Rituximab-containing Regimens Research Articles

Efficacy of prophylactic antiviral therapy and outcomes in HBsAg-negative, anti-HBc-positive patients receiving chemotherapy: a real-life experience.

The aim of this study is to evaluate the outcomes of hepatitis B surface antigen (HBsAg)-negative, anti-HBc-positive patients who received immunosuppressive therapies. We retrospectively evaluated the medical records of HBsAg-negative, anti-HBc-positive patients with hematological diseases or solid tumors who underwent immunosuppressive therapies and were referred because of positive baseline hepatitis B virus (HBV) serology or HBV reactivation. The referral date was according to the judgment of the treating physician at the time of identification of any signs of HBV infection. We included 55 HBsAg-negative, anti-HBc-positive patients. Of these, 31 received antiviral prophylaxis (group 1), whereas 24 patients did not receive any anti-HBV agent (group 2). The majority of patients [49/55 (89%)] had hematological malignancies and most of them 39/55 (71%) received rituximab-containing regimens. Lamivudine was used as antiviral prophylaxis in 13/31 (42%) patients of group 1. One patient in this group experienced HBV reactivation and was treated successfully with tenofovir add-on therapy. All patients in the second group experienced HBV reactivation and most of them [19/24 (79%)] were treated with tenofovir or entecavir as rescue therapy. Two of these patients (one of the tenofovir/entecavir subgroup and one of the lamivudine subgroup) eventually died because of hepatic failure despite rescue treatment. Patients with serological markers of previous HBV infection are still at risk for HBV reactivation. Screening of both anti-HBs and anti-HBc is mandatory before chemotherapy. Pre-emptive antiviral prophylaxis, including lamivudine, is highly effective in all subgroups of such patients, whereas deferring treatment upon HBV reactivation is not enough to rescue all cases.

Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma

AbstractWe recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P = .022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

Is Prior Rituximab Exposure Associated with a Difference in Outcomes in Relapsed Low-Grade Lymphomas Retreated with Rituximab in Comparison to Rituximab NaïVe Patients?

Introduction:Evidence from several randomized clinical trials demonstrates the survival benefit and superior magnitude of disease control of rituximab use in indolent lymphomas compared to chemotherapy alone in remission induction. However, there is a paucity of evidence regarding retreatment with rituximab in patients who have previously been exposed. Despite this, Canadian agencies fund the use of rituximab retreatment in patients who have previously received rituximab, sustained a response, and been treatment free for over a year. The purpose of this study was to describe the characteristics and outcomes of patients with relapsed indolent lymphomas re-treated with a rituximab-containing regimen at Princess Margaret Cancer Centre (PM).Methods:This was a retrospective chart review of patients treated at a Canadian tertiary care centre (PM) with relapsed low-grade lymphomas (follicular, mantle cell, marginal zone, and lymphoplasmacyticlymphomas) between January 2006 and November 2015. The start date of January 2006 is when provincial rituximab funding became available. Patients were identified from our lymphoma and pharmacy databases. Patients were included if they had sustained a treatment free period ³1 year between first- and second-line therapy, and received rituximab as part of their second-line therapy. They were divided into two groups: Group 1 included patients who received any rituximab exposure as part of their first line therapy; Group 2 included patients na•ve to rituximab, who were treated with a non-rituximab containing first-line regimen. Primary outcome was progression-free survival (PFS) from start of second-line treatment. Secondary outcomes were overall survival (OS), overall response rate (ORR), and number of patients achieving a complete response (CR) at the end of second-line treatment.Results:687 patients were identified who received rituximab for indolent lymphoma treatment (any line) during this time period. Of the eligible relapsed subset, 41 transformed to aggressive lymphoma, and 39 progressed < 1yr post-first line therapy. 60 patients (55% female) met inclusion criteria, of which 21 (35%) had been retreated with rituximab during this time period. See Table 1 for patient characteristics. From start of second-line treatment, median follow-up was 43 months (range 4 to 132 months). Multivariate cox regression revealed a significant PFS difference between groups, with Group 1 having inferior PFS (2 year PFS 56% vs 77%, OR 2.38 95% CI 1.08-5.26, p=0.03, see Figure 1). Furthermore, patients who were older, had a higherCharlsoncomorbidity score, and those who did not receive maintenance rituximab had a lower PFS. More patients in Group 2 received oral chemotherapy as their first line treatment (such aschlorambuciland prednisone, reflecting an earlier treatment era, p=0.0003). There was no OS difference between groups (2 year OS 87% vs 79%, OR 1.73, 95%CI 0.64-4.64, p=0.28), although male gender and age were associated with lower OS. There was also no difference in groups in terms of ORR (75% vs 72%, p=0.8), or number achieving a CR at the end of second-line treatment (OR 0.38, 95% CI 0.11-1.37, p=0.14).Conclusions:Retreatment with rituximab was associated with an inferior PFS in patients with indolent lymphoma who sustained a one-year or greater response to first-line therapy with a rituximab-containing regimen, compared to rituximab-na•ve patients. This study is limited by small sample size, but our findings are consistent with other studies that evaluated rituximab retreatment in similar patient populations, and in diffuse large B-cell lymphoma. The PFS in patients retreated with rituximab was still superior to prior studies evaluating the use of second-line treatment with non-rituximab containing regimens in patients previously exposed to rituximab. There was no difference between groups in OS, ORR, or number achieving a CR at the end of treatment. [Display omitted] [Display omitted] DisclosuresCrump:Celgene: Consultancy; Janssen-Ortho: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy. Kukreti:Lundbeck: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Kuruvilla:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Chen:Takeda: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Prica:Celgene: Honoraria; Janssen: Honoraria.

Ibrutinib-Lenalidomide-Rituximab in Patients with Relapsed/Refractory Mantle Cell Lymphoma: First Results from the Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL) over the last 10-15 years, this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, with an overall response rate (ORR) of 68% as a single agent in the relapse situation. In vitro, ibrutinib has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. A phase I trial with this combination has been performed in 22 patients with untreated follicular lymphoma (Alliance 051103). In this trial, rash was the most common adverse event (AE), occuring in 73% of pts, with grade 3 rash in 32%.Methods: Eligibility criteria were: patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing was performed on frozen tumor cells from bone marrow at time of relapse, including the following genes: ATM, CCND1, TP53, KMT2D, NOTCH1, NOTCH2, WHSC1 and BIRC3.Treatment schedule:Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment. Given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle.Results: Accrual of 50 pts was completed in 12 months, June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. In total, 17/50 pts have discontinued treatment (n=9 due to PD, n=4 due to AE, n=2 withdrew consent, n=1 proceeded to alloSCT and n=1 due to other cause). Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). One event of laboratory tumor lysis syndrome was reported, and two events of atrial fibrillation, without reduction or discontinuation of ibrutinib. With a median follow up time of 7 months, 29 patients were evaluable for efficacy as of July 14, 2016. The ORR to date is 83% with 12 patients achieving CR (41%) and 12 PR (41%). Median duration of response and PFS has not been reached. One of three evaluable patients with progression on single agent ibrutinib responded with a PR, with ongoing response at 9 months. Of the 13 patients evaluable for MRD at 6 months, 7/12 patients have achieved molecular remission in blood and 7/13 in bone marrow.Conclusions: So far, the combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in patients with R/R MCL, associated with molecular remission. Cutaneous toxicity was manageable, in contrast to what has been reported with a similar combination in untreated patients with follicular lymphoma. Up-dated results will be presented at the annual meeting, including data on mutational profile as biomarker for efficacy. This trial was registered at http://clinicaltrials.gov as NCT02460276. DisclosuresJerkeman:Gilead: Research Funding; Mundipharma: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Niemann:Abbvie: Research Funding; Roche: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Geisler:Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy.

What Is the Cost-Effectiveness of Obinutuzumab Plus Bendamustine Followed By Obinutuzumab Monotherapy for the Treatment of Follicular Lymphoma Patients Who Relapse after or Are Refractory to a Rituximab-Containing Regimen in the US?

Background. Obinutuzumab (G) was recently approved for the treatment of follicular lymphoma (FL) in patients who relapsed after or are refractory to a rituximab (R)-containing regimen. In the phase III open label GADOLIN study of patients with rituximab-refractory iNHL, patients received either bendamustine (B, 120 mg/m2, d1+2, c1-6) alone, or obinutuzumab (G 1000 mg (d1, 8, 15 c1, d1 c2-6) for up to six 28d cycles) plus B (90 mg/m2, d1+2, c1-6) followed by G monotherapy (100 mg every 2 mo for up to 2 years). The net clinical benefit and economic value of G+B vs. B in R-refractory patients and the larger relapse patient population have not been formally evaluated. The objective of this study was to estimate the cost-effectiveness of G plus B followed by G monotherapy vs. B monotherapy based on results of the phase III GADOLIN trial in rituximab-refractory FL patients as well as model results for a refractory/relapse population. Methods. We developed a Markov model that utilized the GADOLIN trial's progression-free (PFS), and pooled G+B and B post-progression survival (PPS) through 4.5 years to model long-term patient PFS, progression, and death. We fit parametric curves to trial PFS and PPS data; PPS was used in lieu of immature overall survival (OS) data to model transitions to death from the progressed state. We used a U.S. registry of FL patients to inform the PFS and OS curves beyond the trial follow-up time to reflect a refractory/relapse patient population. The National LymphoCare Study is a disease-specific, prospective registry that enrolled more than 2,700 patients with newly diagnosed FL from 2004 to 2007 from more than 200 practice sites in the U.S. Drug utilization and adverse events were based on trial data, and costs were based on Medicare reimbursements and drug wholesale acquisition costs in 2016. Utility estimates were derived from the literature. Sensitivity analyses were conducted to assess uncertainty in the results. Results. Treatment with G+B followed by G monotherapy led to an increase in quality-adjusted life years (QALYs) relative to B-mono (1.23, 95% CR: -0.01, 2.38). The total cost of G+B was $114,815 and B-mono was $62,034, resulting in an incremental cost of $52,781. The average total cost was greater for G+B due primarily to increased drug and administration costs ($106,053 for G+B vs. $50,104 for B-mono), however this was offset by cost-savings for disease progression of -$4268 ($5,558 for G+B vs. $9,826 for B-mono). Adverse event costs were higher for G+B ($3,204) vs. B-mono ($2,103). The incremental cost-effectiveness ratio was $43,000 per QALY gained. In probabilistic sensitivity analyses, there was a 89% probability that G+B followed by G monotherapy was cost-effective versus B-mono at the $100,000 per QALY threshold. Conclusions. Our US-based analysis suggests that treatment with G+B followed by G monotherapy compared to B-mono is cost-effective in patients with FL who relapsed/refractory to a rituximab containing regimen. These findings are driven by the improvement in PFS with G+B treatment that lead to a projected increase in survival and decreased cost of treating disease progression. There was a high probability G+B was cost effective even when all parameters in the model were varied. In conclusion, G+B vs. B monotherapy in follicular lymphoma patients who relapse after or are refractory to a R-containing regimen is very likely cost effective in the US. DisclosuresGuzauskas:Genentech, Inc.: Consultancy. Masaquel:Roche: Equity Ownership; Genentech: Employment. Reyes:Genentech: Employment; Roche: Equity Ownership. Wilhelm:Genentech: Employment; Roche: Equity Ownership. Krivasi:F. Hoffman-La Roche Ltd.: Employment. Veenstra:Genentech, Inc.: Consultancy.

Autologous Stem Cell Transplantation for Patients with Early Progression of Follicular Lymphoma- Retrospective Analysis of 2 Randomized Trials of the German Low Grade Lymphoma Study Group (GLSG)

Background: Follicular lymphoma (FL) is a highly heterogeneous disease. Patients with early progression of disease (POD) have a remarkably poor outcome. Approximately 20% of patients with symptomatic, advanced stage FL experience POD within 24 months of first-line treatment (POD24) and have a 5-year overall survival (OS) of <50%, compared to >85% for patients without POD24 (Casulo et al, JCO 2015; Jurinovic et al, Blood 2016). The optimal salvage treatment for these high-risk patients is unclear. We aimed to assess the role of autologous stem cell transplantation (ASCT) applied as 2nd-line treatment for patients with POD24 who -in principle- qualified for dose-intensified regimens.Methods: Patients with advanced stage FL from 2 successive randomized trials of the German Low Grade Lymphoma Study Group (GLSG1996 [MCP versus CHOP] and GLSG2000 [CHOP versus R-CHOP], followed by randomization for ASCT consolidation versus interferon maintenance, respectively) were eligible for retrospective analysis of 2nd-line treatment if they had progressive, relapsed or refractory FL (ie, less than a partial response), were <65 years, required treatment according to our established criteria, and had not received prior ASCT. Three patients who received an allogeneic transplant (alloTx) as 2nd-line treatment were excluded from this analysis. POD24 was defined as progressive, relapsed or refractory disease within 24 months after 1st-line treatment. Progression-free survival (PFS) and OS were calculated from initiation of 2nd-line treatment (2nd-line PFS and 2nd line-OS, respectively).Results: The evaluable 162 patients were enriched for POD24 (113/162 [70%]). POD24 patients were more likely to receive ASCT as 2nd-line treatment (52/113 [46%] versus 11/49 [22%], p=0.008), whereas rituximab was more commonly added to 2nd-line regimens in patients without POD24 (48% versus 69%, p=0.018). With a median follow-up of 9.4 years, POD24 patients had a significantly shorter 5-year 2nd-line PFS and OS with 35% versus 53% (p=0.04) and 60% versus 83% (p=0.02), respectively, compared to patients without POD24.Within the POD24 group, 52 patients (46%) received ASCT, 54 (48%) received rituximab-containing regimens, 25 (22%) received both ASCT and rituximab as part of their 2nd-line treatment. Patients in the ASCT arm were younger (median age 47 versus 51 years, p=0.018) and more frequently male (73% versus 51%, p=0.026). The distribution of high-risk FLIPI (39% versus 46%, p=0.60), ECOG performance status >1 (10% versus 21%, p=0.15) and the addition of rituximab (48% versus 48%, p=1.0) was not significantly different between the ASCT and no-ASCT groups.In univariate analysis, ASCT for POD24 patients was associated with significantly higher 5-year 2nd-line PFS and OS rates of 51% versus 19% and 77% versus 46% (CI=[35;60]), respectively (Figure). The hazard ratios (HR) for 2nd-line PFS and OS were 0.36 (CI=[0.22;0.59], p<0.0001) and 0.50 (CI=[0.30;0.83], p=0.006).Multivariate analysis demonstrated that ASCT had a stronger impact on favorable treatment outcome compared to the addition of rituximab: the HRs of ASCT for 2nd-line PFS and 2nd-line OS were 0.37 (CI=[0.21;0.63], p=0.0003) and 0.34 (CI=[0.21;0.56], p<0.0001), whereas the HRs of rituximab were 0.63 (CI=[0.39;1.00], p=0.05) and 0.64 (CI=[0.39;1.08], p=0.09), respectively.Finally, to account for the selection bias associated with retrospective studies, we considered patients as ASCT if there had been an attempt to collect an autograft. This included an additional 13 patients from the no-ASCT group and another patient who ultimately received an alloTx as 2nd-line treatment. In this intention-to-treat-like analysis the benefit of ASCT remained statistically significant with a HR=0.48 for 2nd line PFS (CI=[0.30;0.77], p=0.002) and a HR=0.50 for 2nd-line OS (CI=[0.30;0.83], p=0.006).Conclusion: This retrospective analysis suggests that ASCT is an effective 2nd-line treatment option for patients with high-risk FL as defined by the early progression of disease (POD24) who qualify for dose-intensified protocols, and should be evaluated in prospective clinical trials. It remains to be determined if ASCT is also an effective 1st-line treatment strategy for selected patients identified to be high-risk by pre-treatment risk classifiers, such as the recently established clinicogenetic risk-model m7-FLIPI. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline

Rituximab is the first monoclonal antibody to be approved for use by the US Food and Drug Administration in cancer. Its role in the treatment of non-Hodgkin lymphoma, including chronic lymphocytic leukaemia (CLL), has evolved significantly. We aimed to systematically review and update the literature on rituximab in lymphoma and CLL, and provide evidence-based consensus guidelines for its rational use. Validated methodology from the Cancer Care Ontario Program in Evidence-based Care was used. A comprehensive literature search was completed by a methodologist from the Hematology Disease Site Group of Cancer Care Ontario. Data were extracted from randomised controlled trials of rituximab-containing chemotherapy regimens for patients with lymphoma or CLL. Fifty-six primary randomised controlled trials were retrievable and met all inclusion criteria. Clinically important benefits in progression-free survival or overall survival were seen in the following settings: (i) addition of rituximab to combination chemotherapy for initial treatment of aggressive B-cell lymphomas, including diffuse large B-cell lymphoma, Burkitt lymphoma and HIV-related lymphoma with CD4 count ≥50/mm3; (ii) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; (iii) use of rituximab maintenance in patients with indolent B-cell lymphomas who have responded to chemoimmunotherapy; (iv) addition of rituximab to fludarabine-based chemotherapy or chlorambucil for initial treatment of CLL. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications.

Pixantrone: A Review in Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma.

Pixantrone (Pixuvri®) is an aza-anthracenedione with a novel mode of action that is conditionally approved in the EU for use as monotherapy in adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma (NHL). In the randomized, open-label, multinational, phase 3 PIX301 trial in patients with multiply relapsed or refractory aggressive NHL, the complete response (CR) plus unconfirmed CR (uCR) rate at the end of treatment (primary endpoint) was significantly higher with intravenous pixantrone monotherapy than with a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone or gemcitabine). Post hoc analysis also demonstrated a significantly higher CR/uCR rate in the subgroup of patients with centrally confirmed aggressive B-cell NHL who were receiving pixantrone versus a comparator agent as third- or fourth-line therapy. Pixantrone was generally well tolerated in PIX301, with a manageable adverse event profile. In conclusion, pixantrone is a useful option in patients with multiply relapsed or refractory aggressive B-cell NHL. Further results examining the use of pixantrone in combination with rituximab in patients previously treated with rituximab-containing regimens are awaited with interest.

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Evolution of Management and Outcomes in Waldenström Macroglobulinemia: A Population-Based Analysis.

Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM) is a rare lymphoma affecting older patients. Its management largely relies on small phase II trials and it is unclear how their results translate into clinical practice in the community. We evaluated changes in the presentation, management, and survival among 2,666 Medicare beneficiaries diagnosed with WM between 1994 and 2011, using Medicare claims linked to Surveillance, Epidemiology and End Results data. Prevalence of transfusions, anemia, thrombocytopenia, and neuropathy at diagnosis significantly increased over time, whereas the use of plasmapheresis was low (2.5%) and stable. The proportion of patients starting chemotherapy within 1 year of WM diagnosis increased from 39% in 1994 to 62% in 2011 (p < .0001). Treatments based on classic alkylators and purine analogs predominated in the 1990s, but were quickly replaced by rituximab-containing regimens after 2000. Rituximab monotherapy has been prescribed for >50% of patients since 2004, and combination chemoimmunotherapy for a further 30%. Most patients initiating multiagent regimens in 2012-2013 received rituximab with bortezomib or bendamustine. These changes were accompanied by significant improvements in overall and WM-related survival, but also by a significant increase in cost of chemotherapy. Mean Medicare payments for chemotherapy drugs accrued in the first year of treatment rose from $9,464 in 1994-2000 to $29,490 after 2008. Hematologists have rapidly adopted innovative, expensive therapies for WM before completion of randomized trials. This underscores the need to assess the comparative value of such therapies in rare malignancies through a combination of clinical and observational data. Most older patients with Waldenström macroglobulinemia currently treated in the U.S. receive rituximab as monotherapy or in combination with bortezomib or bendamustine. Newly designed trials should consider control arms aligned with this prevalent real-life standard. Compared with the 1990s, patients diagnosed according to current criteria are more likely to have anemia or neuropathy, or to receive early chemotherapy, but only 2.5% require plasmapheresis at diagnosis. The incremental clinical value of newly introduced agents needs to be assessed through a combination of clinical and health services research, taking into consideration their associated survival benefits, toxicities, and associated costs of care.

Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes Compared with Fludarabine and Busulfan after Allogeneic Stem Cell Transplantation for B Cell Malignancies

Reduced-intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation to minimize transplant-related mortality while maintaining the graft-versus-tumor effect. In B cell lymphoid malignancies, reduced-intensity regimens containing rituximab, an antiCD20 antibody, have been associated with favorable survival; however, the long-term outcomes of rituximab-containing versus nonrituximab-containing regimens for allogeneic hematopoietic cell transplantation in B cell lymphoid malignancies remain to be determined. We retrospectively analyzed 94 patients who received an allogeneic transplant for a B cell lymphoid malignancy. Of these, 33 received RIC with fludarabine, cyclophosphamide, and rituximab (FCR) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin inhibitor and mini-methotrexate, and 61 received RIC with fludarabine and busulfan (FluBu) and GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The 2-year overall survival was superior in patients who received FCR versus FluBu (72.7% versus 54.1%, P = .031), and in multivariable analysis adjusted for Disease Risk Index and donor type, only the conditioning regimen (FluBu versus FCR: HR, 2.06; 95% CI, 1.04 to 4.08; P = .037) and Disease Risk Index (low versus intermediate/high: HR, .38; 95% CI, .17 to .86; P = .02) were independent predictors of overall survival. The 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR versus FluBu (24.2% versus 51.7%, P = .01). There was no difference in rate of relapse/progression or acute GVHD. Our results demonstrate that the use of RIC with FCR and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate is associated with decreased chronic GVHD and improved overall survival.

Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial

In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens. In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234. Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio [HR] 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]). Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases. Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.

CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma.

The CD20-targeting monoclonal antibody rituximab is an established component of immunochemotherapeutic regimens against B-cell lymphomas, where its coadministration with conventional anticancer agents has significantly improved long-term outcome. However, the cellular mechanisms by which rituximab exerts its antilymphoma activity are only partially understood. We show here that rituximab induces typical features of cellular senescence, a long-term growth arrest of viable cells with distinct biologic properties, in established B-cell lymphoma cell lines as well as primary transformed B cells. In addition, rituximab-based immunotherapy sensitized lymphoma cells to senescence induction by the chemotherapeutic compound adriamycin (a.k.a. doxorubicin), and, to a lesser extent, by the antimicrotubule agent vincristine. Anti-CD20 treatment further enhanced secretion of senescence-associated cytokines, and augmented the DNA damage response signaling cascade triggered by adriamycin. As the underlying prosenescence mechanism, we found intracellular reactive oxygen species (ROS) levels to be elevated in response to rituximab, and, in turn, the ROS scavenger N-acetylcysteine to largely abrogate rituximab-mediated senescence. Our results, further supported by gene set enrichment analyses in a clinical data set of chronic lymphocytic leukemia patient samples exposed to a rituximab-containing treatment regimen, provide important mechanistic insights into the biologic complexity of anti-CD20-evoked tumor responses, and unveil cellular senescence as a hitherto unrecognized effector principle of the antibody component in lymphoma immunochemotherapy. Mol Cancer Ther; 15(5); 1074-81. ©2016 AACR.

Obinutuzumab for the treatment of indolent lymphoma.

Obinutuzumab is a humanized, type II anti-CD20 monoclonal antibody designed for strong induction of direct cell death and antibody-dependent cell-mediated cytotoxicity. The Phase III GADOLIN trial tested the clinical efficacy of obinutuzumab plus bendamustine followed by obinutuzumab monotherapy in rituximab-refractory indolent non-Hodgkin lymphoma versus treatment with bendamustine alone. It demonstrated significantly longer progression-free survival for the obinutuzumab-containing regimen in this difficult to treat patient group. Based on the results of this trial, US FDA approval was most recently granted for obinutuzumab in the treatment of follicular lymphoma that has relapsed after or was refractory to a rituximab-containing regimen. This article summarizes the available data on chemistry, pharmacokinetics, clinical efficacy and safety of obinutuzumab in the treatment of indolent non-Hodgkin lymphoma.

Favorable outcome of primary mediastinal large B-cell lymphoma patients treated with sequential RCHOP-RICE regimen without radiotherapy.

Outcomes in primary mediastinal B cell lymphoma (PMBL) improved with the introduction of dose intense treatments, consolidation radiotherapy and rituximab. DA-EPOCH-R, which omits radiotherapy has been adopted with worldwide enthusiasm, despite lack of proven superiority in randomized trials. We aimed to evaluate the course and outcome of PMBL using an alternative intensive rituximab-containing regimen, RCHOP-RICE. We also evaluated the prognostic value of (18)FDG-PET-CT (PET-CT). We reviewed the clinical, laboratory and imaging data of PMBL patients receiving 1st-line treatment in Hadassah Medical Center between 8/2002 and 10/2014. Of 47 PMBL patients, 24 (51%) were treated with RCHOP-RICE and 23 (49%) with other protocols. Overall, the 5-year progression-free survival was 93% and the overall survival was 98% (87 and 100%, respectively, for the RCHOP-RICE regimen). Patient characteristics and treatment toxicities were balanced among protocols. A mean of 11.1±1.3 hospitalization days/patient were needed to administer RCHOP-RICE regimen compared to 37±2days/patient for DA-EPOCH-R (n=2). Radiotherapy was given to 3 patients (12%) treated with RCHOP-RICE compared to 18 patients (78%) treated with other protocols (p<0.01). For patients followed with interim and end of treatment (EOT) PET-CT, we observed a significant reduction in the uptake between the two (p<0.0001). Using a Deauville score cutoff of 3, the negative and positive predictive values (NPV and PPV) of EOT PET-CT were 94 and 33%, respectively. The RCHOP-RICE protocol results in excellent survival outcomes, generally permits omission of RT and is simpler to administer than DA-EPOCH-R. Interim PET-CT in PMBL may be unjustified; however, EOT Deauville scores ≤3 predicts a favorable outcome.

Clinical study of 6 patients with Epstein-Barr virus associated hemophagocytic lymphohistiocytosis treated with rituximab-containing regimen

Objective To investigate the efficacy of rituximab-containing regimen in Epstein-Barr virus associated hemophagocytic lymphohistiocytosis (EBV-HLH). Methods A retrospective analysis involving 6 EBV-HLH patients who had received treatment with rituximab-containing regimen was performed. The patients who were diagnosed with lymphoma or primary HLH subsequently were not included in the analysis. Results All patients were males. The median age was 27.5 years (range 20-61 years). Two patients received rituximab-containing regimen as primary therapy, and got partial remission (PR) within 2 weeks after the first course of rituximab, but relapsed within 4 weeks. Four patients received rituximab-containing regimen as salvage therapy, but none achieved remission. The 6 patients died due to HLH and complications, such as infection and hemorrhage. Laboratory data including white blood cell count, haemoglobin concentration, platelet count ferritin, alanine transaminase, aspartate transaminase,total bilirubin, fibrinogen and EBV-DNA did not show statistical significance (all P>0.05). Conclusion The efficacy of rituximab as a treatment for EBV-HLH is not as good as that in the previous study, and a prospective clinical trial of rituximab-based monotherapy is needed to answer the question. Key words: Lymphohistiocytosis, hemophagocytic; Rituximab; Epstein-Barr virus

Risk of graft-versus-host disease with rituximab-containing conditioning regimens in allogeneic hematopoietic stem cell transplant.

Graft-versus-host disease represents a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant patients. There is growing evidence that B lymphocytes may play a role in the pathogenesis of acute graft-versus-host disease. The purpose of this retrospective cohort study was to evaluate the efficacy of rituximab-containing conditioning regimens in decreasing graft-versus-host disease in allogeneic hematopoietic stem cell transplant patients who received standardized tacrolimus-based graft-versus-host disease prophylaxis regimens. Patients were divided into two cohorts, based on the presence (RTX, n = 54) or absence (No-RTX, n = 105) of rituximab in the conditioning regimen and were matched 1:2 for major graft-versus-host disease risk factors. The incidence of grade II-IV acute graft-versus-host disease was not different between the two groups (37% vs. 26%, p = 0.147). When restricting the analysis to recipients of peripheral blood hematopoietic stem cell transplants, the RTX group had a higher incidence of grade II-IV acute graft-versus-host disease, relapse, or death prior to day 100 (55% vs. 36%, p = 0.037). The median time to the onset of acute graft-versus-host disease was no different between the RTX and No-RTX groups (67 vs. 74 days, respectively, p = 0.141). Inhibition of antigen presentation by B cells with rituximab-based conditioning regimens does not appear to reduce the incidence of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplant recipients.

Comparison of Three Chemotherapy Regimens in Elderly Patients with Diffuse Large B Cell Lymphoma: Experience at a Single National Reference Center in Mexico

Background. Although chemotherapy added to rituximab is a standard of care for diffuse large B cell lymphoma (DLBCL), treatment of patients ≥65 years of age remains controversial due to comorbidities. Methods. This is a retrospective, comparative, nonrandomized study of patients ≥65 years of age, who were diagnosed with DLBCL but not previously treated. Demographic characteristics and comorbidities were analyzed. Three rituximab-containing treatment regimens (standard RCHOP, anthracycline dose-reduced RChOP, and RCOP) were compared. Descriptive analyses were conducted. Survival was calculated with the Kaplan-Meier method, and differences were compared with the log-rank test. Results. In total, 141 patients with a median age of 73.9 years were studied. The three treatment groups had comparable demographic characteristics. The overall response was 77%, 72.5%, and 59% in groups treated with RCHOP, RChOP, and RCOP, respectively. After multivariate analysis, the factors influencing the overall survival were the presence of B symptoms, poor performance status (ECOG ≥ 3), and febrile neutropenia. Factors influencing disease-free survival were febrile neutropenia, high-intermediate and high-risk IPI scores, and treatment without anthracycline. Conclusion. A higher ORR (overall response rate) was achieved with standard RCHOP, which influenced DFS and OS, although it was not statistically significant compared with the other groups. Interventional phase 3 trials testing new molecules in patients aged 70 to 80 years and older are required to improve the prognosis within this growing population.

Obinutuzumab in follicular lymphoma.

The CD20 marker continues to be exploited as a therapeutic target for non-Hodgkin's lymphoma. Obinutuzumab is part of a new generation of anti-CD20 monoclonal antibodies, which are synthesized using molecular engineering technology, resulting in novel target epitopes and unprecedented optimization of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Rituximab is the current gold standard for anti-CD20 therapy, yet despite outstanding results published over the past decade, many patients continue to relapse after anti-CD20 regimens. Obinutuzumab is slowly positioning itself in the treatment of CD20+ B-cell neoplasms. On the basis of favorable results from the phase III GADOLIN trial, obinutuzumab was recently approved by the U.S. Food and Drug Administration in combination with bendamustine followed by obinutuzumab maintenance, for the treatment of follicular lymphoma (FL) patients who relapsed or are refractory to a rituximab-containing regimen. Additional phase III trials are underway to test obinutuzumab as a first-line anti-CD20 agent in FL with good preliminary results (GALLIUM trial); thus, it is likely that obinutuzumab will soon achieve a first-line indication. It is plausible that obinutuzumab will replace rituximab as the gold standard for chemoimmunotherapy in FL, although some safety concerns still need to be resolved. This review will address the preclinical pharmacology and the main aspects of the clinical development of obinutuzumab for the treatment of FL.

Reduced Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes When Compared to Fludarabine and Busulfan Following Allogeneic Hematopoietic Cell Transplantation for Lymphoid Malignancies

BackgroundReduced intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation (allo-HCT) to minimize transplant-related mortality while still exploiting the graft-versus-tumor effect. It remains unclear if RIC preparative regimens need to be tumor specific. In B cell malignancies, RIC regimens containing rixtuximab, an antiCD20 antibody with anti-neoplastic activity, are commonly used. Rituximab-containing conditioning regimens have been shown to be associated with favorably event-free survival in a phase II study (Sauter et al, BMT, 2013). However, the long-term outcomes of rituximab-containing versus non-rituximab containing regimens for allo-HCT in B cell malignancies remain to be determined.MethodsWe retrospectively analyzed 94 patients who received an allo-HCT for a B cell neoplasm between 1/1/2005 and 12/31/2013 at Vanderbilt University Medical Center and the Veterans Administration Medical Center, Nashville. Of these, 33 received conditioning with Fludarbine, Cyclophosphamide, and Rituximab (FCR) and 61 received conditioning with Fludarabine and Busulfan (FluBu). For graft-versus-host-disease (GVHD) prophylaxis, patients receiving FCR received a calcineurin inhibitor and methotrexate, and patients receiving FluBu received a calcinuerin inhibitor and mycophenolate mofetil. Additionally, patients with related-donor transplants received anti-thymocyte globulin. Patient-, disease-, and treatment-related characteristic are summarized in Table 1.ResultsPatients who received FCR had more related-donor transplants compared to patients who received FluBu (66.7% vs. 42.6%, p = 0.038). The median follow-up from day of cell infusion for all patients was 36.9 (1.1 - 127.3) months, and 41.8 months (6.4 - 83.5) and 68.4 months (2.7 - 313.8 ), for the FCR and FluBu groups, respectively (p = .97 ).The 2-year overall survival was superior in patients who received FCR (72.7% vs. 54.1%, p = 0.031) (Figure 1). Two-year progression-free survival was also superior in patients who received FCR (63.6% vs. 49.2%, p = 0.04). There was no difference in the 100-day cumulative incidence of grade II-IV acute GVHD (45.5% vs. 63.9, p = 0.12) or grade III-IV acute GVHD (9.1% vs 16.4%, p = 0.53) for patients who received FCR compared to FluBu. However, the 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR compared to FluBu (27.3% vs 51.7%, p = 0.031).In a multivariable analysis adjusted for diagnosis (CLL/SLL vs. other B cell malignancies) and donor type (related vs. unrelated), only the conditioning regimen (FluBu vs. FCR: hazard ratio [HR] 1.95, 95%CI 0.98 - 3.85, p = 0.049) and CIBMTR disease risk (low vs. intermediate/high risk: HR 0.5, 95%CI 0.35 - 1.01, p = 0.053) were independent predictors of overall survival.ConclusionsThis study shows that use of a rituximab-containing RIC regimen in allo-HCT for lymphoid malignancies is associated with improved overall survival. In addition, a rituximab-containing regimen is associated with decreased incidence of chronic GVHD. If validated in a larger prospective cohort, these findings make rituximab-containing regimens preferable for B cell malignancies requiring allo-HCT.Table 1VariablesFCRFluBup-valueRecipient Age (Median, Range)52.9 (43.6 - 64)55.3 (33.3 - 70.1)0.95Donor Type0.038Related66.7%42.6%Unrelated33.3%57.4%Primary Disease0.34Chronic Lymphocytic Leukemia/ Small Cell Lymphoma39.4%27.9%Mantle Cell Lymphoma24.2%14.8%Diffuse Large B-Cell Lymphoma12.1%27.9%Follicular Cell Lymphoma21.2%26.2%Other B Cell Lymphoma3.1%3.2%CIBMTR Disease Risk0.61Low71%78%Intermediate/High29%22% [Display omitted] DisclosuresOff Label Use: fludarabine, cyclophosphamide, rituxiamb, anti-thymocyte globulin.