derived cells is synergized by rituximab. A retrospective chart review was conducted to characterize treatment-naïve outpatients and those with relapsed disease aged 70 years and over with CLL receiving bendamustine (with or without rituximab) and to evaluate real-world patterns of care, safety, and effectiveness. Using McKesson Specialty Care/US Oncology Network iKnowMed databases, 91 outpatients with at least two recorded visits and at least two cycles of bendamustine monotherapy or bendamustine-rituximab combination therapy were identified and included. Mean age at diagnosis and start of first therapy was 70.3 and 77.4 years respectively, and 63.7% of patients were men. Observed overall response rate was 56.3% in pooled treatment-naïve patients [n = 9; complete response (CR) 18.8%; partial response (PR) 37.5%; nodular partial response (nPR) 0%] and 58.7% in pooled patients with relapsed disease (n = 44; CR 13.3%; PR 44.0%; nPR 1.3%). Median time to progressive disease has not been reached for the 16 treatment-naïve patients (median follow up 15.1 months), and was 18.4 months for those with relapsed disease (n = 73). No unexpected toxicities were observed. Overall rate of blood/bone marrow toxicities (all grades) was 40.7%; grade 3/4 rates were 18.8% in treatment-naïve patients and 25.3% in those with relapsed disease. Most frequent nonhematologic adverse events were fatigue and rash. In this retrospective chart review of 91 outpatients with CLL aged 70 years and over, bendamustine (with or without rituximab) was an effective therapeutic option with manageable toxicity.

Combination therapy of rituximab and corticosteroids for patients with refractory chronic immune thrombocytopenic purpura: Report on two cases

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder, for which rituximab has been proven to be an effective treatment. The response rate was reported to be approximately 60% in refractory ITP patients. However, the response time is slower than expected, and the mechanism of action of rituximab in ITP is still unclear. Thus, sometimes, the use of a combination therapy with rituximab according to different patient conditions is necessary. We report two refractory chronic ITP cases. The two patients were administered a low dose of dexamethasone (10 mg, weekly) combined with rituximab and a smaller dose of prednisone (10 mg, daily) as maintenance therapy. Although their peripheral B cells were almost eliminated, no complete reaction was observed. The maintenance therapy with prednisone was helpful in the prevention of bleeding. The patients’ responses to rituximab treatment suggest that multiple immunological mechanisms are involved in ITP pathogenesis and that the use of a combination therapy with rituximab according to the different patient conditions is necessary.

Chronic hepatitis B virus screening prior to rituximab: A quality improvement project.

199 Background: Patients’ with chronic hepatitis B (HBV) are at risk for HBV reactivation and liver failure with initiation of rituximab therapy. HBV testing prior to rituximab for patients with non-Hodgkin lymphoma was a quality measure for the American Society of Clinical Oncology’s Quality Oncology Practice Initiative in Spring 2011. Methods: We assessed the pre-intervention HBV screening rate retrospectively from July 2009 to July 2011. Patient demographics, pathology, regimen, and prescriber were abstracted from the electronic medical record. Screening was complete if serum HBVsurface antigen was checked within 3 months prior to rituximab. A quality improvement (QI) intervention was initiated and all prescribers were informed of the screening rate in December 2011. Post-intervention, patients who received rituximab from January 2012 to July 2012 were identified and the same data was abstracted. HBV screening rates across categories pre and post-intervention were analyzed with Fisher’s exact test and multivariate logistic regression analysis. Results: A total of 146 patients (127 pre-intervention, 19 post-intervention) were included. There were more male and rituximab combination therapy in the post-intervention group. The HBV screening rate increased from 59% to 90% (p<0.01) after our QI project. In univariate analysis, factors associated with HBV screening were (1) prior treatment with rituximab (no: 72% vs. yes: 46%, p<0.01), (2) treatment regimen (rituximab alone: 68% vs. combination: 42%, <0.01) and (3) prescriber (full time: 69% vs. part time: 7%, <0.01) In multivariate logistic regression analysis, the odds of HBV screening increased 4.8 times in the post-intervention group compared to pre-intervention group although this was statistically not significant (p=0.07). Prior rituximab (Odds Ratio (OR) 0.4, 95%CI 0.2-0.9), combination regimen (OR 3.2, 95% CI 1.5-7.2), and full-time prescriber (OR 25.1, 95% CI 2.8-255.4) were statistically significant for HBV screening. Conclusions: The HBV screening rate improved after QI intervention although statistically insignificant in multivariate analysis. We identified characteristics associated with low screening rates which will guide future QI strategy.

Immunoglobulin G4–related sclerosing disease of the paranasal sinus

Immunoglobulin G4 (IgG4)-related sclerosing disease is a systemic disease characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. We present a case of a 69-year-old man with maxillary sinus IgG4 sclerosing disease, with orbital invasion treated with rituximab and dexamethasone pulse therapy. Surgery was used as well to debulk the disease and to obtain tissue for diagnosis. A PubMed search using the key phrase "IgG4-related Sclerosing Disease" was performed. There were 304 different articles regarding the disease for a multitude of different organ sites. Of the 304 articles, there were 3 articles that reported this disease in the paranasal sinuses. IgG4-related sclerosing disease is a rare entity in the head and neck. There are documented reports of steroid therapy for this disease, but the patient presented here demonstrated clinical progression of disease with steroids alone. The use of combination therapy of surgery, dexamethasone, and rituximab provided clinical improvement and stable disease determined by radiographic means.

Rituximab, used alone or in combination, is superior to other treatment modalities in splenic marginal zone lymphoma

Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy, with no standard treatment other than splenectomy. Rituximab has shown encouraging results. We therefore retrospectively assessed 43 patients from two centres, who received rituximab, either alone or with chemotherapy. All patients responded, 34/43 (79%) achieving a complete response (CR), compared with 3/10 (30%) after chemotherapy without rituximab (P=0·005). Of these 10 patients, 9 (90%) subsequently achieved a CR after rituximab (P=0·02). Rituximab monotherapy appeared equally as effective as rituximab combination therapy (90% vs. 79% CR, P=0·7) with significantly less toxicity (12·5% vs. 83%, P=0·002). Splenectomized patients were more likely to obtain a CR with rituximab (16/16, 100%) than unsplenectomized patients (18/27, 67%, P=0·008). Disease-free survival (DFS) at 3years was better after rituximab than after splenectomy alone [79% (95% confidence interval 60-89) vs. 29% (8-54), Hazard ratio (HR) 0·28 (0·12-0·68), P=0·003] and better than after chemotherapy without rituximab [25% (4-55), HR 0·21 (0·08-0·51), P=0·0004]. Survival at 3years after rituximab was 98%. In summary, the CR and DFS rates after rituximab, given alone or with chemotherapy, were significantly better than after chemotherapy without rituximab in the same patients, with manageable toxicity. Rituximab, with or without splenectomy, should be considered for the treatment of SMZL.

Rituximab and thalidomide combination therapy for Castleman disease

Rituximab and thalidomide combination therapy for Castleman disease

Lymphomatoid granulomatosis with spinal involvement after childhood acute lymphoblastic leukemia.

Lymphomatoid granulomatosis (LYG) is a lymphoproliferative disease involving the lungs most frequently; however, it may also involve the kidneys, skin and especially the central nervous system. Unique initial presentation of spinal involvement is extremely rare and epidural lesion of thoracic spine has not been reported. The prognosis for LYG has been reported to be poor, and there currently exists no satisfactory established treatment protocol. The purpose of this study is to report a case of successful treatment with surgery and rituximab combination therapy in thoracic spinal LYG.

Rituximab and Mycophenolate Combination Therapy in Refractory Dermatomyositis With Multiple Autoimmune Disorders

We report a case of dermatomyositis associated with rheumatoid arthritis, Hashimoto thyroiditis, and diabetes mellitus responsive only to combination of rituximab with mycophenolate. A 42-year-old woman presented with proximal muscle weakness, myalgias, fever, night sweats, and shortness of breath. Creatinine kinase was 8155 IU/L, and muscle biopsy was diagnostic of dermatomyositis. She was started on glucocorticoids; her systemic symptoms improved, but her muscle weakness persisted. She was serially treated with intravenous immunoglobulin, azathioprine, and mycophenolate mofetil without improvement in her weakness. She responded dramatically to combination therapy with rituximab and mycophenolate, with improvement in strength and normalization of creatinine kinase. She has been well controlled on rituximab infusion every 6 months and maintenance mycophenolate mofetil.

Effectiveness of subcutaneous low-dose alemtuzumab and rituximab combination therapy for steroid-resistant chronic graft-versus-host disease

Chronic graft-versus-host disease is a common late complication of allogeneic hematopoietic stem cell transplantation. Corticosteroids are the standard initial treatment. Second-line treatment has not been well defined. We evaluated the effectiveness and safety of low doses of alemtuzumab plus low doses of rituximab in the treatment of steroid-refractory chronic graft-versus-host disease. Ten men and 5 women were prospectively included in the study. All patients received one cycle of subcutaneous alemtuzumab 10 mg/day/3 days and intravenous rituximab 100 mg on Days +4, +11, +18 and +25. The therapeutic response was measured on Days +30, +90 and +365 of the protocol. Median age was 41 years. The main site involved was the oral mucosa (86.7%) followed by the eyes (66.7%), liver (60%), skin (53%), lungs (13.3%) and intestinal tract (6.7%). The overall response was 100% at Day +30 evaluation: 10 patients (67%) had partial remission, 5 (33%) had complete remission. At Day +90 evaluation, 7 (50%) patients had partial remission, 4 (28%) had complete remission; 3 (21%) had relapsed chronic graft-versus-host disease and one patient did not reach the evaluation time point. So far, 5 patients have reached the Day +365 follow-up evaluation; 2 (40%) had partial remission, 2 had complete remission and one experienced chronic graft-versus-host disease progression. Adverse effects were mainly infections in 67% of patients; these were all quickly solved, except for one patient who died from pneumonia. This combination therapy appears to be an efficacious and safe treatment for steroid-refractory chronic graft-versus-host disease. Longer follow up to determine the durability of response and survival is required (ClinicalTrials.gov: NCT01042509).

Rituximab, Either As Single Agent or in Combination, Is Superior to Other Treatments in Terms of Response Rate and Progression-Free Survival (PFS) in Patients with Splenic Marginal Zone Lymphoma (SMZL)

Abstract 4986 Background.Splenic marginal zone lymphoma (SMZL) is an uncommon indolent B-cell non-Hodgkin's lymphoma usually presenting with marked splenomegaly and bone marrow (BM) and/or peripheral blood (PB) involvement. Although splenectomy has traditionally been the treatment of choice in symptomatic patients, systemic treatment is required in cases of widespread disease, high risk from surgery, or relapse after splenectomy. There is no standard first line treatment in SMZL, but the anti-CD20 monoclonal antibody Rituximab has shown encouraging results in SMZL, with sustained responses. Aims.To assess, retrospectively, response to treatment, toxicity profile, progression-free survival (PFS) and overall survival (OS) after treatment with rituximab in SMZL. Methods.Twenty-nine patients from two different centers, diagnosed with SMZL between 1982 and 2011, received one or more treatments with rituximab. Eighteen patients (62%) received rituximab alone and 20 (69%) combined with chemotherapy; thus 9 patients received each of these treatments sequentially, to improve response, with or without interim relapse. The median age at diagnosis was 62 years (range 37–89 years); the male:female ratio was 2:3; B symptoms were present in 12 patients; ECOG performance status was 0–2 in 28/29 patients. All presented with splenomegaly, with involvement of the BM in 27 patients, PB in 24, lymph nodes in 11 and extranodal involvement in 7 patients. Diagnosis was made according to the WHO 2008 classification by spleen histology (n=12), BM histology (n=19), PB morphology (n=12) and immunophenotype (n=13). Rituximab monotherapy was administered at 375 mg/m2/weekly x4 weeks. In combination with fludarabine-based regimens (n=14), or other regimens including CHOP (n= 6), rituximab was administered on day 1 of each cycle. Responses were assessed according to the Response Criteria Guidelines for SMZL (Matutes, Leukemia 2008). Toxicity was graded according to the CTCAE v3.0. The Fisher exact test was used to compare best responses between groups. Survival was estimated using the Kaplan-Meier method. Results.All patients responded to rituximab monotherapy and/or to a combination treatment. At least one complete response (CR) was achieved in 20/29 patients (69%). This compares with a CR in only 4/17 (24%) of these same patients after any prior therapy (p=0.005): 11 patients had received splenectomy, with or without chemotherapy and 6 had received chemotherapy only. There was no difference in the CR rate between rituximab monotherapy (71%) versus rituximab combinations (68%). The most common adverse event was grade 3–4 neutropenia (n=7, 24%). Two patients had grade 3–4 infections. Anemia (n=3) and thrombocytopenia (n=2) were grade 1–2 only. Four cases presented with histological transformation prior to rituximab, all achieving CR with rituximab combination therapy. After a median follow-up of 24 months from rituximab treatment (range 4–102 months), progression-free survival (PFS) has been evaluated in 28/29 patients (1 patient not assessed yet at the time of presenting these data). PFS was longer after rituximab (n=32 evaluable treatments), either alone or in combination, than it had been in these same patients after prior therapy (n=17 prior treatments in total) (p=0.002) (Fig 1). When we compared PFS between rituximab monotherapy (n=17) and rituximab combined with chemotherapy (n=15 combined treatments), single agent rituximab was superior to rituximab in combination (p=0.02) (Fig 2). The median overall survival was not yet reached. Survival at 2 years after rituximab was 100%. Only one death, due to lung cancer, occurred at 48 months follow-up. Conclusions.In patients with SMZL, the CR rate after rituximab, either alone or in combination with chemotherapy, was significantly better than the CR rate after other prior treatments in the same patients, with manageable toxicity. Although we observed no difference in the CR rate between rituximab monotherapy or combination therapy, PFS was longer in patients receiving rituximab as single agent. Therefore, the addition of chemotherapy did not appear to add any advantage over rituximab alone in our cohort. Rituximab, with or without splenectomy, should be considered in the therapeutic scenario of SMZL. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Combination therapy with rituximab and cyclophosphamide in the treatment of anti-neutrophil cytoplasmic antibodies (ANCA) positive pulmonary hemorrhage: case report

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with pulmonary hemorrhage is rare in childhood. Standard treatment includes corticosteroids and cyclophosphamide (CYC), which is associated with a high level of toxicity. We report a white female with ANCA positive pulmonary hemorrhage who was treated with cyclophosphamide (CYC) and rituximab (RTX) combination therapy.