Rituximab-containing Therapy Research Articles

Subcutaneous Injections of IMMU-114 (Anti-HLA-DR IgG4 Monoclonal Antibody): Initial Results of a Phase I First-in-Man Study in Hematologic Malignancies

Introduction. HLA-DR is expressed in non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and other B-cell malignancies at significantly higher levels than typical B-cell markers, including CD20. Prior attempts to develop anti-HLA-DR antibodies in this population have been hampered by toxicity, notably infusion-related toxicities (Lin et al, Leuk Lymphoma, 2009). In preclinical studies, a novel anti-HLA-DR IgG4 antibody, L243, was consistently more cytotoxic than rituximab in the cell lines studied, with minimal CDC and ADCC, but activating internal signaling and inducing apoptosis via the AKT survival pathway (Stein et al, Blood, 2006 & 2010). After demonstrating safety in canine lymphoma (Stein et al, Leuk Lymphoma, 2011), this Phase I first-in-man study was undertaken to evaluate IMMU-114 (humanized L243) administered via subcutaneous (SQ) injection in patients with B-cell NHL or CLL.Methods. Eligible patients had recurrent/relapsed NHL/CLL with at least one prior therapy, ECOG performance status <3, normal baseline renal and liver function, with platelets ≥ 50,000/mm3 and ANC ≥ 1000/mm3. Cohorts of 3-6 patients received 200 mg IMMU-114 administered once-, twice-, or thrice-weekly for the first 3 weeks of a 4-week cycle. All patients received 2 consecutive treatment cycles, followed 4 weeks later by elective maintenance therapy (one week of treatment every 4 weeks x 4). NCI-CTCAE v. 4.0 was used to grade adverse events (AEs). Treatment response was assessed 4 weeks after cycle 2, then every 3 months until progression, using 2007 IWG-NHL or 2008 IW-CLL criteria.Results. Eleven patients (46-80 years old) with 2 median prior treatments (range, 1-5; all had received rituximab) have now been treated at dose level (DL) 1 (200 mg weekly, n=3), 2 (400 mg weekly, n=5), and 3 (600 mg weekly, n=3). They had diffuse large B-cell lymphoma (DLBCL, n=5); follicular lymphoma (FL, n=3); CLL (n=1), small lymphocytic lymphoma (SLL, n=1), or marginal zone lymphoma (MZL, n=1). Administration reactions were limited and all were Grade 1-2 events, predominantly injection site erythema. No serious adverse events (SAEs) occurred at DL1 or DL2, but at DL3, one DLBCL patient with unrelated anorexia/hypovolemia withdrew prior to cycle 2 with acute renal failure and fatal gastrointestinal bleeding and one MZL patient developed fatal septic shock after completing cycle 2. Safety laboratories were unremarkable and there has been no evidence of human anti-IMMU-114 antibodies in 5 patients currently evaluated. Circulating leukemic cells in the single CLL patient decreased with each cycle, but normal B-cell changes in the NHL patients were modest. At DL1, 2 DLBCL patients progressed after cycle 2, but one FL patient had stable disease (47% tumor shrinkage, progressing 3 months later after completing maintenance treatment). At DL 2, one DLBCL patient with unrelated pneumonia withdrew after one dose, one DLBCL patient had a partial response (PR, 60% shrinkage, next scan pending), one FL patient progressed after cycle 2, one FL patient achieved a PR (83% shrinkage, continuing now 10 months later), and one CLL patient had an unconfirmed PR during cycle 1 (WBC 84% decreased, progressing after 2 months). At DL3, one patient with SLL progressed after cycle 2 and the other 2 patients with SAEs were not assessed for treatment response. In total, 4/8 (50%) assessable patients (CLL, DLBCL, FL X 2) demonstrated objective evidence of treatment activity.Conclusion. SQ injections of IMMU-114 appears to avoid the significant administration reactions that has limited the development of other anti-HLA-DR antibodies given IV. With lack of toxicity and preliminary efficacy observed at the two lowest dose levels, DL 2 was declared an acceptable choice for subsequent expansion cohorts. While IMMU-114 demonstrated activity in this population relapsed/refractory to rituximab-containing therapies, the presence of short responses in some patients suggests treatment should be maintained beyond 2 cycles. Thus, the dosing scheme is being amended to allow treatment cycles to be repeated until disease progression, with a goal of determining an appropriate dosing schedule for undertaking a phase II study. DisclosuresStephens:Acerta Pharma BV: Research Funding; Immunomedics: Research Funding. Off Label Use: IMMU-114 for treatment of hematologic malignancies. Starodub:Immunomedics: Research Funding. Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Stock Options, Patents & Royalties. Christian:Celgene: Consultancy; Seattle Genetics: Consultancy, Research Funding; Acerta: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding; Novartis: Other: IDSM.

Late-Onset Neutropenia After Rituximab-Containing Therapy for Non-Hodgkin Lymphoma.

Late-onset neutropenia (LON) is a known adverse effect to rituximab therapy. Information about its real incidence and clinical implications comes from case reports and few retrospective studies specifically designed to study LON. However, large prospective studies of LON are lacking in the literature. We aimed to determine the incidence of LON in a group of non-Hodgkin lymphoma patients treated with rituximab and to analyze the clinical course, complications, and risk factors associated with LON. We retrospectively reviewed 183 patients with a diagnosis of non-Hodgkin lymphoma consecutively treated with rituximab alone or in combination with chemotherapy. We identified 11 patients with grade 3/4 LON (13 episodes) out of 183 patients (6%). The median time to onset of LON was 75 days, and the median time to recovery from neutropenia was 100 days. The median neutrophil count nadir was 0.55× 10(9)/L (range, 0.06-0.9× 10(9)/L). Two patients presented infectious complications, one with fatal outcome. In our experience, the incidence of recognized LON is low (6%), although its real incidence may be greater because of the asymptomatic course and quick recovery in most cases. Infectious complications are unusual, but life-threatening complications can emerge. A careful evaluation of all cases of LON is warranted.

Risk of Reverse Seroconversion of Hepatitis B Virus Surface Antigen in Rituximab-Treated Non-Hodgkin Lymphoma Patients

Rituximab causes hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-seronegative patients with CD20-positive B-cell non-Hodgkin lymphoma (CD20+ NHL), especially for those seropositive to the antibody of core antigen (anti-HBc). Clinical hepatitis usually develops after reverse seroconversion of HBsAg (HBV-RS), indicated by the reappearance of HBsAg in serum. Because of the relatively high prevalence of anti-HBc seropositivity in unvaccinated HBsAg-seronegative adults in an HBV hyperendemic area, we aimed to investigate additional factors influencing the development of rituximab-associated HBV-RS.Between January 2000 and December 2010, unvaccinated HBsAg-seronegative adults with CD20+ NHL who had received rituximab-containing therapy but not anti-HBV agents were enrolled. Patients with and without HBV-RS were compared in terms of clinical factors and treatments including the number of cycles of rituximab therapy, and transplantation. Competing risk regression was used to identify the factors associated with HBV-RS.For the 482 patients enrolled, the serological status of anti-HBc was available in 75.9%, with a seropositivity rate of 86.6%. At the last follow-up, a total of 33 (6.85%) patients had HBV-RS, with 95.8% anti-HBc seropositive, 78.9% anti-HBs seropositive, and none anti-HCV seropositive. HBV-RS patients have received more cycles (≥6) and prolonged durations of rituximab therapy, and hematopoietic stem cell transplantation. The overall survival was not different between patients with and those without HBV-RS. At the time of HBV-RS, a total of 25 (78.1%) patients had hepatitis flare, especially when HBV-RS appeared during/after induction therapy (100%, 10 of 10). Three (9.1%) patients had fulminant hepatitis, resulting in death in 1 (3%) patient. A higher rituximab cycle intensity was associated with a higher rate of hepatitis flare at the time of HBV-RS. When death in the absence of HBV-RS was considered as the competing risk, the univariate and multivariate regression analyses showed that several factors were independently associated with the development of HBV-RS, including anti-HCV seronegativity, histological subtype of posttransplant lymphoproliferative disorders, ≥6 cycles of rituximab therapy, and succeeding hematopoietic stem cell transplantation.The findings of our study identify additional factors influencing the development of rituximab-associated HBV-RS in HBsAg-seronegative adults with CD20+ NHL.

Hepatitis B virus reactivation and hepatitis in diffuse large B-cell lymphoma patients with resolved hepatitis B receiving rituximab-containing chemotherapy: risk factors and survival

IntroductionHepatitis B virus (HBV) reactivation has been reported in B-cell lymphoma patients with resolved hepatitis B (hepatitis B surface antigen [HBsAg]-negative and hepatitis B core antibody [HBcAb]-positive). This study aimed to assess HBV reactivation and hepatitis occurrence in diffuse large B-cell lymphoma (DLBCL) patients with resolved hepatitis B receiving rituximab-containing chemotherapy compared with HBsAg-negative/HBcAb-negative patients to identify risk factors for HBV reactivation and hepatitis occurrence and to analyze whether HBV reactivation and hepatitis affect the survival of DLBCL patients with resolved hepatitis B.MethodsWe reviewed the clinical data of 278 patients with DLBCL treated with rituximab-containing therapy between January 2004 and May 2008 at Sun Yat-sen University Cancer Center, China. Predictive factors for HBV reactivation, hepatitis development, and survival were examined by univariate analysis using the chi-square or Fisher’s exact test and by multivariate analysis using the Cox regression model.ResultsAmong the 278 patients, 165 were HBsAg-negative. Among these 165 patients, 6 (10.9%) of 55 HBcAb-positive (resolved HBV infection) patients experienced HBV reactivation compared with none (0%) of 110 HBcAb-negative patients (P = 0.001). Patients with resolved hepatitis B had a higher hepatitis occurrence rate than HBsAg-negative/HBcAb-negative patients (21.8% vs. 8.2%, P = 0.013). HBcAb positivity and elevated baseline alanine aminotransferase (ALT) levels were independent risk factors for hepatitis. Among the 55 patients with resolved hepatitis B, patients with elevated baseline serum ALT or aspartate aminotransferase (AST) levels were more likely to develop hepatitis than those with normal serum ALT or AST levels (P = 0.037, P = 0.005, respectively). An elevated baseline AST level was an independent risk factor for hepatitis in these patients. Six patients with HBV reactivation recovered after immediate antiviral therapy, and chemotherapy was continued. HBcAb positivity, HBV reactivation, or hepatitis did not negatively affect the survival of DLBCL patients.ConclusionsDLBCL patients with resolved hepatitis B may have a higher risk of developing HBV reactivation and hepatitis than HBsAg-negative/HBcAb-negative patients. Close monitoring and prompt antiviral therapy are required in these patients.

Clinical role of obinutuzumab in the treatment of naive patients with chronic lymphocytic leukemia.

The introduction of targeted therapy against CD20+ with the monoclonal antibody rituximab has dramatically improved the survival of B-cell non-Hodgkin lymphoma including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. Unfortunately, CLL remains incurable with chemoimmunotherapy, with many patients having refractory or relapsing disease after rituximab-containing therapy. Obinutuzumab (GA101) is a novel humanized Type II anti-CD20 monoclonal antibody that has been investigated and compared to rituximab. Here, we provide an overview of obinutuzumab, including its mechanisms of action, preclinical data, and Phase I to III clinical studies. Preclinical data illustrate obinutuzumab’s higher potency compared to rituximab through antibody-dependent cellular cytotoxicity and direct cell death. Recently, the CLL11 study presented a significant benefit from obinutuzumab chemoimmunotherapy and supports its use for treatment-naive unfit CLL patients. Herein, we review that obinutuzumab is both a safe and effective alternative to rituximab.

Lymphocyte/monocyte ratio and cycles of rituximab-containing therapy are risk factors for hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma and resolved hepatitis B

Reactivation of hepatitis B virus (HBV) following rituximab (R)-containing chemotherapy for lymphoma is a major concern, and risk factors remain to be defined. We enrolled 190 patients diagnosed with diffuse large B-cell lymphoma (DLBCL) and resolved hepatitis B, receiving first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based regimens. Twenty-seven patients (14.2%) developed HBV reactivation during a median follow-up of 23.6 months. Two independent risk factors were identified: cycles of rituximab > 8 (hazard ratio [HR], 2.797; 95% confidence interval [CI], 1.184–6.612) and lymphocyte/monocyte ratio (LMR) < 2.50 (HR, 2.733; 95% CI, 1.122–6.657). Two-year overall survival in patients with or without HBV reactivation was 53.8% vs. 77.6% (p = 0.025). Regarding the negative impact on clinical outcome, patients at “super high risk” of HBV reactivation, including those receiving more than eight cycles of R and having low LMR at diagnosis, may warrant first priority for antiviral prophylaxis.

B-cell Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, without the development of Richter's Syndrome, with Neoplastic Cells Lacking CD20 Antigen Expression after Rituximab Treatment

A 40-year-old man was admitted to our hospital with systemic swelling of the lymphnodes (LNs). The histopathological findings of the neck LNs revealed a diffuse proliferation of neoplastic small lymphocytes. LN and bone marrow (BM) cells were subjected to immunostaining and flow cytometric analysis of the cell surface, showing CD5, CD19, CD20, and CD23 positivity and CD3, CD10, and cyclin D1 negativity. The patient was diagnosed with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL). He received a cycle of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and 6 cycles of RFC (rituximab, fludarabine, and cyclophosphamide), after which complete remission was obtained. Fifteen months after the diagnosis, the lymphoma relapsed and massive systemic LN swelling and BM infiltration were observed, characterized by a lack of CD20 antigen expression in the neoplastic cells. Two salvage chemotherapy regimens proved ineffective and the lymphoma progressed. The patient died two months after the relapse. The pathological findings at autopsy revealed the multiple organ infiltration of CLL/SLL cells which lacked CD20 expression. There were no evidence of Richter’s syndrome. Patients with relapsed B-CLL/SLL who are undergoing rituximab-containing therapy should be monitored for the loss of CD20 antigen expression in the neoplastic cells.

Outcomes of HCV-Positive Patients with Lymphoma Treated with Rituximab-Containing Therapies

Abstract Introduction: The impact that hepatitis C virus (HCV) infection has on the clinical outcome of patients with lymphoma treated with rituximab-containing therapies is uncertain. Rituximab has improved outcomes in patients with aggressive lymphomas however the prognostic value of rituximab in HCV infected patients has not been well established. It has been shown that reactivation is a common complication in patients with hepatitis B treated with rituximab. It is possible that patients with hepatitis C also develop reactivation with rituximab resulting in worsening liver function and a poor clinical outcome. A prior Japanese study showed that HCV-positive patients with diffuse large B-cell lymphoma have a high incidence of severe hepatic toxicity (Ennishi, D., Maeda, Y., et al. 2010). In this study we wanted to further analyze this idea and see if it is applicable to American population with hepatitis C and lymphoma receiving rituximab-containing therapies. Methods: We collected data from patients who were HCV-positive with lymphoma treated with rituximab between 2003 and 2014 at Montefiore Medical Center. Patients were included who were over 18 years old with a positive HCV test prior to treatment. Data was analyzed using statistical software Stata (version 12.0, StataCorp LP, College Station, TX, USA). Results: A total of 33 HCV-positive patients with lymphoma were included. Most of these patients (82%) had diffuse large B-cell lymphoma (DLBCL). Of the 33 patients, 24 (73%) showed worsening liver function after starting Rituximab containing therapy. Hepatitis C viral load before and after the treatment was documented for 8 patients. 5 of these 8 patients had clear reactivation of hepatitis C with rising hepatitis C viral load. All of these 5 patients noted with worsening of liver function tests. These patients received an average of 2 doses of Rituximab before having the rise in liver function tests (LFTs). Also, the median duration to see a rise in liver transaminases was at 2.5 months with the peak level in liver enzymes observed at 4 months after starting rituximab. Conclusion: These results show that patients with HCV infection have a high incidence of hepatic toxicity with rituximab. Some of these patients also showed evidence of reactivation with increased hepatitis C viral load. Further studies need to be done to determine if addition of new oral hepatitis C treatments like Sofosbuvir to the chemotherapy would change the course of viral reactivation and hepatic toxicity. These patients may need closer hepatic monitoring during and after treatment with rituximab.

The Bruton’s Tyrosine Kinase (BTK) Inhibitor ONO-4059: Promising Single Agent Activity and Well Tolerated in Patients with High Risk Chronic Lymphocytic Leukaemia (CLL)

IntroductionBruton’s tyrosine kinase (BTK) is a critical kinase involved in B-cell receptor signal transduction. ONO-4059, a highly potent and selective oral BTK inhibitor has demonstrated anti-tumour activity in pre-clinical models (Yasuhiro et al, AACR2013) and in the clinic in both CLL and NHL patients (Morschhauser et al, EHA 2014; Rule et al, EHA 2014). Here, we present data from 25 CLL patients enrolled in the ongoing Phase I study ONO-4059POE001.MethodsTwenty five CLL patients were administered ONO-4059 as monotherapy, given once daily (QD) to determine safety, pharmacokinetics and pharmacodynamics, and preliminary efficacy. Patients can receive ONO-4059 for up to a maximum of 3 years and upon completion of the first 6 months of treatment, intra-patient dose escalation is permitted. Here, we present data for 25 evaluable patients treated with ONO-4059 at doses ranging from 20-600mg (8 cohorts).Patients had a median age 67 yrs [range 40-79], median baseline tumour burden 3,943 mm2 [461-19,750 mm2], median of 4 prior therapies [2-8], including fludarabine (23/25) and rituximab-containing therapy (23/25). Baseline median haematology parameters included lymphocytes 34.6 x 109/L [0.1-391], haemoglobins 11.1 g/dL [8.5-15.2], platelets 97 x 109/L [23-185], neutrophils 2.39 x 109/L [0.5-11.1]. 9/24 patients were 17p deleted [38%] and 6/24 had the 11q deletion [25%], 20/24 were IgVH unmutated status [83%], with 13/24 [54%] displaying TP53 mutation).ResultsTo date, 19 of 25 patients remain on treatment with a median duration of treatment of 363 days [27-659]. ONO-4059 was found to be well tolerated with few adverse reactions over a long duration. A total of sixty two ONO-4059-related Grade 1- 2 adverse events were reported in 19 out of 25 patients. Eight dose independent ONO-4059-related G3 or G4 haematological toxicities were reported in 5 patients; with neutropenia in 3 patients, [G3 x 1, G4 x 2]), febrile neutropenia in 1 patient [G3] and leucopenia in 2 patients [G3 x 4]. Six Grade 3 ONO-4059-related non-haematological events were reported (pyrexia x 1, Hepatitis E reactivation x 1, Lymphocytic infiltration, Purpura, Urinary tract infection and Haematoma in just one patient). Nine ONO-4059-related SAEs were reported in 6 patients (febrile neutropenia [G3] and pyrexia [G3] at 20 mg, rash [G2] at 80 mg, hepatitis E reactivation [G3] at 320mg, neutropenia [G4] at 320 mg, purpura x 2 [G2, G3] and lymphocytic infiltration [G3] at 400 mg, haematoma [G2] at 500mg).All patients experienced rapid reductions in lymphadenopathy observed early in treatment between Cycle1 and Cycle3, accompanied by an increase in absolute lymphocyte count in 72% of patients. Almost all patients have durable response over a long duration. Best overall response rate according to IWCLL criteria (including modified PR with lymphocytosis) was 84% [based on CT-scan and P/E for 21/25 evaluable patients with 17 PR, 4 PR with lymphocytosis (for 21 responding patients, median reduction of lymph nodes was 83% [51-100]), 1 SD and 2 PD], with 89% response rate on 17p deleted. The early tumour shrinkage was associated with a rise in haemoglobin and platelet count. An increase in exposure (as assessed by Cmax and AUC) that was proportional to an increase in dose was seen for all doses of ONO-4059 ranging from 20-600mg.ConclusionONO-4059 is a highly potent and selective oral Btk inhibitor with a favourable safety profile along with promising efficacy over a long duration in this heavily pre-treated population, with responses observed in relapsed, refractory and currently poor prognostic 17p deleted patients. DisclosuresFegan:ONO PHARMA: Honoraria. Salles:celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; genetech: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Karlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Morschhauser:ONO PHARMA: Honoraria; Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Dyer:ONO PHARMA: Research Funding. Cartron:ONO PHARMA: Honoraria. Honda:Ono Pharmaceutical Co., Ltd.: Employment. Yasuhiro:Ono Pharmaceutical Co., Ltd.: Employment. Yoshizawa:Ono Pharmaceutical Co., Ltd.: Employment.

A Phase IIa, Open-Label, Multicenter Study of Single-Agent MOR00208, an Fc-Optimized Anti-CD19 Antibody, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphoma

Background: A number of second-generation monoclonal antibodies (mAbs) that target the antigens CD20 and CD19 have been evaluated across a range of non-Hodgkin’s lymphoma (NHL) subtypes combined with chemotherapy, as a single agent, or as maintenance therapy. Although these agents are usually well tolerated and have demonstrated clinical activity in patients (pts) with NHL, there is still a high unmet medical need for pts with refractory or relapsed NHL. MOR00208 is an Fc-engineered humanized mAb that targets the antigen CD19 and possesses significantly enhanced antibody-dependent cell-mediated cytotoxicity, a key mechanism for tumor cell killing.Methods: This non-randomized, phase IIa, open-label, multicenter study (NCT01685008) was designed to assess the efficacy and safety of single-agent MOR00208 in pts ≥18 years with relapsed or refractory NHL previously treated with rituximab, who were not candidates for high-dose therapy with stem cell support. Pts with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and other indolent NHL (iNHL), who had received at least one prior rituximab-containing therapy, were eligible. Additional eligibility criteria included European Cooperative Oncology Group Performance Status (ECOG PS) 0-2, measurable disease ≥1.5 cm, adequate bone marrow function, renal and liver function test. Pts were treated with MOR00208 12 mg/kg IV weekly for a total of 8 doses. Those with at least stable disease according to International Response Criteria (Cheson, JCO 2007), were to continue MOR00208 treatment for an additional 4 weeks. After completion of these 12 weekly doses of treatment, responding pts (complete or partial remission [CR or PR]) received maintenance MOR00208 every 2 weeks until progression. The study utilized a 2-stage design. In stage 1, ≥10 pts were to be enrolled in each of the 4 NHL disease cohorts. Cohorts with ≥2 responses (CR or PR) in stage 1 were expanded by an additional 20 patients in stage 2. Disease cohorts with <2 responses in stage 1 were stopped for futility. Enrollment of a minimum of 40 and a maximum of 120 pts was planned.Results: Herein we report the efficacy results for the 51 pts enrolled in stage 1 and the safety for 85 pts enrolled to date in stages 1 and 2 of this trial. The median age for all 51 stage 1 pts was 70 (35–90) years, 46 had stage III-IV disease, and the median number of prior therapies was 3 (2-4). Treatment cohorts consisted of DLBCL (n=14), FL (n=14), MCL (n=12) and iNHL (n=11). The investigator assessed overall response rate in stage 1 over all NHL subtypes was 24% (12/51), with responses observed in the DLBCL, FL, and iNHL cohorts (Table). As of February 2014, 62/85 (72.9%) stage 1 and stage 2 pts had developed treatment emergent adverse events (TEAEs). The most frequently reported TEAEs of any grade were thrombocytopenia (11.8%), anemia and headache (10.6% each), and neutropenia (9.4%). Infusion-related toxicities were all grade 1-2 (except for one case of dyspnea of grade 4). There have been no treatment-related deaths. Most of the TEAEs occurred in pts with DLBCL (30/36 [83.3%]). In pts with DLBCL, the most frequently reported grade ≥3 TEAEs were neutropenia (13.9%), thrombocytopenia and anemia (8.3% each).Conclusion: The Fc-engineered humanized anti-CD19 antibody, M0R00208, is well tolerated without significant infusional toxicity and demonstrates preliminary efficacy in pts with relapsed/refractory DLBCL, FL, and iNHL. Accrual to stage 2 for pts with DLBCL and FL is ongoing. [Display omitted] DisclosuresBlum:MorphoSys: Research Funding. Maddocks:MorphoSys: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Other. Nagy:AMGEN: Consultancy. Zinzani:MorphoSys: Membership on an entity’s Board of Directors or advisory committees. Robak:MorphoSys AG: Research Funding. Korolkiewicz:MorphoSys AG: Employment. Winderlich:MorphoSys: Employment, Patents & Royalties. Jurczak:Celgene: Research Funding; Eisai: Research Funding; Gilead: Research Funding; Jansen: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Sandoz-Novartis: Research Funding; Spectrum: Research Funding; Takeda: Research Funding; Teva: Research Funding; Mundipgharma: Consultancy; Spectrum: Consultancy; Teva: Consultancy; Takeda: Consultancy; Roche: Consultancy; Sanoz-Novartis: Consultancy.

Severe infusion-related reactions are uncommon in rituximab-treated CLL patients in clinical practice: Results from a Swedish national observational study

There have been concerns about serious infusion-related adverse drug reactions (ADR) with rituximab in chronic lymphocytic leukemia (CLL). We therefore conducted an observational trial in which CLL patients planned for rituximab-containing therapy were eligible. Ninety-six patients from 19 centers were enrolled. The most common regimen was rituximab, fludarabine and cyclophosphamide. Fifty-six patients experienced ADR during rituximab infusion. Reactions≥grade 3 occurred in five patients and no cases of tumor lysis syndrome were recorded.Despite a high number of circulating tumor cells few severe ADR were noted. Thus, rituximab-containing regimens can be considered safe for CLL patients in general practice.

Peripheral blood lymphocyte/monocyte ratio predicts outcome in follicular lymphoma and in diffuse large B-cell lymphoma patients in the rituximab era.

Diffuse large B-cell lymphoma is an aggressive lymphoma and a large number of studies have therefore focused on the search for prognostic factors. The same interest concerns FL, for which identification of patients candidates for watch and wait (W&W) strategy is still an option. Studies about the number and type of lymphocytes and monocytes detectable in patients with Hodgkin and non-Hodgkin lymphomas indicate they might affect the pathogenesis and prognosis of these diseases. LMR is recently under investigation as a new prognostic parameter in DLBCL; the role of this ratio in FL in the rituximab era is unknown. We retrospectively analyzed 137 DLBCL and 132 FL patients referred to our institution; among FL pts, a W&W approach was performed at diagnosis for 42 patients. The remaining patients were treated with rituximab-containing therapy. We analyzed different LMR cutoff values at diagnosis and we wanted to investigate the prognostic effect among DLBCL and FL. We found that the most discriminative LMR was 2.4 for DLBCL and 2 for FL. Among DLBCL patients, an LMR value< 2.4 was associated with a worse 2-year progression-free survival (PFS), and we observed no difference in overall survival and complete response rate. Considering FL patients, LMR > 2 was associated with a longer time to treatment start compared with the LMR< 2 group (P= .0096). Among the 92 patients treated with rituximab chemotherapy, 2-year PFS was superior in the LMR > 2 group. LMR at diagnosis is a simple tool to better define long-term outcome of DLBCL and FL patients. The use of this tool might better define selection in FL of ideal candidates for W&W strategy.

Impact of prior rituximab on outcomes of autologous stem-cell transplantation in patients with relapsed or refractory aggressive B-cell lymphoma: a multicentre retrospective Spanish group of lymphoma/autologous bone marrow transplant study

The use of highly effective rituximab-containing therapy for treating diffuse large B-cell lymphoma (DLBCL) makes it more difficult to salvage relapsed or refractory patients. Autologous stem-cell transplantation (ASCT) is the reference treatment for these patients, but the impact of previous exposure to rituximab on the subsequent results of ASCT remains unknown. We analysed 248 patients with relapsed or refractory DLBCL or grade 3B follicular lymphoma pre-treated with rituximab as part of first-line therapy (R+ group) who received ASCT, in comparison with a control group of 127 patients without previous exposure to rituximab (R- group). The complete remission (CR) rates were similar in both groups. Multivariate analysis identified age-adjusted International Prognostic Index at diagnosis, extranodal involvement and disease status at transplant, and the number of previous chemotherapy lines as independent factors with a negative influence on CR rate. Compared with R- patients, those in the R+ group had a significantly better progression-free survival (63% vs. 48% at 5years) and overall survival (72% vs. 61% at 5years). This observation was independent of other prognostic factors that affected these outcomes. In conclusion, ASCT is no less effective in patients with relapsed or refractory aggressive B-cell lymphoma pre-treated with first-line rituximab-containing therapy than in rituximab-naive patients.

Lenalidomide In Combination With R-ESHAP (LR-ESHAP) In Patients With Relapsed Or Refractory Diffuse Large B-Cell Lymphoma Candidates To Autologous Stem-Cell Transplantation: A Phase 1b Study From Spanish Group Geltamo

BackgroundDiffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory disease after rituximab-containing first-line therapy have a poor outcome with the current salvage regimens. Consequently, new drugs designed to increase the response rate of salvage regimens should be explored (Gisselbrecht et al, J Clin Oncol 2010, 28: 4184-90). We conducted a phase Ib trial (3+3 design) to establish the safety, tolerability and determination of the maximum-tolerated dose (MTD) of lenalidomide in combination with R-ESHAP (LR-ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were also collected as secondary objective. Patients and MethodsEligible patients must be refractory to, or have relapsed following, first-line treatment with rituximab in combination with an anthracycline-containing regimen, and be eligible for autologous stem-cell transplantation (ASCT). Subjects received three cycles of lenalidomide (5, 10 or 15 mg) given on days 1 to 14 of every 21-day cycle, in combination with R-ESHAP salvage chemotherapy at standard doses (rituximab 375 mg/m2 day 1, etoposide 40 mg/m2 days 1-4, cisplatine 25 mg/m2 days 1-4; citarabine 2000 mg/m2 day 5, and methilprednisolone 500 mg days 1-5). Responding patients received BEAM followed by ASCT. ResultsDuring the escalating phase, 3 patients had dose-limiting toxicity in the 15 mg cohort: 1 grade 3 angioedema, and 2 mobilization failures. The MTD was therefore established at 10 mg of lenalidomide and this cohort was expanded to further explore the safety and efficacy of LR-ESHAP. A total of 20 patients (3, 13, and 4 in the 5, 10, and 15 mg lenalidomide cohorts, respectively) were enrolled (18 with DLBCL-NOS, and 2 with Burkitt-like lymphoma): 60% male, median age 58 (23–70) years. First-line treatment consisted of R-CHOP or similar in 18 patients and Burkitt's lymphoma protocols in 2. Disease status at LR-ESHAP was: primary refractory disease in 13 patients (partial response [PR], n=7; and<PR, n=6), and relapsed disease in 7 (3 early and 4 late relapses). IPI was 0-1 in 35%, 2-3 in 40%, and 4-5 in 25%. To date, 16 serious adverse events (SAEs) have been reported, including 5 episodes of febrile neutropenia, 2 pneumonia, 2 sepsis, 1 ionic imbalance, 1 renal toxicity, 1 facial angioedema, 2 thrombosis, and 1 hepatic toxicity, all of them recovered, and there were no treatment-related deaths. Seventeen patients (85%) completed the planned three cycles of treatment (3 without lenalidomide in the third cycle due to significant toxicity) and 1 patient two cycles (due to persistent neutropenia and thrombocytopenia after the second cycle). Two patients discontinued treatment during the first cycle (1 due to angioedema and 1 due to hepatic toxicity). Of the 18 patients with at least one post-baseline tumor assessment, the overall response rate to LR-ESHAP was 77.8% (44.4% complete remission). All 18 patients were successfully mobilized after one (13 patients) or two (5 patients) mobilization procedures, and 14 (70% of the overall series) underwent ASCT according to protocol. Reasons for not performing the transplant were: early progression of lymphoma (n=4), clinical trial discontinuation due to toxicity (n=2). At the time of this analysis, 8 patients had disease progression and 5 patients have died (all of them from lymphoma). With a median follow-up of 7.4 (2.9 to 27.6) months, the estimated 1-year progression-free survival and overall survival were 52% and 72%, respectively. ConclusionsLR-ESHAP shows an acceptable safety profile and encouraging activity in rituximab-pretreated relapsed or refractory DLBCL patients. Further investigation with this regimen is warranted. Disclosures:No relevant conflicts of interest to declare.

A multicentre, phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B‐cell lymphoma

This international, multicentre phase II study was conducted to assess ofatumumab, a human anti-CD20 monoclonal antibody, in patients with relapsed/progressive diffuse large B-cell lymphoma (DLBCL) who were ineligible for autologous stem cell transplantation (TI) or who had relapse/progression after transplantation (PT). Eighty-one patients received ofatumumab 300 mg intravenously (IV) on Day 1, followed by seven weekly IV infusions of 1000 mg. Patients in the TI and PT groups had received a median of 3 (range, 1-7) and 5 (range, 2-7) prior therapies, respectively. One-third of patients did not respond to the last prior therapy, and 53% had failed two or more rituximab-containing therapies. Overall response rate was 13% for the TI group (seven partial responses) and 8% for the PT group (two complete responses). Median progression-free survival was 2·6 months, and median duration of response was 9·5 months. The most common Grade 3-4 adverse events were neutropenia (11%), leucopenia (6%), lymphopenia (6%) and thrombocytopenia (6%). Sixteen deaths have been reported, with disease progression as the most common cause of death. In conclusion, ofatumumab monotherapy was well tolerated and provided clinical benefit to some DLBCL patients in this study.

Prognostic implications of histologic grade and intensity of Bcl-2 expression in follicular lymphomas undergoing rituximab-containing therapy

This study aimed to determine the correlations of 7 histopathologic prognostic indicators of follicular lymphoma (follicular lymphoma grade, CD10 expression, Bcl-2 expression, IGH/BCL2 fusion, diffuse area, fibrosis, and marginal zone differentiation) with progression-free survival, overall survival, and follicular lymphoma histologic grade in 255 follicular lymphoma patients who were treated with rituximab-containing therapy. The complete response, overall response, 6-year progression-free survival, and 6-year overall survival rates were 83%, 96%, 56%, and 97%, respectively. Patients with follicular lymphoma grades 3a and 3b showed 100% 6-year and 10-year overall survival, and progression-free survival did not significantly differ between patients with follicular lymphoma grade 3 and those with follicular lymphoma grades 1 and 2. The absence or presence of Bcl-2 expression and intensity of Bcl-2 expression were not significant prognostic indicators of progression-free survival and overall survival. Likewise, the presence of IGH/BCL2 fusion, diffuse area, fibrosis, and marginal zone differentiation were not significantly correlated with progression-free survival and overall survival. Follicular lymphoma grade 3 was correlated with nodal disease and negative or lower intensity of Bcl-2 expression, but not with age, stage, or IGH/BCL2 status. In the prerituximab era, grade 3 disease was reported to be associated with a poor prognosis; however, the opposite was true for patients treated with rituximab-containing therapy, regardless of their age or disease stage. Bcl-2 expression and marginal zone differentiation were not prognostic indicators in follicular lymphoma patients treated with rituximab-containing therapy.

Phase I study of a novel humanized anti-CD20 antibody, BM-ca, in patients (pts) with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) pretreated with rituximab.

8551 Background: BM-ca is a novel humanized type-I/II anti-CD20 antibody, which is effective against rituximab-resistant cell line RC-K8, and has more potent anti-cell-proliferation activity than rituximab or ofatumumab when combined with cancer chemotherapeutics. The aim of this study was to evaluate the safety, efficacy, and PK profile of BM-ca in pts with indolent B-NHL. Methods: A total of 12 pts {age: median 61 (50-73), number of prior regimens: median 2 (1-13)} with indolent B-NHL relapsed after or refractory to rituximab-containing therapy underwent treatment by IV infusion of BM-ca weekly for 4 weeks at a dose of 5, 10, or 15 mg/kg. Initially, 3 pts were to undergo BM-ca therapy at a dose of 5 mg/kg using the conventional 3+3 dose escalation design. To minimize infusion reactions (IRs), pts were pretreated with acetaminophen and d-chlorpheniramine maleate. Allopurinol and/or hydrocortisone were also administered if necessary. Infusion was started at 50 or 100 mg/h and was gradually increased to a maximum of 400 mg/h. Since no DLTs were observed, all 12 pts completed weekly 4 doses of BM-ca. Results: The most frequent AE was IRs (11 of 12 pts), which occurred mostly in the first infusion, and the highest grade of AE was neutropenia (grade 4 in one pt of 15 mg/kg after the last infusion). Anti-BM-ca antibodies were not detected. Of the 12 pts examined, 2 achieved CR (10 mg/kg) and 2 PR (15 mg/kg); these 4 pts had follicular histology. The remaining 8 pts including one each of extranodal marginal zone, nodal marginal zone, and small lymphocytic histology were judged to achieve SD. The CR states in 2 pts continued at least &gt;14 and &gt;11 months, respectively. The PK properties of BM-ca were comparable to those of other naked anti-CD20 antibodies including rituximab (AUC and Cmax were proportional to the doses; Vdss≈4 L; t1/2≈750 h). Since at 10 mg/kg the response was the best and no grade 4 AE observed, 10 mg/kg was suggested as a recommended phase II dose. Conclusions: Four weekly IV administration of BM-ca up to 15 mg/kg was well tolerated and safe with promising preliminary anti-lymphoma activity in pts with indolent B-NHL. Further evaluation is warranted. Clinical trial information: 000004805.

Follow-up Data of 10 Patients With B-cell Non-Hodgkin Lymphoma With a CD20-negative Phenotypic Change After Rituximab-containing Therapy

Recently, a CD20-negative phenotypic change in CD20-positive B-cell non-Hodgkin lymphoma (B-NHL) after rituximab therapy was described. We report the follow-up data of 10 B-NHL patients showing this change after rituximab therapy. Ten patients (4 men and 6 women; median age, 57 y) with B-NHL who were initially CD20 positive and became CD20 negative after rituximab therapy were analyzed. Clinicopathologic features, including clinical course, CD20 expression, and histopathology, were examined. CD20 expression in lymphoma cells was evaluated using immunohistochemistry and/or flow cytometry. Histopathologically, diagnosis at initial presentation was follicular lymphoma (FL) in 7 patients; diffuse large B-cell lymphoma in 1; and chronic lymphocytic leukemia in 2. Six patients (60%, 3 FL, 1 diffuse large B-cell lymphoma, and 2 chronic lymphocytic leukemia patients) showed continuous CD20 negativity until 24 months after the phenotypic change. Three patients (30%) with FL regained CD20 expression within 1 to 7 months after detection of the CD20 change. Two patients (20%) with FL, including 1 who regained CD20 expression, showed heterogenous CD20 expression with a CD20-negative low-grade component and a CD20-positive large cell component. The overall response rate to therapy before the CD20-negative change was 70%. We reported the follow-up data of 10 B-NHL patients with a CD20-negative phenotypic change associated with rituximab-containing therapy. The most common histologic phenotypes were continuous CD20 negativity, recovery of CD20 expression within 7 months, and heterogenous CD20 expression. As the changes in morphology and CD20 expression after rituximab therapy vary widely, careful follow-up and rebiopsy are recommended.

What Is the Role of Stem-Cell Transplantation for Follicular Non-Hodgkin Lymphoma in the Rituximab Era?

Defining the best treatment for follicular lymphoma (FL) is still a challenge, partly because the available treatment options are often associated with prolonged overall survival (OS) as a result of the long natural history of this disease. Many clinical studies have used progression-free survival (PFS) as their end point but suffer from insufficient follow-up or lack of statistical power to assess OS, which is the indisputably best end point. Until the introduction of rituximab, standard chemotherapy (varying from low-dose oral chlorambucil to intensive multidrug schedules) was effective in producing responses but did not result in a survival benefit. The introduction of autologous peripheral-blood stem-cell transplantation with its inherent low morbidity and mortality in comparison with autologous bone marrow transplantation resulted in three trials applying high-dose therapy as first-line treatment for FL. All these studies showed an improvement of antitumor efficacy, but none had a significant impact on OS. This is most likely the result of the inability to select patients who might benefit most from this procedure or, again, insufficient follow-up. Patients who experience relapse, especially early relapse, have shown that they have a lymphoma with a clinically less benign behavior. In this patient population, several phase II studies suggested an improved survival, which was confirmed by the only randomized study in relapsed FL that showed a significantly improved OS in patients who underwent transplantation as compared with standard chemotherapy. Several authors have described a relatively high incidence of myelodysplasia, attributed to the high-dose therapy. However, this may also be the result of extensive pretreatment, suggesting that high-dose therapy might be of greater benefit earlier in the treatment course, as opposed to after multiple relapses. After the introduction of rituximab, several groups chose to investigate whether OS was improved with the incorporation of rituximab in standard-dose, first-line treatment of FL. The general conclusion is that PFS was improved in all, but OS was prolonged in only some, of these trials. Likewise, incorporating rituximab into highdose chemotherapy as part of first-line therapy resulted in better PFS but an OS benefit was observed in only one such trial. In the article that accompanies this editorial, Pettengel et al describe the results of the randomized European Group for Blood and Marrow Transplantation (EBMT) LYM-1 study. Rituximab-naive patients with relapsed chemosensitive FL were randomly assigned to analyze the efficacy of in vivo purging and maintenance therapy with rituximab in combination with high-dose therapy and autologous stem-cell transplantation. In 7 years, 280 patients were included. The authors conclude that in vivo purging did not improve outcome; however, maintenance therapy did improve PFS, but not OS at the time of this report. This study was not designed to assess the value of high-dose therapy because all patients received this treatment, which the authors considered standard therapy in relapsed FL. Although an important observation, it is important to realize that the patients in the EBMT LYM-1 study all were rituximab naive, which limits conclusions on current applicability. In addition, from the French Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) study, we have learned that the results of high-dose therapy in patients with diffuse large B-cell lymphoma who experience relapse after first-line rituximab-containing therapy are significantly inferior, especially in the situation of an early relapse. Whether this is also the case in FL is an open question, but data from another French study in FL may be reassuring that this is not necessarily the case in FL. We can conclude that high-dose therapy changes the natural behavior of FL in relapsed disease and, probably, also in first-line therapy if PFS is a convincing end point. However, it is not clear that PFS is the best end point in FL. How can we improve the outlook for patients with FL? One approach is to wait for the current studies to mature and report OS data. Alternative options are new and more effective monoclonal antibodies or monoclonals conjugated to either radionuclides or toxins. Currently, there are no randomized data in support of these expensive options. Is allogeneic transplantation the panacea? Although complicated by a high treatment-related mortality (TRM), myeloablative transplants resulted in convincing evidence of cure in patients for whom other intensive therapies had failed. With the introduction of nonmyeloablative transplants, the decreased TRM resulted in better outcomes, even in patients who had previously undergone autograft. The high TRM after allografting in comparison with autografting limits its role in first-line salvage. It remains to be seen whether tandem transplantation combining the efficacy of highdose therapy with the immunological graft versus lymphoma effect will lead to the desired more favorable outcome. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 13 MAY 1 2013

Reactivation of hepatitis viruses following immunomodulating systemic chemotherapy

Reactivation of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection following anticancer chemotherapy and immunosuppressive therapy is a well-known complication. HBV reactivation has been reported to be associated with anti-CD20 monoclonal antibody rituximab-containing chemotherapy and tumor necrosis factor-α inhibitor-containing immunosuppressive therapy in HBV resolved patients (hepatitis B surface antigen negative and antibodies against hepatitis B core antigen positive and/or antibodies against surface antigen positive). On the other hand, HCV reactivation has been reported to be associated with liver damage or hepatic dysfunction, but fulminant hepatitis due to HCV reactivation is a rare complication. In this review, we describe the pathophysiology of the reactivation of HBV and HCV infection, as well as the clinical evidence and management of HCV reactivation.