90Y Ibritumomab Tiuxetan Research Articles

A Systematic Literature Review (SLR) and Meta-Analysis of Clinical Evidence of Second Line or Later (2L+) Treatments for Follicular Lymphoma (FL) in Adult Patients

Background:First-line (1L)standard of care (SOC) options for patients with FL include an anti-CD20 monoclonal antibody with or without chemotherapy, and second-line (2L) therapeutic options are similar to 1L. There is no defined SOC for patients who require treatment in third, fourth, and later lines of therapy (LOT). Additionally, patients with high-risk FL who relapse ≤ 24 months after frontline treatment (POD24) have limited treatment options that can provide a durable response. Recently, novel treatments such as CAR T cell therapies and T cell engager regimens have been shown to improve efficacy outcomes in third line or later (3L+) and POD24 populations. We conducted an SLR of all relevant clinical evidence to evaluate the efficacy and safety of available therapies used in the treatment of adult patients with R/R FL in 3L+, fourth line or later (4L+), and 2L+ POD24 settings. We also aimed to conduct meta-analyses to derive pooled effect estimates for response and survival outcomes in these settings. Methods: Publications from 01/01/1998 to 09/17/2022 were identified using Ovid MEDLINE ®, Embase, and Cochrane Central Register of Controlled Trials, with supplemental hand searches of key conferences and bibliographies of recent relevant SLRs. Study eligibility was assessed according to prespecified population, intervention, comparator, outcome, and study design criteria. Studies were eligible if they were in English and enrolled patients with R/R FL (grade 1‒3A) in 3L+, 4L+, and POD24 settings. Eligible treatments included CAR T cell therapies (axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel), T cell engagers (mosunetuzumab, glofitamab, epcoritamab, odronextamab), phosphatidylinositol 3-kinase (PI3K) inhibitors (copanlisib, duvelisib, idelalisib), HSCT, yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, and conventional therapies (immunochemotherapies, single- or multiagent chemo- or immunotherapies, and alkylating agents). Outcomes of interest were OS, PFS, ORR, CR rate, PR, duration of response, and time to next treatment. Independent review committee (IRC) data were extracted when both IRC- and investigator-assessed data were reported. Pooled estimates for ORR, CR rate, OS, and PFS across all treatments were calculated among 3L+, 4L+, and POD24 patient populations. For POD24 studies, we combined POD24 definitions (ie, definitions with respect to POD24 from frontline therapy or baseline) and POD24 patients across LOTs (ie, presenting in 2L+). For each outcome in 3L+, 4L+, and POD24 settings, ≥ 4 sufficiently similar studies were required for a meta-analysis to be deemed feasible. Results: Of 5250 records screened, 112 were included, representing 60 unique studies. Of 60 studies, 33 (55%) were retrospective or prospective observational, while 27 (45%) were clinical trials (randomized, nonrandomized, and single arm). There was significant heterogeneity in patient populations and baseline characteristics across studies. Most studies (n = 48; 80%) reported findings for 3L+ FL, with limited evidence for 4L+ and POD24 patients. Results for ORR, CR rate, PFS, and OS by treatment type across 3L+, 4L+, and POD24 patients are presented in Table 1. ORR and CR rate data were highly variable depending on treatment used and length of follow-up period in the study. Across 3L+, 4L+, and POD24 patients, the highest ORR and CR rate ranges were observed for CAR T cell therapies, T cell engagers, and HSCT. Median PFS was highest for HSCT, T cell engagers, and CAR T cell therapy in the 3L+ setting and was not reported or not reached for HSCT and T cell engagers in 4L+ and POD24 settings. Median OS was not reached for patients receiving T cell engagers in the 3L+ setting or those receiving CAR T cell therapy in the 3L+, 4L+, and POD24 settings. Various meta-analyses including all treatments were considered feasible for 3L+, 4L+, and POD24 populations (Table 2). For ORR and CR rate in the 3L+ population, sensitivity analyses excluding CAR T cell therapies, T cell engager regimens, and HSCT were feasible and showed lower ORR and CR rate when these therapies were removed. Conclusions: This SLR demonstrated an evolving FL treatment landscape, with new agents such as CAR T cell therapies and T cell engagers exhibiting potential for improving effectiveness of treatment for patients in 3L+, 4L+, and 2L+ POD24 populations.

Theranostics in Hematooncology.

In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes 90Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as 131I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of 131I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.

Results of a Phase II Trial of Allogeneic Hematopoietic Stem Cell Transplantation Using 90Y-Ibritumomab Tiuxetan (Zevalin) in Combination With Fludarabine and Melphalan in Patients With High-Risk B-Cell Non-Hodgkin's Lymphoma

BackgroundAllogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (B-cell NHL). However, relapse remains a major cause of treatment failure, especially in patients with either positron emission tomography (PET)-positive and/or chemoresistant disease prior to alloHCT. 90Y-ibritumomab tiuxetan (Zevalin) is a radiolabeled anti-CD20 antibody which is a safe and effective therapy in multiple histologic subtypes of B-cell NHL and has also been incorporated in both autologous HCT (autoHCT) and alloHCT conditioning regimens. ObjectivesThe purpose of this study was to evaluate the efficacy and confirm the safety of the radiolabeled anti-CD20 antibody ibritumomab tiuxetan (Zevalin) combined with the reduced intensity conditioning (RIC) regimen of fludarabine and melphalan (Flu/Mel) in patients with high-risk B-cell NHL. Study DesignWe conducted a phase II trial (NCT00577278) of Zevalin with Flu/Mel in patients with high-risk B-cell NHL. We enrolled 41 patients from October 2007 to April 2014, all of whom had either a fully matched sibling or 8/8 or 7/8 matched unrelated donor (MUD). Patients received 111In-Zevalin (5.0 mCi) on day −21 pre-HCT, followed by 90Y-Zevalin (0.4 mCi/kg) on day −14. Fludarabine (25 mg/m2 daily) was given from days −9 to −5 and melphalan (140 mg/m2) was administered on day −4. All patients received rituximab 250 mg/m2 on day +8 and an additional dose on either day +1 or −21 depending on the baseline rituximab level. Patients with a low rituximab level were given rituximab on days −21 and −15. All patients received tacrolimus/sirolimus (T/S) with or without methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis starting on day −3, and stem cells were infused on day 0. ResultsThe 2-year overall survival (OS) and progression-free survival (PFS) for all patients were 63% and 61%, respectively. The incidence of relapse at 2 years was 20%. Nonrelapse mortality (NRM) at day +100 and 1 year were 5% and 12%, respectively. The overall cumulative incidence of grade II-IV and III-IV acute GVHD (aGVHD) were 44% and 15%, respectively. Extensive chronic GVHD (cGVHD) occurred in 44% of patients. On univariate analysis, histology (diffuse large B cell lymphoma (DLBCL) vs. others) was negatively predictive for OS (P = .0013) and PFS (P = .0004), while histology (DLBCL vs. others, P = .0128) predicted for relapse. PET positivity pre-HCT did not correlate with any of the efficacy endpoints. ConclusionAddition of Zevalin to Flu/Mel is safe and effective in high-risk NHL and met the prespecific endpoint. Results were suboptimal in patients with DLBCL.

Clinical Outcomes in Patients with Mantle Cell Lymphoma Who Received Autologous Stem Cell Transplant in the Second Line Setting

Background: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with a variable clinical outcome. The standard of care for transplant-eligible patients has been to employ autologous stem cell transplant (ASCT) in first remission and this strategy is currently being tested in the NCTN trial EA4151. The utilization and outcomes of ASCT in second line (2L) treatment is unclear and this knowledge is important for those in the non-transplant control arm in EA4151. In this report, we studied the outcomes of patients who received ASCT in 2L for relapsed/refractory (R/R) MCL. Methods: Patients with newly diagnosed MCL between August 2002 and April 2015 were enrolled in the Mayo Clinic/University of Iowa Lymphoma SPORE Molecular Epidemiology Resource (MER) prospective cohort study. Patients who received ASCT at 2L, or at 1L as a reference group, were included in this study. Clinical characteristics and treatment details were abstracted from MER and by additional chart review. Event-free Survival (EFS) was defined as time from ASCT to progression, retreatment, or death due to any cause, and overall Survival (OS) was defined as time from ASCT to death due to any cause. Survival rates were generated using the Kaplan-Meier method in Rv4.1.2. Results: Among a total of 343 patients with MCL enrolled in the MER, 177 had disease progression or relapse following 1L therapy and had complete 2L treatment information available. Eighteen patients were considered for ASCT as part of 2L therapy. Two (11%) patients did not have an adequate response to 2L induction therapy, and 1 (6%) patient did not meet criteria due to failure of the stem cell mobilization and harvest. Therefore, 15 (83%) patients went on to receive ASCT at the 2L. For the 15 patients who received ASCT at 2L, 1L therapies were R-CHOP (N=9, 60%), rituximab and bendamustine (R-bendamustine, N=2, 13%), rituximab and cladribine (N=3, 20%); 1 (7%) received surgical intervention. All 15 patients were considered for ASCT at 1L. Eight (53%) did not proceed due to inadequate response or progression of disease in the 1L setting; 2 (13%) were treated on clinical trials at 1L that precluded ASCT (one with R-CHOP with 90Yibritumomab tiuxetan and the other with R-Bendamustine); 2 (13%) were considered low risk for relapse and deferred ASCT, and 1 (7%) decided not to proceed (patient decision); the reason was unclear in 2 (13%) other patients. The median time from diagnosis to 1L disease progression/relapse was 6.4 months (range 1.1-35.8). Of the 15 patients who received ASCT as 2L therapy, the median age at time of ASCT was 58 years old, 14 (93%) were male, 13 (87%) had stage III/IV disease, and MCL international prognostic index (MIPI) score was low in 5 (63%) and intermediate in 3 (38%) (MIPI missing in 7 patients). Induction therapy at 2L prior to ASCT included R-CHOP alternating with R-DHAP (N=1, 7%), Hyper-CVAD (N=2, 13%), R-CHOP (N=3, 20%), R-DHAP (N=2, 13%), R-EPOCH (N=1, 7%), ROAD (N=1, 7%), R-ICE (N=1, 7%), R-bendamustine (N=3, 20%), and ibrutinib (N=1, 7%). At a median follow-up of 6.3 years from transplant for patients receiving ASCT at 2L, 9 patients had disease progression or relapse, and 8 patients died (3 without known progression or relapse). The median EFS was 3.8 years and the 2-year EFS rate was 59% (CI 38-91%) and 5-year EFS rate was 37% (CI 18-73%). The 2-year OS rate was 73% (CI 54-99%) and 5-year OS rate was 60% (CI 41-91%). As a reference, 113 patients in the MER received ASCT in the 1L setting. The median EFS from date of ASCT was 5.2 years and the 2-year EFS rate was 77% (CI 70-85%) and the 5-year rate was EFS 54% (CI 45-64%). The 2-year OS rate was 86% (CI 80-93%) and 5-year OS rate was 79% (CI 72-87%). Conclusion: ASCT consolidation after salvage therapy in the 2L setting appeared feasible in select patients with R/R MCL. The PFS and OS outcomes following 2L appeared reasonable. In the evolving landscape of R/R MCL treatment, it is unclear whether ASCT will still have a role. It is possible that select patients with R/R MCL would still benefit from ASCT. Larger studies, although likely limited to retrospective setting, are needed to further evaluate the feasibility, outcomes, and prognostic factors of ASCT at 2L and beyond. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immunotherapy in indolent Non-Hodgkin's Lymphoma

Treatment of non-Hodgkin lymphoma (NHL) in general has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy. NHL is divided into B cell NHL and T cell NHL. Treatment of NHL was based on the subtype of NHL and its staging. NHL is divided into aggressive and indolent NHL (iNHL). Subtypes of iNHL include: Follicular lymphoma (FL), Marginal zone lymphoma (MZL), Chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (CLL/SLL), Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, Lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, Nodal marginal zone lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL). Chemotherapy was the main stay treatment of iNHL until the emergence of Rituximab, anti-CD20 MAB targeting CD-20 surface cell antigens that are present on B-cells lymphoma and not on precursor cells, mainly efficacious in B cell iNHL, It became the mainstay treatment in follicular lymphoma (FL) as a single agent modality or in combination with chemotherapy. The anti-CD20 Rituximab played an important role in the development of the treatment of iNHL to become FDA approved in 1997. It was also proven effective in multiple other types of lymphoma. MAB through targeting the cell surface antigen leads to a direct or immune mediated cytotoxicity. This carries few side effects, including allergic reactions. Other than that, a resistance mechanism to rituximab emerged by inducing a failure in the apoptosis mechanism. Alternative mechanisms of resistance included the presence of soluble antigens that could act by binding to the antibody present before the drug itself can bind the lymphoma cell. Thus, the interest in immunotherapy grew further to explore the possibility of conjugating an immune mediated drug to a radio-sensitizing agent in order to enhance the selectivity of the drug. Here came the development of 90Y-ibritumomab tiuxetan and 131I-tositumomab. After it, humanized anti-CD20 emerged ofatumumab, IMMU106 (veltuzumab) in 2005, and ocrelizumab which are considered as second generation anti-CD20 and 3rd generation anti-CD20 include AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutuzumab). Also multiple other agents emerged targeting different surface cell antigens like CD52 (alemtuzumab), CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab], Brentuximab vedotin), CD40 (SGN-40), and CD79b (Polatuzumab). Other agents include MAB targeting T-Cells like mogamulizumab, Denileukin Diftitox and BiTEs or bispecific T cell engagers like Mosunetuzumab, Glofitamab, and Epcoritamab. Moreover, further studies came up to evaluate the role of immunotherapy in combination chemotherapy as a pathway to evade the resistance mechanisms. Side effects of the treatment were mainly infusion related adverse reactions, myelosuppression in conjugated forms leading to immunosuppression and subsequently to infectious complications. Another important aspect in immunotherapy is the half-lives of the medication which is an important factor that can influence the evaluation of the response. The MAB treatment showed important benefit in the treatment of iNHL and it continuously shows how rapidly it can develop to provide optimum care and benefit to patients with iNHL.

Megadose 90Y-ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma

AbstractAllogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCLs), although outcomes are worse in aggressive disease, and most patients will still experience relapse. Radioimmunotherapy using 90Y-ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that megadoses of 90Y-ibritumomab tiuxetan with reduced-intensity conditioning could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-ibritumomab tiuxetan (1.5 mCi/kg; maximum, 120 mCi), fludarabine, and then 2 Gy total body irradiation before HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy, including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y-ibritumomab tiuxetan activity of 113.6 mCi (range, 71.2-129.2 mCi) was administered, delivering a median of 552 cGy to the liver (range, 499-2411 cGy). The estimated 1- and 5-year progression-free survival was 55% (95% confidence interval [CI], 31-73) and 50% (95% CI, 27-69) with a median progression-free survival of 1.57 years. The estimated 1- and 5-year overall survival was 80% (95% CI, 54-92) and 63% (95% CI, 38-81) with a median overall survival of 6.45 years. Sixteen patients (80%) experienced grade 3 or higher toxicities, although nonrelapse mortality was 10% at 1 year. No patients developed secondary acute myeloid leukemia/myelodysplastic syndrome. Megadose 90Y-ibritumomab tiuxetan, fludarabine, and low-dose total body irradiation followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified end point while producing nonhematologic toxicities comparable to those of standard reduced-intensity conditioning regimens.

A randomized phase II study comparing consolidation with a single dose of 90Y ibritumomab tiuxetan vs. maintenance with rituximab for two years in patients with newly diagnosed follicular lymphoma responding to R-CHOP. Long-term follow-up results

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to 90Y-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m2 every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving 90Y-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.

Long-Term Follow up of 90y-Ibritumomab Tiuxetan, Fluadarabine and TBI Based Non-Myeloablative Allogeneic Transplant Conditioning for Persistent High-Risk B-Cell Lymphoma

Purpose:Non-myeloablative allogeneic hematopoietic cell transplantation (NMA-HCT) can provide prolonged remissions in patients with advanced B-cell lymphoma (B-NHL) via the graft versus lymphoma (GVL) effect, though inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy (RIT) can safely induce responses in B-NHL with little non-hematologic toxicity. Initial results of this approach demonstrated early safety and disease control (Blood, 2011) but with short follow up. Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions.Patients and Methods:Eligible patients with persistent CD20+ B-NHL or CLL, with HLA-matched related or unrelated donors, and adequate organ function, underwent NMA-HCT. Patients were not excluded based on cytopenia or marrow involvement with lymphoma. Conditioning included 0.4 mCi/kg (max 32mCi) 90Y-ibritumomab tiuxetan (day-14), fludarabine (days -7 to -5) and 2 Gy total body irradiation (day 0) followed by transplantation from HLA-matched related or unrelated donors along with post-grafting immunosuppression with cyclosporine and mycophenolate mofetil. Long-term follow up was updated through July 1, 2017.Results:We accrued 40 patients to this prospective trial. Baseline features included: median age 58 years (range 29-69), median prior regimens = 6 (range 3 to 12), chemosensitive disease = 6 (15%), CR pretransplant = 0 (0%), bulk >5 cm = 17 cm (range 5.2-18.6cm, 43%), >25% bone marrow involvement with B-NHL = 10 (25%, range of marrow involvement 40-95%), comorbidity score ≥1 = 35 (85%), median comorbiditiy score 3 (range 0-10), pretransplant IPI ≥3 = 21 (53%). Histologies included: indolent (18; CLL/SLL-10, follicular lymphoma-6, hairy cell leukemia-1, and marginal zone lymphoma-1), Diffuse large B-cell (DLBCL, 14), and mantle cell lymphoma (MCL, 8). Patients received HCT from 15 matched related or from 25 matched unrelated donors.Eleven of 40 patients are alive with a median follow up of 9 years (range 5.3-10.2). There were 14 (35%) deaths due to disease progression, and 14 (35%) deaths attributed to complications from HSCT. One patient died of a Merkel cell carcinoma. The median progression-free and overall survival of the entire group was 1.1 years and 2.9 years, respectively (Figure 1). The best outcomes were observed in patients with indolent histology with an estimated 5-year PFS and OS of 44% and 67% respectively (Figure 2). Early CR/PR was achieved by 7/8 (83%) patients with indolent lymphoma, 4/1 (36%) with DLBCL, and 2/2 (50%) with MCL. Long-term PFS was observed in 7 of 15 of patients with indolent NHL and 2 of 4 MCL with early remission. None of the patients with DLBCL were long-term disease free survivors regardless of early remission status. No late complications attributable to RIT (such as secondary myeloid malignancies) were observed in any patient.Conclusions:Long-term disease control of high-risk B-NHL not in CR who underwent NMA-HCT with 90Y-ibritumomab tiuxetan conditioning varied by histology. 90Y-ibritumomab tiuxetan based allografting induced high-early response rates and favorable long-term outcomes in patients with indolent histologies likely based on both the efficacy of RIT and GVL effect in this population. Only early MCL responders to RIT had long term PFS, and none of the DLBCL patients survived regardless of response. Improved strategies are needed for these populations. Our current study escalates the dose of 90Y-ibritumomab tiuxetan prior to NMA-HCT for DLBCL for this purpose. [Display omitted] DisclosuresFlowers:Pharmacyclics: Consultancy. Maloney:Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board; Celgene: Other: Advisory board; Kite Pharmaceuticals: Other: Advisory board. Press:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Gopal:Seattle Genetics: Consultancy, Research Funding.

Efficacy of 90Y-Ibritumomab Tiuxetan in the Older Population with Non-Hodgkin Lymphoma Pre-Treated with Rituximab-Based Regimens: A Single-Institution Experience

Background: The use of (90)Y-Ibritumomab tiuxetan (90Y-IT) as radioimmunotherapy in the treatment of B-cell non-Hodgkin lymphoma (NHL) has been approved for consolidation and salvage treatment of follicular and indolent lymphoma. It has also been studied in the treatment of diffuse large B-cell and mantle cell lymphoma. Toxicities primarily include myelosuppression with a risk of treatment-associated myelodysplastic syndrome (t-MDS).Methods: Retrospective cohort analysis of patients with B-cell NHL who received 90Y-IT from 2010 to 2016 at Geisinger Medical Center. 90Y-IT was administered as both consolidation and salvage treatment according to recommended dosing guidelines and cytopenia was monitored at routine intervals. A random subset of patients received maintenance Rituximab (R) at 375 mg/m2 every three months for eight doses.Results: Sixty-six patients with NHL received 90Y-IT at a median age of 68 years (range 32-91), 33 (50%) patients were male, and 37 (56%) were greater than 65 years of age. Disease subtypes included: follicular center cell (n=31, 47%), diffuse large B-cell (n=22, 33%), mantle cell (n=3, 4.5%), marginal zone (n=7, 10.6%), small lymphocytic (n=1, 1.5%), and Waldenstrom macroglobulinema (n=2, 3.03%). Thirty-three patients (50.0%) had aggressive NHL and 38 (57.6%) had stage III/IV disease. Disease status prior to 90Y-IT was as follows: CR (n=33, 50%), PR (n=22, 33.3%), and relapse/refractory (n=11, 16.7%).Twenty-nine patients (43.9%) received >1 line of treatment prior to 90Y-IT therapy. The median duration of disease prior to 90Y-IT was 18 months (range 4-184). Sixty-four patients received R prior to 90Y-IT and no patient received fludarabine-based therapy. The median PFS and OS were 27 and 30 months, respectively, for all patients. There was no significant difference in PFS and OS between patients younger and older than 65 years of age, between patients in CR and not in CR at the time of 90Y-IT, or between patients with aggressive and indolent disease.The median follow-up period was 30 months (range 15-87). The overall response rate (ORR) was 92.4% (n=61) with a PR-to-CR conversion rate of 22.7%. In the salvage setting, the ORR was 84.8%. In the relapse/refractory setting, the ORR was 72.7%. Patients not in CR at the time of 90Y-IT were found to be responsive to R maintenance: PFS improved from median 21 to 56 months and OS improved from median 28 to 66.5 months (p=0.002).Fifteen patients (22.7%) received R maintenance after 90Y-IT and demonstrated improvement in PFS (mean 26.9 to 49.8 months, p=0.0004) and OS (mean 32.7 to 55.7 months, p=0.0004). In the diffuse large B-cell lymphoma population, the patients with R maintenance had demonstrated benefit in PFS (mean 21.4 to 46.0 months, p=0.0423) and OS (mean 23.7 to 46.0 months, p=0.0417). Among the indolent lymphomas, the addition of R maintenance demonstrated improvement in OS from 35.4 to 57.1 months (p=0.0197).Among patients with grade 3/4 hematologic toxicities, six (9.1%) required blood transfusion, four (6.1%) needed platelet transfusion, and 17 (25.8%) received pegfilgastrim. Two patients required hospitalization for febrile neutropenia. Ten patients (15.2%) relapsed after 90Y-IT at median 65.0 months, and one patient (1.5%) developed t-MDS (del 5q, del 20q) 54 months after treatment. There were 14 deaths (six were secondary to progressive lymphoma or chemotherapy-related neutropenic sepsis).Conclusions: This is one of the largest single-center experiences of 90Y-IT administered to a predominantly elderly population with B-cell NHL pre-treated with Rituximab-based regimens. This study demonstrates the safety and feasibility of 90Y-IT in the elderly population with manageable toxicity, with no increased risk of treatment-related myelodysplastic events. This study also demonstrated PFS and OS benefit in administering Rituximab maintenance post 90Y-IT to both indolent and aggressive B-cell NHL and should be further investigated in future studies. DisclosuresKhan:Spectrum Pharmaceuticals, Inc.: Other: Advisory Board, Speakers Bureau.

Prospective SPECT-CT Organ Dosimetry-Driven Radiation-Absorbed Dose Escalation Using the In-111 (111In)/Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) Theranostic Pair in Patients with Lymphoma at Myeloablative Dose Levels.

Simple SummaryWe prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin’s lymphoma using the theranostic pair of 111In and 90Y anti-CD20 ibritumomab tiuxetan (Zevalin®) at myeloablative radiation-absorbed doses with autologous stem cell support. Unlike most routine dose escalation approaches, our approach used patient-individualized measurements of organ radiation absorbed dose from the tracer study, with patient-specific adjustments of the injected therapy dose to deliver a pre-specified radiation absorbed dose to the liver. Our approach was feasible, stem cell engraftment was swift, resulted in an 89% tumor response rate in treated patients, demonstrated over 3 fold variability in liver dosimetry/injected activity among patients, allowed us to exceed the FDA approved administered activity by over 5 fold and demonstrated the normal liver maximum tolerated dose to exceed 28 Gy. Dose escalation was not continued due to lack of drug availability. With modern dosimetry approaches, patient specific dosimetry-driven radiation dose escalation is feasible, allows adjustment of administered activity for heterogeneous pharmacokinetics and allows marked dose escalation vs. non-dosimetry driven approaches.Purpose: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin’s lymphoma using the theranostic pair of 111In and 90Y anti-CD20 ibritumomab tiuxetan (Zevalin®) at myeloablative radiation-absorbed doses with autologous stem cell support. We also assessed acute non-hematopoietic toxicity and early tumor response in this two-center outpatient study. Methods: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts > 75,000/mm3, and <35% tumor involvement in the marrow were treated with Rituximab (375 mg/m2) weekly for 4 consecutive weeks, then one dose of cyclophosphamide 2.5 g/m2 with filgrastim 10 mcg/kg/day until stem cell collection. Of these, 18 patients with successful stem cell collection (at least 2 × 106 CD34 cells/kg) proceeded to RIT. A dosimetric administration of 111In ibritumomab tiuxetan (185 MBq) followed by five sequential quantitative planar and one SPECT/CT scan was used to determine predicted organ radiation-absorbed dose. Two weeks later, 90Y ibritumomab tiuxetan was administered in an outpatient setting at a cohort- and patient-specific predicted organ radiation-absorbed dose guided by a Continuous Response Assessment (CRM) methodology with the following cohorts for dose escalation: 14.8 MBq/kg, and targeted 18, 24, 28, and 30.5 Gy to the liver. Autologous stem cell infusion occurred when the estimated marrow radiation-absorbed dose rate was predicted to be <1 cGy/h. Feasibility, short-term toxicities, and tumor response were assessed. Results: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of 90Y (range: 12.1–41.4 MBq/kg)) of ibritumomab tiuxetan that was required to deliver 10 Gy to the liver. Infused stem cells engrafted rapidly. The most common treatment-related toxicities were hematological and were reversible following stem cell infusion. No significant hepatotoxicity was seen. One patient died from probable treatment-related causes—pneumonia at day 27 post-transplant. One patient at dose level 18 Gy developed myelodysplastic syndrome (MDS), 4 patients required admission post-90Y RIT for febrile neutropenia, 16/18 patients receiving 90Y ibritumomab tiuxetan (89%) responded to the therapy, with 13 CR (72%) and 3/18 PR (17%), at 60 days post-treatment. Two patients had progressive disease at sixty days. One patient was lost to follow-up. Median time to progression was estimated to be at least 13 months. MTD to the liver is greater than 28 Gy, but the MTD was not reached as the study was terminated due to unexpected discontinuation of availability of the therapeutic agent. Conclusions: Patient-specific outpatient 90Y ibritumomab tiuxetan RIT with myeloablative doses of RIT up to a targeted 30.5 Gy to the liver is feasible, guided by prospective SPECT/CT + planar imaging with the theranostic pair of 111In and 90Y anti-CD20, with outpatient autologous stem cell transplant support. Administered activity over 5 times the standard FDA-approved activity was well-tolerated. The non-hematopoietic MTD in this study exceeds 28 Gy to the liver. Initial tumor responses were common at all dose levels. This study supports the feasibility of organ dosimetry-driven patient-specific dose escalation in the treatment of NHL with stem cell transplant and provides additional information on the radiation tolerance of the normal liver to radiopharmaceutical therapy.

Efficacy and safety of new anti-CD20 monoclonal antibodies versus rituximab for induction therapy of CD20+ B-cell non-Hodgkin lymphomas: a systematic review and meta-analysis

Rituximab combined with chemotherapy is the first-line induction therapy of CD20 positive B-cell non-Hodgkin lymphomas (CD20+ B-NHL). Recently new anti-CD20 monoclonal antibodies (mAbs) have been developed, but their efficacy and safety compared with rituximab are still controversial. We searched MEDLINE, Embase, and Cochrane Library for eligible randomized controlled trials (RCTs) that compared new anti-CD20 mAbs with rituximab in induction therapy of B-NHL. The primary outcomes are progression-free survival (PFS) and overall survival (OS), additional outcomes include event-free survival (EFS), disease-free survival (DFS), overall response rate (ORR), complete response rate (CRR) and incidences of adverse events (AEs). Time-to-event data were pooled as hazard ratios (HRs) using the generic inverse-variance method and dichotomous outcomes were pooled as odds ratios (ORs) using the Mantel–Haenszel method with their respective 95% confidence interval (CI). Eleven RCTs comprising 5261 patients with CD20+ B-NHL were included. Compared with rituximab, obinutuzumab significantly prolonged PFS (HR 0.84, 95% CI 0.73–0.96, P = 0.01), had no improvement on OS, ORR, and CRR, but increased the incidences of serious AEs (OR 1.29, 95% CI 1.13–1.48, P < 0.001). Ofatumumab was inferior to rituximab in consideration of ORR (OR 0.73, 95% CI 0.55–0.96, P = 0.02), and had no significant differences with rituximab in regard to PFS, OS and CRR. 131I-tositumomab yielded similar PFS, OS, ORR and CRR with rituximab. 90Y-ibritumomab tiuxetan increased ORR (OR 3.07, 95% CI 1.47–6.43, P = 0.003), but did not improve PFS, DFS, OS and CRR compared with rituximab. In conclusion, compared with rituximab in induction therapy of CD20+ B-NHL, obinutuzumab significantly improves PFS but with higher incidence of AEs, ofatumumab decreases ORR, 90Y-ibritumomab tiuxetan increases ORR.

The standardized uptake value calculated from 111In-ibritumomab tiuxetan single-photon emission computed tomography/computed tomography is a useful predictor of the clinical response in patients treated by 90Y- ibritumomab tiuxetan therapy.

90Y-Ibritumomab tiuxetan (IT) therapy is a radioimmunotherapy for indolent B-cell lymphoma. Several predictors of insufficient therapeutic effects have been reported. We performed a retrospective study at a single institute to investigate whether 111In SPECT/CT can predict the therapeutic effects and grade of cytopenia due to 90Y-IT therapy. We enrolled 16 consecutive patients who underwent 90Y-IT therapy, including 15 who underwent 111In-IT SPECT/CT. After 90Y-IT therapy, there were 4 patients in complete remission in whom the lesion SUVmax on 111In-IT SPECT/CT and soluble IL-2 receptor were significantly lower than those of the other patients (P<0.05 and P<0.05, respectively). Based on the log-rank test of factors associated with the progression-free survival (PFS), ≥2 previous treatment regimens was significantly associated with a poor prognosis (P<0.05). The SUV on 111In-IT SPECT/CT may be a good predictor of the clinical response to 90Y-IT therapy.

Systematic Literature Review of the Clinical Efficacy, Safety, and Patient-Reported Outcomes of Treatments in Patients with Relapsed or Refractory Follicular Lymphoma after Two Prior Therapies

Introduction For patients (pts) with relapsed or refractory follicular lymphoma (r/r FL) beyond front-line therapy, there is no well-defined standard of care (SOC) treatment, especially in the third-line or later (3L+) setting. Treatment decisions for symptomatic patients depend on comorbidities, extent of disease, lines of prior therapy and duration of response to initial anti-CD20 containing treatment. Treatment options for 3L+ may include similar options to the ones in earlier lines, with a preference for non-cross-resistant schemes. Recently, a plethora of new compounds are being studied in clinical trials. A systematic literature review (SLR) was conducted to identify relevant evidence on clinical outcomes in pts with r/r FL, including conventional treatments and emerging compounds, within the 3L+ setting. Methods We performed a SLR on March 17, 2020. Clinical trials and observational studies were searched through Embase, PubMed, and Cochrane Central Register of Controlled Clinical Trials from 1998 to 2020, followed by relevant conference proceedings and regulatory documents. Evidence assessing any intervention as 3L+ FL and published in English language was included. If a study included broader indolent non-Hodgkin's lymphoma (iNHL) pts, only FL data was reported; if a study included pts with fewer than 3L+, 3L+ data was included, with mixed line results excluded. Conventional treatments, defined as approved or clinical guideline recommended treatments, included anti-CD20 monoclonal antibody (mAb)-containing regimen, mAb alone, chemotherapy alone, phosphatidylinositol 3-kinase (PI3K) inhibitors (idelalisib, copanlisib, duvelisib), lenalidomide + rituximab (R2), radio-immunotherapy (RIT) with yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, autologous and allogeneic stem cell transplantation (auto- and allo-SCT). Emerging compounds included new treatments that are not approved but were tested in the context of clinical trials (bruton tyrosine kinase inhibitors, bortezomib, polatuzumab vedotin, daratumumab, inotuzumab, bi-specific T-cell engaging CD19 mAb, anti-CD19 chimeric antigen receptor T-cell [CAR-T] therapy). Results Of the 3747 publications identified, 74 studies assessing 26 treatment regimens, including conventional ones like rituximab (R)-containing immunochemotherapy to emerging compounds such as CAR-T therapies, were selected. Across the conventional regimens, 7 studies reported clinical trial data with relatively large 3L+ FL populations (Table 1). With R monotherapy, PI3K inhibitors and tazemetostat, the reported complete response (CR) rates and overall response rates (ORR) ranged from 1-20% and 34-77%, while median duration of response (mDOR) ranged between 7.9-16.3 months. Three clinical trials with PI3K inhibitors reported proportions of pts achieving a response of at least 6 months in duration ranging from 18-30%; median progression-free survival (mPFS) ranging from 8.3-11.2 months. For tazemetostat, mPFS was 11.0 months in EZH2 mutant vs 5.7 months in wild-type FL. With allo-SCT, 2-yr PFS rate was 88% and 57% for pts with CR and PR, respectively. Overall survival (OS) data varied: median overall survival (mOS) was 28-38 months for PI3K inhibitors while mOS was up to 85 months after allo-SCT, despite high non-relapse mortality (NRM) rates with most common causes of death being graft-versus-host disease (GvHD) and infections. Safety profiles were also different across treatments, with most common side effects being hepatotoxicity, diarrhea and infections (PI3K inhibitors) to GvHD (allo-SCT). Three trials presented patient-reported outcomes (PRO) data, all using the Functional Assessment of Cancer Therapy (FACT) questionnaire. Two studies with PI3K inhibitors demonstrated favorable or clinically significant improvement on pts quality of life (QoL), but 1 allo-SCT trial did not show a significant difference between baseline and 2 years post-transplant scores. Conclusion To our knowledge, this is the first SLR focusing on 3L+ treatments of FL. Heterogeneity in study design, patient population, safety profile and reported outcomes make it challenging to identify an optimal treatment regimen for FL in the 3L+ setting. More PRO data are needed considering the important role pt QoL plays in treatment selection. Disclosures Ma: Novartis:Current Employment.Kaur:Novartis:Current Employment.Zhao:Novartis:Current Employment.Zhang:Novartis:Current Employment.Ramos:Novartis:Current Employment.Kumar:Novartis:Current Employment.John:Novartis:Current Employment.Bubuteishvili Pacaud:Novartis:Current Employment.Forcina:Novartis:Current Employment.

Yittrium 90 Ibritumomab Tiuxetan (Zevalin®) in the Treatment of Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphoma; Integrated Analysis of Three Japanese Institution’s Experience with Improvement Trend of the Long-Term Responses over a 10 Year Study Period

Background This study investigated all cases treated by Yittrium 90 Ibritumomab Tiuxetan (90Y-IT, Zevalin®) for relapsed or refractory indolent B-cell non-Hodgkin lymphoma at the three Japanese institutions between 2008/10/14 and 2018/5/15. 90Y-IT is the only radioimmunoconjugate agent available on the Japanese market since August 2008. J3Zi study (UMIN-CTR: 000037105) created integrated dataset of 90Y-IT treatment, and subjects were requiring at least two years follow-up period. Methods A total of 347 cases were registered and 316 patients of the per-protocol set were analyzed creating the integrated dataset. Overall response rate (ORR) and complete response rate (CR) were evaluated using positron emission tomography (PET, 84%), computed tomography (CT, 8%) or other methods (8%) at 8-12 weeks after 90Y-IT treatment. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. The prognostic factors of PFS and OS were analyzed using Cox regression analysis. Results All patients had previously been administered with median of 2 (mean 3.9) chemotherapeutic regimens at a mean age of 65 years. The majority of cases were follicular lymphoma (FL) patients (75%) followed by mucosa-associated lymphoid tissue lymphoma/marginal zone lymphoma (MALT/MZL) patients (13%). The ORR was 89% and CR was 66%. The Kaplan-Meier survival curves of PFS and OS extending over the 10 year study period were shown in Figure 1A. The progression free 2-year cumulative survival rate (PFS 2-years) was 61%. The PFS 2-years of the early phase (2008/10/14-2013/7/9) defined as the cut-off date of the previous report, and the late phase (2013/7/10-2018/5/15) were 51% and 73%, respectively (p&amp;lt;0.0001). The overall 5-year cumulative survival rate (OS 5-years) was 77%. The OS 5-years of the early phase and the late phase were 73% and 83% respectively (p=0.0565). The evident improvement trend of the long-term responses during the 10 year study period was demonstrated (Figure 1B). Among several prognostic factors, treatment response (CR/non-CR), number of prior treatments (≦2/≧3), sIL-2R (≦500/&amp;gt;500 U/ml) and progression of disease within 24 months after the first-line treatment initiation (POD24, no/yes), were the significant factors (univariate analysis, p&amp;lt;0.05) for both PFS and OS. The number of prior treatment and POD24 showed correlation with each other, but also showed a significant different between the early phase and the late phase of the study, thus the factors resulting in the improvement trend shown in figure 1 have to be carefully discussed. In 316 cases, 26 (8.2%) of second primary malignancy (SPM) including 9 (2.8%) haematological malignancy (7 myelodysplastic syndrome, 1 acute myeloid leukemia and 1 chronic myeloid leukemia) were observed and 1 death (treatment related Sepsis) in 15 infection cases recorded. All the long-term follow-up safety reports were consistent with the previous studies of the relapsed/refractory low-grade follicular lymphoma, and there was no obvious trend associated with radioimmunoconjugate therapy. Conclusions The study represents the largest reported cohort for therapeutic use of 90Y-IT in Japan. The improvement trend of the long-term responses (PFS and OS) during the 10 year study period was demonstrated. The response and survival data in this large real-world cohort is superior to the previously published 90Y-IT trial data including the US phase-3 trial conducted 20 years ago. The factors resulting in this improvement trend have to be carefully assessed in attempt to achieve better outcomes for 90Y-IT treatment in future. Figure-1 Legend (A) Overall survival (OS, black line) and progression-free survival (PFS, gray line) with 95% confidence intervals (n=316), Kaplan-Meier method. (B) Improvement trend of the long-term (2-year) treatment responses (PFS and OS) over the 4 periods of 90Y ibritumomab tiuxetan treatment (n=316) dated; 2008/10/14-2011/7/9 (n=91), 2011/7/10-2013/7/9 (n=86), 2013/7/10-2015/7/10 (n=60), 2015/7/10-2018/5/15 (n=79). Disclosures This study was sponsored by Mundipharma. Data management and statistical analysis under the direction of investigators Ilseung Choi, Masaya Okada and Tomoki Ito was provided by L Data Science, Co., Ltd. and was funded by Mundipharma. Figure Disclosures No relevant conflicts of interest to declare.

Impact of Treatment Sequencing on Outcomes and Costs in Relapsed Follicular or Other Low Grade B-Cell Non-Hodgkin Lymphoma - Results of an Evidence-Based Budget Impact Model

Introduction: The choice of initial therapy in follicular lymphoma can be a key determinant in future therapy, as irreversible toxicities with first line regimens can impact the patient's ability to tolerate future treatment. Minimizing drug exposure will result in less frequent occurrence of significant adverse events and associated treatment costs. In the era of COVID-19 pandemic, there is additional benefit to minimizing the number of patient visits and hospital admissions. Limited information exists related to the outcomes and associated costs of existing treatment sequences. Additionally, treatment administration at different types of clinical sites results in varied reimbursement models, making informed evaluation of clinical and financial evidence challenging. Methods: The current study applies a budget impact model methodology in order to describe the associated impact of treatment selection and sequencing on outcomes and costs in the treatment of relapsed or refractory low-grade follicular lymphoma in first line therapy followed by Consolidation and also in first line therapy to second line therapy. Key model inputs included: Number of treatment cycles, number of days a treatment was received, duration of response (DOR), rate of side effects and associated costs, and total treatment costs, including drugs, medical treatment, laboratory testing and adverse event costs. Treatment outcomes were based on the published literature that summarized the overall response rate, median DOR, and toxicity. Treatment regimen costs were evaluated based on payer pricing, Wholesale Acquisition Cost (WAC), Average Selling Price (ASP) and Average Wholesale Price (AWP) and modified to adjust for weight-based dosing and negotiate payer reimbursement rates. Associated medical costs for medical treatment and supportive care were estimated using current Medicare fee schedule rates. Included were seven options for first line therapy of follicular lymphoma from 2020 NCCN Guidelines - (Bendamustine + rituximab (BR); Bendamustine + Obinutuzumab (OB); CHOP rituximab (RCHOP); CHOP + Obinutuzumab (OCHOP); CVP+ rituximab (RCVP); CVP + Obinutuzumab (OCVP); Lenalidomide + rituximab (R2)), followed by three for Consolidation (Rituximab maintenance (RM); Obinutuzumab maintenance (O); Radioimmunotherapy (RIT with 90 Y-ibritumomab tiuxetan (Y90-IT, Zevalin)) and three Second Line therapy options (RIT; Lenalidomide only; Lenalidomide + Obinutuzumab (LO)). Results: The treatment sequence of first line BR followed by Consolidation with RIT Y90 (Zevalin) had the longest predicted DOR (2586 days). The associated treatment sequence costs were $212,485 for BR followed by Y90-IT, compared with $233, 388 for BR followed by rituximab maintenance, which had a predicted DOR of 2478 days. The predicted DOR for treatment sequences starting with OCHOP, OCVP and RCHOP and followed by RIT with Y90-IT was approximately 1000 days less than BR followed by Y90-IT for a cost difference of $4,421, $12,914 and $25,826, respectively. The treatment sequence of first line BR followed by Second Line RIT Y90-IT had the second longest predicted DOR of 2586 days at costs of $212,485, compared to 2778 days for BR followed by LO, at a total sequence costs of $796,695. Conclusion: The use of Y90-IT in Consolidation or Second Line treatment demonstrated desired patient outcomes at one of the lowest cost profiles. Additionally, Y90-IT administration can be completed in only two clinic visits, reducing patient travel and contact, improving safety in an era of COVID-19 precautionary measures and reducing cost. Figure 1. Duration of Response and Total Sequence Costs for Twelve First Line to Consolidation and First Line to Second Line Treatment Regimens. Disclosures McBride: Merck: Speakers Bureau; Coherus BioSciences: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy.

Efficacy and Safety of New Anti-CD20 Monoclonal Antibodies Versus Rituximab for Induction Therapy of CD20+ B-Cell Non-Hodgkin Lymphomas: A Systematic Review and Meta-Analysis

Rituximab combined with chemotherapy is the first-line induction therapy of CD20positive B-cell non-Hodgkin lymphomas (CD20+ B-NHL). Recently new anti-CD20 monoclonal antibodies (mAbs) have been developed, but their efficacy and safety compared with rituximab are still controversial. We aimed to assess the efficacy and safety of new anti-CD20 mAbs compared with rituximab in the induction therapy of CD20+ B-NHL with a systematic review and meta-analysis. We searched MEDLINE, Embase, and Cochrane Library for eligible randomised controlled trials (RCTs) that compared new anti-CD20 mAbs with rituximab in induction therapy of B-NHL. The primary outcomes are progression-free survival (PFS) and overall survival (OS), additional outcomes include event-free survival (EFS), disease-free survival (DFS), overall response rate (ORR), complete response rate (CRR) and incidences of adverse events (AEs). Time-to-event data were pooled as hazard ratios (HRs) using the generic inverse-variance method and dichotomous outcomes were pooled as odds ratios (ORs) using the Mantel-Haenszel method with their respective 95% confidence interval (CI). Eleven RCTs comprising 5,261 patients with CD20+ B-NHL were included. Compared with rituximab, obinutuzumab significantly prolonged PFS (HR 0.84, 95% CI 0.73-0.96, P = 0.01), had no improvement on OS, ORR, and CRR, but increased the incidences of serious AEs (OR 1.29, 95%CI 1.13-1.48, P &amp;lt; 0.001). Ofatumumab was inferior to rituximab in consideration of ORR (OR 0.73, 95% CI 0.55-0.96, P = 0.02), and had no significant differences with rituximab in regard to PFS, OS and CRR. 131I-tositumomab yield similar PFS, OS, ORR and CRR with rituximab. 90Y-ibritumomab tiuxetan increased ORR (OR 3.07, 95%CI 1.47-6.43, P = 0.003), but did not improve PFS, DFS, OS and CRR compared with rituximab. In conclusion, compared with rituximab in induction therapy of CD20+ B-NHL, obinutuzumab can significantly improves PFS but with higher incidence of AEs, ofatumumab decrease ORR, 90Y-ibritumomab tiuxetan increase ORR. Disclosures No relevant conflicts of interest to declare.

Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

Radioimmunotherapy in Non-Hodgkin's Lymphoma: Retrospective Adverse Event Profiling of Zevalin and Bexxar.

The development of monoclonal antibodies has dramatically changed the outcome of patients with non-Hodgkin’s lymphoma (NHL), the most common hematological malignancy. However, despite the satisfying results of monoclonal antibody treatment, only few NHL patients are permanently cured with single-agent therapies. In this context, radioimmunotherapy, the administration of radionuclides conjugated to monoclonal antibodies, is aimed to augment the single-agent efficacy of immunotherapy in order to deliver targeted radiation to tumors, particularly CD20+ B-cell lymphomas. Based on evidence from several trials in NHL, the radiolabeled antibodies 90Y-ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals) and 131I-tositumomab (Bexxar, GlaxoSmithKline) received FDA approval in 2002 and 2003, respectively. However, none of the two radioimmunotherapeutic agents has been broadly applied in clinical practice. The main reason for the under-utilization of radioimmunotherapy includes economic and logistic considerations. However, concerns about potential side effects have also been raised. Driven by these developments, we performed retrospective analysis of adverse events reporting Zevalin or Bexxar, extracted from the FDA’s Adverse Event Reporting System (FAERS) and the World Health Organization’s VigiBase repository. Our results indicate that the two radioimmunotherapeutic agents have both related and distinct side effect profiles and confirm their known toxicological considerations. Our work also suggests that computational analysis of real-world post-marketing data can provide informative clinical insights. While more prospective studies are necessary to fully characterize the efficacy and safety of radioimmunotherapy, we expect that it has not yet reached its full therapeutic potential in modern hematological oncology.

Predictive value of pre-treatment FDG PET in patients with non-Hodgkin lymphoma treated with radioimmunotherapy: a systematic review

We aimed to systematically review studies addressing the value of baseline FDG PET as predictive biomarker for response to RIT in patients with NHL. We searched (last update: March 2019) the databases PubMed, PMC, Google Scholar and Medline using both as text and as MeSH (Medical Subject Headings) terms the following: “positron emission tomography—PET”, “PET/CT”, “FDG”, “18F-fluorodeoxyglucose”, and “radioimmunotherapy”, ‘90Y-ibritumomab tiuxetan” and “non-Hodgkin lymphoma” and “follicular lymphoma”. Among all the retrieved articles, we selected only those specifically analyzing role, predictive and overall value of pretreatment FDG PET in patients with NHL submitted to RIT. The initial search retrieved seventy articles, however, only eight specifically analyzed the predictive value of pretreatment FDG PET in patients with NHL submitted to RIT and were thus discussed. Eight studies in 254 patients evaluated the role of FDG PET as a predictor of response prior to RIT. Despite several methodological issues, patients- and lesion-based analyses carried out to-date seem to suggest a relevant prognostic role of both morphological computed tomography and metabolic imaging. Although it is still not possible to specifically define the best PET-based predictor (i.e. SUVmax, TLG, MTV), FDG-PET is a promising tool for a more accurate and individualized selection of NHL patients candidates to RIT. The availability of FDG PET examinations in homogenous group of patients included in already completed clinical trials might be used in the next future also to specifically assess the prognostic value of baseline FDG PET in patients treated with RIT based on the study design.

Consolidation with 90Y ibritumomab tiuxetan radioimmunotherapy in mantle cell lymphoma patients ineligible for high dose therapy: results of the phase II multicentre Polish Lymphoma Research Group trial, after 8-year long follow-up

Polish Lymphoma Research Group performed a phase-II trial to test whether 90Y ibritumomab tiuxetan radioimmunotherapy (Y90) may constitute an alternative consolidation for mantle cell lymphoma patients unfit for high-dose therapy. Forty-six patients were consolidated with Y90 following response to the 1st (n = 34) or 2nd line (n = 12) (immuno)chemotherapy. Majority of the patients had advanced disease (stage IV and presence of B-symptoms in 85% and 70%, respectively) and high MIPI (5.8, range 4–7). Consolidation with Y90 increased the complete remission (CR) rate obtained by the 1st line therapy from 41% to 91% and allowed for median PFS of 3.3 and OS of 6.5 years. In the first relapse, CR rate increased from 16% to 75%, while median PFS and OS totaled 2.2 and 6.5 years, respectively. At 8 years, 30% of patients, consolidated in the 1st line CR were alive, without relapse. Toxicity associated with Y90 is manageable, more severe after fludarabine-based regimens.