Radioimmunotherapy Consolidation Research Articles

A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG Study S1001 (NCT01359592)

A Phase II Intergroup Trial of PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG Study S1001 (NCT01359592)

PET-Directed Therapy for Patients with Limited-Stage Diffuse Large B-Cell Lymphoma - Results of Intergroup Nctn Study S1001

PET-Directed Therapy for Patients with Limited-Stage Diffuse Large B-Cell Lymphoma - Results of Intergroup Nctn Study S1001

R-CHOP, radioimmunotherapy, and maintenance rituximab in untreated follicular lymphoma (SWOG S0801): a single-arm, phase 2, multicentre study

Despite an abundance of therapeutic options, advanced-stage follicular lymphoma remains incurable. Furthermore, the ideal sequence and absolute benefit of post-induction therapy is unclear. We designed SWOG S0801 to assess the efficacy and safety of consolidative radioimmunotherapy and sequential maintenance rituximab following chemoimmunotherapy. For this single-arm, phase 2, multicentre study, we enrolled patients aged 18 years and older with a diagnosis of stage III, IV, or bulky stage II follicular lymphoma, grades 1, 2, or 3a, who had not received previous therapy, from from 20 institutions within the United States National Cancer Institute Clinical Trials Network. Patients were assigned to a 5-year treatment plan consisting of R-CHOP (rituximab plus cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], vincristine [1·4 mg/m2], and prednisone or prednisolone [100 mg]) every 21 days for up to six cycles, with rituximab 375 mg/m2 given on day 1 of cycles 1-4, followed by 131iodine tositumomab radioimmunotherapy and subsequent maintenance rituximab 375 mg/m2 within 12 weeks after the sixth cycle of R-CHOP, every 3 months for up to 4 years. The primary endpoint was 3-year progression-free survival in the intention-to-treat population. Efficacy and safety analyses were done in the intention-to-treat population and the per-protocol population. This trial was registered with ClinicalTrials.gov, number NCT00770224. Between April 1, 2009, and Dec 15, 2010, we enrolled 84 evaluable patients, of whom 73 completed R-CHOP and radioimmunotherapy. Of 69 patients who registered to maintenance therapy, only 41 completed the 4-year rituximab maintenance treatment. Progression-free survival at 3 years was 90% (95% CI 82-95). The most common grade 3 or worse adverse events included neutropenia in 48 (57%) patients, leucopenia in 34 (40%) patients, thrombocytopenia in 17 (20%) patients, and febrile neutropenia in 14 (17%) patients. Nine patients had possible treatment-related deaths during the study from secondary or unknown causes (n=3), cirrhosis (n=1), cardiac arrest (n=1), and secondary malignancies (n=4). Secondary malignancies occurred in seven patients, including two sarcomas, two colorectal carcinomas, two acute myelogenous leukaemias, and one case of renal-cell carcinoma. SWOG S0801 showed near universal responses following chemoimmunotherapy and radioimmunotherapy. However, most discontinuations occurred during maintenance therapy, suggesting that rituximab over a 4-year span is not feasible for many patients. Nonetheless, this sequential therapeutic strategy resulted in good overall outcomes for patients, including a low incidence of early disease progression. The National Cancer Institute and GlaxoSmithKline.

Phase 2 study of CHOP-R-14 followed by 90Y-ibritumomab tiuxetan in patients with previously untreated diffuse large B-cell lymphoma.

The aim of this open-label, single-center, phase 2 study was to assess the efficacy and safety of dose-dense CHOP-R-14 followed by 90Y-ibritumomab radioimmunotherapy (RIT) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by 90Y-ibritumomab tiuxetan consolidation. Sixteen patients completed RIT consolidation (rituximab 250 mg/m2 on day 1 and day 7, 8, or 9, followed by a single injection of 90Y-ibritumomab). Complete response (CR) rates of 75 and 95% were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response after CHOP-R-14 converted to CR following treatment with RIT. With a median follow-up of 89.7 months, the progression-free and overall survival rates for the cohort were 75 and 85%, respectively. Hematological adverse events were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption. Therefore, this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity.

Sequential RCHOP, Radioimmunotherapy and Rituximab Maintenance Improves Early Outcomes in Advanced Stage Follicular Lymphoma: 5 Year Outcomes from SWOG 0801

Background:Despite an abundance of effective therapeutic options, advanced stage follicular lymphoma (FL) remains incurable. Further, prospective trials consistently demonstrate that 20% of patients relapse within 2 years and ultimately have an inferior survival (Casulo 2015). Maintenace rituximab following chemoimmunotherapy induction is able to delay disease progression but has not demonstrated a benefit in overall survival (Salles 2011). Additionally, radioimmunotherapy (RIT) is one of the most effective single agent options in FL but is not commonly utilized as part of upfront treatment. As such, the role of both remains unclear. Based on results demonstrated with RIT consolidation in SWOG 0016 and the efficacy of rituximab maintenance, SWOG 0801 was designed as a phase 2 single arm trial, conducted to evaluate the utility of consolidative RIT and sequential maintenance rituximab following chemoimmunotherapy induction.Methods:Eligible patients (pts) with treatment naïve stage III/IV or bulky stage II FL received RCHOP for 6 cycles (without rituximab for the last 2 cycles) followed by iodine-131 tositumomab and subsequent rituximab administered every 3 months for up to 4 years. The primary endpoint was progression-free survival (PFS) at 3 years. Secondary endpoints included 5-year overall survival (OS), overall response rate (ORR), and safety.Results:Of 87 pts registered to this study, 85 were deemed eligible following central pathologic review. One additional patient withdrew consent and received no treatment on protocol.Of the 84 evaluable patients, the median age was 52 years (range 29 - 80) ) and 18%, 40%, and 42%had low, intermediate and high risk FLIPI scores, respectively. Seventy-three pts completed RCHOP and I-131 tositumomab. Grade ≥3 AEs occurring ≥5% of pts included neutropenia (57%), leukopenia (40%), thrombocytopenia (20%), febrile neutropenia (17%), fatigue (10%), neuropathy (8%), anemia (7%) and hyperglycemia (5%). Reasons for discontinuation included refusal of tositumumab (6 pts), prolonged myelosuppression (2 pts), ascites (1pt), inability to provide tositumumab (1 pt), and an unrelated lower extremity wound (1 pt). Following induction and RIT, 59 complete responses and 23 partial responses were observed, for a ORR of 99% (95% CI: 93.5%, 99.9%)Sixty nine eligible patients registered to maintenance therapy with 42 completing the 4 year treatment plan. The only grade ≥3 AE that occurred in ≥5% of pts was leukopenia (5%). Twenty-seven pts discontinued maintenance therapy, including 11 in the first 2 years and 16 in the last 2 years, due to the following reasons: infection (8 pts), patient preference (8 pts), deaths (2 pts), treatment delay (2 pts), secondary solid tumors (2 pts), bowel perforation (1 pt), joint pain (1 pt), hepatic transaminase elevation (1 pt), insurance refusal (1 pt), and dose error (1 pt).Four additional secondary malignancies were reported following completion of therapy including solid tumors (3 pts) and AML (1 pt). To date, 9 deaths have occurred due to secondary malignancies (3 pts), unknown etiology (3 pts), cardiac arrest (2 pts) and non-alcoholic cirrhosis (1 pt).After median follow-up of 5.6 years (range 3-7 years), 17 events have occurred including 9 pts experiencing progressive FL resulting in a progression free survival of 90% (95% CI: 81.9%, 95.1%) at 3 years and 84%(95% CI: 74.5%, 90.6%) at 5 years (Figure). Three-year overall survival is 96% (95% CI: 89.3%, 98.8%) and 5-year overall survival is 94% (95% CI: 86.2%, 97.5%).Conclusions:SWOG 0801 demonstrates near universal responses following chemoimmunotherapy and RIT. This sequential therapeutic strategy appears to improve early outcomes as 94% of pts are without disease progression at 2 years, consistent with the best results ever demonstrated for FL in the National Clinical Trials Network. However, the majority of discontinuations occurred during maintenance suggesting that rituximab over a 4-year span is not feasible for many patients due to cumulative toxicity. Future studies investigating precision strategies in high-risk FL may consider an aggressive chemoimmunotherapy induction and RIT consolidation platform to overcome early FL progression given these promising outcomes.Support: NIH/NCI grants CA180888, CA180819, and in part by GlaxoSmithKline. [Display omitted] DisclosuresBarr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Smith:Amgen: Other: Educational lecture to sales force; Juno: Consultancy; Pharmacyclics: Consultancy; AbbVie: Consultancy; Portola: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; TGTX: Consultancy. Gopal:Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy. Persky:Merck: Research Funding; Gilead: Speakers Bureau. Press:Roche / Genentech: Consultancy, Research Funding. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Other: Data Safety Monitoring Committee.

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

Short-course R-CHOP followed by (90)Y-Ibritumomab tiuxetan in previously untreated high-risk elderly diffuse large B-cell lymphoma patients: 7-year long-term results.

An update at 7 years was conceived for our multicenter phase II study in which 55 elderly high-risk untreated diffuse large B-cell lymphoma patients were treated with 90Y-ibritumomab tiuxetan after a short course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) as long-term follow-up analyses of this combined therapeutic modality are lacking. The overall response rate to the entire regimen was 80%, including 73% (40/55) of complete response (CR) rate and 7% (4/55) of partial response rate. At the time of writing, 24/55 (43.6%) patients experienced a progression disease and 20 of 40 (50%) patients who obtained a CR are still alive in continuous CR. With a median follow-up of 7 years, the disease-free survival was 43.3% and the progression-free survival was 36.1%. The overall survival at 7.9 years was 38.9% (27 deaths mainly because of lymphoma). Two patients developed secondary hematological malignancies, an acute myeloid leukemia and a myelodysplastic syndrome, at 4 and 3 years from radioimmunotherapy, respectively. Our data confirm the feasibility, efficacy and safety of four cycles of R-CHOP followed by radioimmunotherapy consolidation even in the long term: this combination allows dispensing less chemotherapy in a frail group of patients without invalidating response quality and duration.

Consolidative Radioimmunotherapy After Chemoimmunotherapy in Patients With Histologic Transformation of Indolent Non-Hodgkin Lymphoma.

Histologic transformation (HT) of indolent non-Hodgkin lymphomas is an event that results in considerable morbidity and mortality. The introduction of chemoimmunotherapy regimens has resulted in an improvement in the management of this disease, and consolidation of responses with autologous stem cell transplantation appears efficacious. Many patients are not eligible for high-dose therapy, however. Radioimmunotherapy (RIT) has demonstrated single-agent efficacy in HT and can be used safely as consolidation after chemoimmunotherapy. For these reasons, RIT consolidation after chemoimmunotherapy induction has been our standard treatment approach at the University of Rochester for patients with HT who were ineligible for autologous stem cell transplantation. A retrospective cohort study was performed to describe the clinical outcomes of these patients. Twenty-one patients were identified who received RIT consolidation. The Kaplan-Meier method was used to estimate the distributions of overall survival and progression-free survival. Comparisons were made between patients with pathologic HT and the combination of clinical HT and composite lymphoma using the log-rank test to compare survival curves. The median overall survival of the cohort was 84 months, and progression-free survival was 38months. The major toxicity was myelosuppression, and 2 deaths were attributed to therapy. One case of therapy-related acute myeloid leukemia was noted. In a population of patients ineligible for high-dose therapy with autologous stem cell support, consolidation of response to chemoimmunotherapy with RIT was well tolerated and should be considered in patients with disease responsive to induction therapy.

Rituximab-Pecc Induction Followed By 90y-Ibritumomab Tiuxetan Consolidation in Relapsed or Refractory DLBCL Patients Who Are Not Eligible for or Have Failed ASCT: Results from a Phase II HOVON Study

Background: Patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. Treatment with salvage chemotherapy has generally been disappointing. In many centers in the Netherlands the oral PECC regimen is used for such patients. 90Y-ibritumomab tiuxetan (Zevalin®, Spectrum Pharmaceuticals) radioimmunotherapy (RIT) is clinically active as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating salvage therapy with Rituximab (R)-PECC, in responsive patients followed by 90Y-ibritumomab tiuxetan consolidation.Methods: Adult patients with refractory/relapsed DLBCL, more than one year after or not eligible for ASCT, were treated with R-PECC (Prednisone 40 mg/m2 po D1-5; Etoposide 100 mg/m2 po D1-5; Chlorambucil 8 mg/m2 po D1-5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1) q 28 days for 4 cycles. Complete (CR) or partial responders (PR) received consolidation with a single dose 90Y-ibritumomab tiuxetan (15 MBq/kg, 0.4 mCi/kg). Response was evaluated according to the revised Cheson criteria (2007).Results: Between November 2008 and February 2012 62 patients were enrolled. Median age was 70 years (range, 45-82). Secondary IPI score was high-intermediate or high in 42% patients. All patients had received CHOP at first-line, 12 without rituximab. Prior therapies consisted of (R)-CHOP (65%), R-CHOP and R-DHAP/VIM (24%) or R-CHOP and R-DHAP/VIM plus ASCT (11%). Fourteen patients (23%) were refractory to the last prior therapy. After 4 cycles of R-PECC the overall response rate (ORR) was 31/62 (50%), with 14 of 62 (23%) patients achieving a CR and 17 of 62 (27%) achieving a PR, 13 of 62 (21%) patients had progressive disease. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (63% vs 7%, p=0.0001). 29 of 31 responsive patients received consolidation with RIT. The remaining two patients with PR did not proceed to RIT because of one toxic death and one misinterpretation of the response. The ORR after the end of the entire treatment was 29% (23% CR, 6% PR), RIT consolidation improved the overall best response (from PR to CR) in 5 of the 17 PR pts after the R-PECC only regimen. The median follow-up time of patients still alive is 48 months (range, 0-67 months). The median response duration in the patients that received R-PECC only was 9 months (range 3-63 months). The median response duration in the patients that received RIT consolidation was 20 months (range 0-59 months). The failure free survival at 1 yr from start of RIT consolidation was 52% (95% CI=[33%,68%]) and the overall survival 62% (95% CI=[42%,77%]). There was one treatment related death, due to sepsis and pneumonia after the first R-PECC cycle. The R-PECC regimen was well tolerated by most patients. The most common grade 3 or 4 adverse events during R-PECC treatment were hematological toxicity (27%), infection (19%) and malaise (11%). Adverse events after RIT were primarily hematologic. Grade 3 to 4 trombocytopenia and neutropenia occurred in 8 patients (28%) and 5 patients (17%), respectively. Eight patients received platelet transfusions and 6 patients red blood cell transfusions.Conclusions: The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile. Consolidation with RIT was well tolerated and resulted in long response durations in half of the patients. DisclosuresLugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Roche: Consultancy; Celgene: Consultancy. Off Label Use: 90Ytrium-ibritumomab tiuxetan for diffuse large B-cell lymphoma. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Doorduijn:Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Hoogendoorn:Gilead: Consultancy; Novartis: Consultancy.

Initial Therapy for Mantle Cell Lymphoma with Abbreviated R-CHOP Followed By Y90-Ibritumomab Tiuxetan: Ten Year Follow-up of the Phase 2 ECOG-ACRIN Study E1499

There is no single accepted treatment approach for mantle cell lymphoma (MCL), varying from intensive therapy in young, fit patients (pts) to less intensive for the more common older or less fit pts. R-CHOP remains a commonly used initial therapy for MCL, yielding high response rates but with limited durability, and still serves as a comparator in recently published studies. E1499 was designed to test the hypothesis that 1 dose of radioimmunotherapy (RIT) consolidation with 90Y-ibritumomab tiuxetan after only 4 cycles of R-CHOP-21 as initial therapy for MCL would be safe, well-tolerated and improve time-to-treatment failure (TTF) compared with historical R-CHOP data. E1499 met its primary endpoint with TTF at 1.5 years of 69% (95% CI 58-78%) (Smith et al JCO 2012) and treatment was well-tolerated. Here we report 10 year follow-up data on this uniformly-treated cohort of pts with MCL.56 eligible pts with previously untreated MCL and adequate organ function were enrolled between 11/03-2/05. Median age at enrollment was 60 (range 33-83) yrs, 73% were male and MIPI was low in 50%, intermediate in 27% and high in 21%. All cases were centrally reviewed. Therapy was standard dose R-CHOP given every 3 weeks for only 4 cycles, followed in pts whose disease did not progress with a single standard administration of 90Y-ibritumomab tiuxetan. All planned therapy was administered to 91% (5 did not receive RIT: 3 PD, 1 death from MI, 1 pt preference). The overall response rate after all treatment was 82% (55% CR/CRu). Median follow-up is now 9.8 years (May 2015 data cut-off). Median TTF is 34 months (mos). By MIPI, TTF was 36 mos for low, 25 mos for intermediate and 10 mos for the 12 pts with high MIPI. Pts who achieved CR had median TTF of 38 mos vs 15 mos for PR (p = 0.01).Median overall survival (OS) for the 56 eligible pts is 7.9 yrs. For pts < 65 median OS has not been reached at 10 yrs, compared with 7 yrs for those ≥ 65 (p = 0.07). OS for low MIPI pts also has not been reached at 10 yr, is 8 yr for intermediate and 5.5 yrs for high MIPI. Although TTF was longer for pts with CR/CRu, OS did not differ. There has been no additional therapy-related myeloid neoplasia (t-MN) other than 1 previously reported t-MN which occurred after additional therapy. Other malignancies include 2 non-small cell lung cancers, 1 bladder cancer, 1 ampullary adenocarcinoma and 2 resected localized non-melanoma skin cancers.Long-term follow-up of this cohort of pts treated with a simple 4 month outpatient regimen continues to suggest a benefit for RIT consolidation in prolonging TTF, with median TTF of almost 3 yrs. Though in somewhat older populations, median PFS was 14 mos for 6xR-CHOP alone and 25 mos for 6xVR-CAP (Robak T NEJM 2015), and 22 mos for 6xR-CHOP in StiL trial (Rummel M Lancet 2013). Ongoing rituximab maintenance after 8xR-CHOP is also effective (Kluin-Nelemans NEJM 2015) with 57% of pts progression-free at 4 yrs. For OS, age is the single most important prognostic factor in this cohort. Pts with high MIPI had short TTF, but their OS suggests that additional therapies were effective. As novel agents rapidly move into first-line regimens, often based on early assessments of efficacy, these long-term data inform benchmark expectations of PFS and OS in MCL. OS in our cohort is comparable to contemporaneous studies using either intense or non-intense initial therapy, raising questions regarding the value of intensive treatment strategies in MCL. [Display omitted] DisclosuresSmith:celegene, spectrum, genentech: Honoraria. Off Label Use: Y90-ibritumomab tiuxetan is not approved for use in mantle cell lymphoma. Gordon:Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending; Northwestern University: Employment. Horning:Genentech: Employment.

Comparing the Cost-Effectiveness of Rituximab Maintenance and Radioimmunotherapy Consolidation versus Observation Following First-Line Therapy in Patients with Follicular Lymphoma

BackgroundPhase 3 randomized trials have shown that maintenance rituximab (MR) therapy or radioimmunotherapy (RIT) consolidation following frontline therapy can improve progression-free survival for patients with follicular lymphoma (FL), but the cost-effectiveness of these approaches with respect to observation has not been examined using a common modeling framework. ObjectivesTo evaluate and compare the economic impact of MR and RIT consolidation versus observation, respectively, following the first-line induction therapy for patients with advanced-stage FL. MethodsWe developed Markov models to estimate patients’ lifetime costs, quality-adjusted life-years (QALYs), and life-years (LYs) after MR, RIT, and observation following frontline FL treatment from the US payer’s perspective. Progression risks, adverse event probabilities, costs, and utilities were estimated from clinical data of Primary RItuximab and MAintenance (PRIMA) trial, Eastern Cooperative Oncology Group (ECOG) trial (for MR), and First-line Indolent Trial (for RIT) and the published literature. We evaluated the incremental cost-effectiveness ratio for direct comparisons between MR/RIT and observation. Model robustness was addressed by one-way and probabilistic sensitivity analyses. ResultsCompared with observation, MR provided an additional 1.089 QALYs (1.099 LYs) and 1.399 QALYs (1.391 LYs) on the basis of the PRIMA trial and the ECOG trial, respectively, and RIT provided an additional 1.026 QALYs (1.034 LYs). The incremental cost per QALY gained was $40,335 (PRIMA) or $37,412 (ECOG) for MR and $40,851 for RIT. MR and RIT had comparable incremental QALYs before first progression, whereas RIT had higher incremental costs of adverse events due to higher incidences of cytopenias. ConclusionsMR and RIT following frontline FL therapy demonstrated favorable and similar cost-effectiveness profiles. The model results should be interpreted within the specific clinical settings of each trial. Selection of MR, RIT, or observation should be based on patient characteristics and expected trade-offs for these alternatives.

Consolidation of first remission using radioimmunotherapy with yttrium-90-ibritumomab-tiuxetan in adult patients with Burkitt lymphoma

The addition of anti-CD20 antibodies to high intensity polychemotherapy regimens has improved response and survival rates in newly diagnosed patients with Burkitt lymphoma (BL). However, the role of additional anti-CD20 directed radioimmunotherapy for consolidation of first remission (CR1) has not been reported so far in BL patients receiving rituximab during first-line treatment. We compared five BL patients receiving Y-90-IT radioimmunotherapy consolidation in CR1 to 22 consecutive BL patients without consolidation. We observed that Y-90-IT treatment was associated with clinically relevant myelosuppression. After a median follow-up of 50 months, none of the patients with Y-90-IT treatment relapsed, and no patient died. In contrast, one patient (4.5%) in the non-Y-90-IT group relapsed (50 months-PFS 95.5%; p=0.6336), and one patient died (50 months-OS 95.5%; p=0.6171). In conclusion, our data suggest that survival rates are excellent and equal in rituximab pretreated BL patients with or without Y-90-IT consolidation in first remission.

Consolidative Radioimmunotherapy after Chemoimmunotherapy in Patients with Histologic Transformation of Indolent Lymphoma

Abstract Introduction:Histologic transformation (HT) has been well characterized in follicular lymphoma (FL), and has historically carried a poor prognosis with median overall survival (OS) of 1.2-1.8 years (yrs) in the pre-rituximab era (Montoto et al, 2007; Al-Tourah et al 2008). Despite improved outcomes in the rituximab era (Link et al, 2013), HT still represents a major source of mortality and morbidity in these patients (pts). While there is emerging evidence that autologous stem cell transplant (ASCT) confers a survival advantage compared to chemotherapy with rituximab alone (Ban-Hoefen et al, 2013; Villa et al, 2013), many of these patients have contraindications such as advanced age and frailty precluding ASCT as an option. We report a strategy of radioimmunotherapy (RIT) consolidation after chemoimmunotherapy to address this unmet need. Methods: Consecutive pts ≥ 18 yrs old, who received RIT as consolidation after chemoimmunotherapy for HT at the Wilmot Cancer Institute were identified who had been deemed ineligible for ASCT. Inclusion criteria were as follows: 1) clinical, composite or pathologic diagnosis of HT, and 2) receipt of RIT after response to rituximab and chemotherapy. HT was defined as biopsy confirmed diffuse large B cell or Burkitt-like lymphoma by the WHO classification ≥6 months following a biopsy establishing indolent lymphoma diagnosis (pathologic HT), or clinical evidence of transformation as defined in previous cohorts (Al-Tourah et al, 2008; Link et al, 2013) in the absence of biopsy confirmation (clinical HT). Composite diagnosis of HT was defined as concurrent indolent and large cell lymphoma. The primary endpoint was overall survival (OS). Progression free survival (PFS) was a secondary outcome. Kaplan-Meier survival estimation curves were generated using SAS (SAS Institute Inc., Cary, NC, USA), and p values were generated using the log rank test. Results: 21 consecutive pts who had a clinical, composite, or pathologic HT diagnosis were included in this analysis. All of these pts responded to rituximab and chemotherapy (CHOP like n=18, other n=3), and were treated with RIT for consolidation. The median age at the time of HT was 66 yrs (44-90). Nine pts received I-131 tositumomab and 12 received Y-90 ibritumomab tiuxetan. The median OS from HT was 6.9 yrs in the entire cohort with a median follow up of 3.5 yrs (Figure). There were no statistical differences in outcomes between the pathologic (n=11) and clinical/composite (n=10) HT pts (p=0.33). There was also no difference between those who received rituximab prior to HT (n=13), and those who did not (n=8; p=0.88). Twelve pts experienced grade 3-4 thrombocytopenia, which was the most common adverse event (AE). Nine deaths occurred. Disease-related death was the most common cause (n=4), followed by death unrelated to disease or treatment (n=3) and treatment-related death (n=2). Figure: Kaplan-Meier estimate of OS after HT in pts receiving RIT after chemoimmunotherapy (n=21) Figure:. Kaplan-Meier estimate of OS after HT in pts receiving RIT after chemoimmunotherapy (n=21) Conclusions: We report the use of RIT as consolidation of response to chemoimmunotherapy in pts with HT. This represents one of the largest series focused on pts with HT who were deemed unfit for ASCT. The RIT was well tolerated in this analysis with only 2 treatment related deaths, one of which was secondary to therapy related acute myeloid leukemia. Our observed median OS compares favorably to published reports of pts with HT who are younger and able to tolerate more aggressive therapeutic options. Consolidative RIT should be considered as a treatment approach in this vulnerable population of pts, and can serve as a platform for the incorporation of novel agents into prospective clinical trials. Disclosures Barr: Pharmacyclics: Research Funding.

Comparing The Cost-Effectiveness Of Rituximab Maintenance (MR) and Radioimmunotherapy (RIT) Consolidation Therapy Following First-Line Chemo/Immunochemotherapies For Follicular Lymphoma

BackgroundFollicular lymphoma (FL), the most common indolent non-Hodgkin's lymphoma, has been regarded incurable and no consensus in management strategy has existed so far. In current clinical practice, the most commonly used frontline therapy is the immunochemotherapy (R-chemotherapy). Several phase III randomized trials - ECOG1496(Hochster, JCO2009), PRIMA(Salles, Lancet2011), and FIT(Morschhauser, JCO2008) - have shown that rituximab maintenance (MR) therapy and radioimmunotherapy (RIT) consolidation in addition to the frontline R-chemotherapy can improve progression-free survival (PFS) and help achieve a higher response quality. We conducted a cost-effectiveness analysis of maintenance or consolidation therapy versus observation after frontline treatment from the US payer's perspective. MethodsWe developed separate Markov models over patients' lifetime for PRIMA, ECOG, and FIT trial to compare the cost and effectiveness of observation with MR/RIT after completion of frontline treatment. Published progression free survival (PFS) and overall survival (OS) curves were extracted and fitted with Log-logistic regression survival model. Progression risks and cause-specific mortality after first-line treatment were extrapolated from the corresponding fitted PFS and OS model for each arm. Risk estimates after second-line treatment were identical for different models, estimated from the published survivals of observation arm in EORTC20981 trial. Costs for administration, monitoring, and management of adverse events were based on Medicare reimbursement rates for physician services, and drug costs were the wholesale acquisition cost, all valued in 2013 US dollars. In the microsimulation, initial age at diagnosis was sampled from the age distribution according to Surveillance Epidemiology and End Result (SEER) database. All costs and effectiveness were discounted at 3% per year. Primary outcomes were incremental cost per life-year gained (LY) and cost per quality adjusted life-year (QALY) gained. Model robustness in parameter uncertainties were addressed by one-way and probabilistic sensitivity analysis. ResultsCompared with observation, MR therapy provided 0.998 QALYs (0.901 LYs) at a cost of $43234 in PRIMA study, 1.070 QALYs (0.866 LYs) at a cost of $50146 in ECOG study, while RIT consolidation provided 0.795 QALYs (0.653 LYs) at a cost of $46085 in FIT trial. The incremental cost per QALY gained for RIT in FIT, and MR in PRIMA and ECOG were $57975, $43301, and $46844, respectively. From the table summarizing effectiveness and cost results, RIT and MR had comparable incremental QALYs before first progression, while RIT had higher incremental costs of adverse events due to relatively high incidence of adverse events in the RIT arm. ConclusionsWe used the same modeling framework and consistent parameter estimates to evaluate the cost-effectiveness of MR and RIT compared to observation after frontline treatment for FL patients. All strategies showed favorable cost-effectiveness profile with ICER below $100,000/QALY willingness-to-pay. Differences in induction therapies in three trials should also be noted when the ICERs of three models are compared.TableCost effectiveness results of micro-simulation.FITPRIMAECOGRITOBSMROBSMROBSLife yearsBefore first progression5.143.3116.4144.5454.8322.564Total LYs10.1649.51110.98610.0859.7078.841Incremental LYs compared to observation0.6530.9010.866QALYsBefore first progression4.3182.7485.6454.0004.2522.257Total QALYs7.6696.8748.6897.6917.5036.433Incremental0.7950.9981.07Costs ($)Adverse Event8692.934211.997348.21587.054148.31387.056Before first progression66185.247027.55663154.319545.08770964.435298.18First progression to second progression26326.0432018.5324035.728815.1125651.6332428.89After second progression30959.4738339.0528545.7634140.7730130.9638873.22Total123470.877385.13115735.872500.9712674776600.28Incremental46085.6243234.850146.74Incremental cost per LY gained70532.9847974.9857933.77Incremental cost per QALY gained57975.5743301.9546844.72 Disclosures:Flowers:Abbott, Celgene, Millennium/Takeda, Sanofi, Spectrum, Janssen: Research Funding; Celgene, Genentech Bio-oncology : Consultancy.

131I-Tositumomab Consolidation Radioimmunotherapy (RIT) In Patients With B-Cell Chronic Lymphocytic Leukemia (CLL) Or Small Lymphocytic Lymphoma (SLL) In First Remission

BackgroundDespite the initial response to combination chemotherapy in CLL/SLL patients, disease relapse and minimal residual disease (MRD) remain major issues in treatment of these diseases. Therefore, developing more effective treatments for CLL/SLL patients is a necessity. One strategy is to eliminate persistent disease using radioimmunotherapy (RIT), such as 131I-tositumomab (Bexxar®), as consolidation after an objective complete (CR) or partial response (PR) after an induction regimen. In this study we investigated the tolerability and efficacy of standard non-myeloablative doses of 131I-tositumomab following primary induction chemotherapy in CLL/SLL patients in first remission. Patients and MethodsPatients older than 18 with CLL/SLL with indication for treatment were included if they were in first CR or PR from prior treatments and had <25% bone marrow involvement and acceptable peripheral counts. 131I-tositumomab (75 cGy total-body dose) was delivered between days 90 and 180 from the first day of the last chemotherapy treatment. The dose was reduced to 65 cGy in cases of thrombocytopenia (between 100,000-150,000/µL). Three months after the treatment dose, efficacy and response criteria were specified per NCI working group guidelines and toxicity assessments were recorded based on the CTCAEv3.0. Rituximab levels were determined using ELISA with a monoclonal anti-rituximab idiotype antibody. Results16 patients (CLL11, SLL 5) received consolidative 131I-tositumomab in first remission between 2005-2012. The median age was 61 (38-78). Seven patients (43.7%) had high-risk disease based on cytogenetics or molecular profile. Two patients (12.5%) had 11q deletion and one had mutated TP53 (6.25%). Increased CD38 and ZAP-70 expression was present in 3 of 11 and 6 of 7 patients who were tested and unmutated IgVH was detected in 1 of 3 patients. Twelve patients (75%) were in PR when entered the study while 4 (25%) were in CR. Eight patients (50%) had minimal residual disease (MRD) assessed by multiparametric flow cytometry (MFC). Prior chemotherapy consisted of FR in 9 patients (56.2%), FCR in 4 patients (25%), BR in 2 patients (12.5%) and R-CHOP in 1 patient (6.2%). The median time from the first day of the last treatment cycle to the RIT dose was 15.4 weeks (10 - 29). 7 patients (43.7%) needed dose reduction. At 3 months, CR was achieved or sustained in 12 patients (80%). Conversion from PR to CR following RIT occurred in 4 of 8 patients (50%). Likewise, 131I-tositumomab eliminated MRD in 4 of 8 patients (50%) by negative MFC at 3 months. One patient (6.6%) had PR, one (6.6%) had nodular PR and one had disease progression (6.6%) after administration of 131I-tositumomab. Lymphadenopathy was improved in 83% (5 of 6) of the patients with measureable disease prior to 131I-tositumomab. Overall, the patients with CR at 3 months had significantly higher levels of pre-treatment Rituximab levels (11.0 vs. 2.32 µg/ml, p = 0.01. There was no difference in the pre-treatment levels in patients with pre-treatment MRD who had a negative MFC analysis at 3 months compared to the ones to had residual MRD (12.5 vs. 7.6 µg/ml, p = 0.50) or in patients with PR before receiving 131I-tositumomab who achieved CR at 3 months compared to the ones who did not (11.7 vs. 5.8 µg/ml, p = 0.19). These Results suggest that the levels of Rituximab may be blocking CD20 sites at the lymph node and/or marrow level. The median follow-up was 9.4 months (2.7-54.3). Hematologic toxicities at 3 months were grade 3 anemia in 1 patient (6.2%), grade 3 or 4 neutropenia in 13 (81%), and grade 3 or 4 thrombocytopenia in 8 (50%). Six patients (37.5%) required blood or platelet transfusions. Two patients (12.5%) needed myeloid growth factor support. One patient was hospitalized within 3 months of RIT for neutropenia-related sepsis/typhlitis. Two patients (12.5%) had disease progression and dysplastic changes were found in one. One patient died 3 years after treatment for an unrelated medical reason. Persistent cytopenias were reported in 4 patients (25%) during the follow-up period. ConclusionOverall, consolidation RIT with 131I-tositumomab after first remission appears to be a feasible approach and may provide the potential benefit of converting PR to CR or eliminating MRD in CLL/SLL patients. Further long–term follow-up to assess possible prolonged side effects and clinical effectiveness of this approach remain on-going. [Display omitted] Disclosures:Off Label Use: Bexxar is not FDA approved for consolidation of CLL. Gopal:GSK : Research Funding. Becker:Pfizer: Consultancy. Maloney:GSK: Consultancy. Press:Roche/Genentech: Consultancy.

Is hematopoietic cell transplantation still a valid option for mantle cell lymphoma in first remission in the chemoimmunotherapy-era?

Modern chemoimmunotherapies have produced higher response rates and improved survival in mantle cell lymphoma (MCL); however, disease relapse remains a challenge. The availability of various post-remission maintenance or consolidation strategies, have led some to question the role of upfront autologous hematopoietic cell transplantation (auto-HCT) consolidation for MCL, in the chemoimmunotherapy-era. A one size fits all approach is no longer appropriate for MCL in first remission, and the choice of preferred post-remission (observation, maintenance or consolidation) strategy is increasingly becoming a factor of patient age, comorbidities and disease risk stratification. In select low-risk patients (based on Mantle cell lymphoma International Prognostic Index (MIPI)), observation following rituximab plus Hyper-CVAD-like inductions seems appropriate. Rituximab maintenance after anthracycline-based chemoimmunotherapies in elderly transplant ineligible patients has shown survival benefit and should be considered a valid option. Limited studies suggest feasibility of radioimmunotherapy consolidation in first remission; however, in the absence of randomized data, this modality remains investigational. In younger, transplant-eligible patients receiving cytarabine-containing inductions, upfront consolidation with auto-HCT has shown survival benefit, and remains a standard-of-care option in the modern-era. Hyper-CVAD associated stem cell mobilization failure is an increasingly recognized problem, underscoring the need for alternative inductions, or consideration for early stem cell collection, when this induction regimen is used. Outcomes of high-risk MIPI patients remain suboptimal with currently available induction and post-remission strategies and represents an area where adoptive immunotherapy in the form of allogeneic-HCT warrants investigation. Incorporation of novel MoAbs and targeted agents (PI3K inhibitors, mTOR inhibitors, BTK inhibitors and so on.) in maintenance and consolidation strategies will build on the significant therapeutic gains of last decade, in coming years.

Radioimmunotherapy of B-cell non-Hodgkin’s lymphoma

This manuscript reviews current advances in the use of radioimmunotherapy (RIT) for the treatment of B-cell non-Hodgkin’s lymphoma (NHL). RIT has been in use for more than 20 years and has progressed significantly with the discovery of new molecular targets, the development of new stable chelates, the humanization of monoclonal antibodies (MAbs), and the use of pretargeting techniques. Today, two products targeting the CD20 antigen are approved: 131I-tositumomab (Bexxar®), and 90Y-ibritumomab tiuxetan (Zevalin®). 131I-tositumomab is available in the United States, and 90Y-ibritumumab tiuxetan in Europe, the United States, Asia, and Africa. RIT can be integrated in clinical practice using non-ablative activities for treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy in front-line treatment in FL patients. Despite the lack of phase III studies to clearly define the efficacy of RIT in the management of B lymphoma in the era of rituximab-based therapy, RIT efficacy in NHL has been demonstrated. In relapsing refractory FL and transformed NHL, RIT as a monotherapy induces around 30% complete response with a possibility of durable remissions. RIT consolidation after induction therapy significantly improves the quality of the response. Dose-limiting toxicity of RIT is hematological, depending on bone marrow involvement and prior treatment. Non-hematological toxicity is generally low. Different studies have been published assessing innovative protocols of RIT or new indications, in particular treatment in patients with aggressive lymphomas. High-dose treatment, RIT as consolidation after different therapeutic induction modalities, RIT in first-line treatment or fractionated RIT showed promising results. New MAbs, in particular humanized MAbs, or combinations of naked and radiolabeled MAbs, also appear promising. Personalized dosimetry protocols should be developed to determine injected activity.

Phase III Randomized Intergroup Trial of CHOP Plus Rituximab Compared With CHOP Chemotherapy Plus131Iodine-Tositumomab for Previously Untreated Follicular Non-Hodgkin Lymphoma: SWOG S0016

Advanced follicular lymphomas (FL) are considered incurable with conventional chemotherapy and there is no consensus on the best treatment approach. Southwest Oncology Group (SWOG) and Cancer and Leukemia Group B compared the safety and efficacy of two immunochemotherapy regimens for FL in a phase III randomized intergroup protocol (SWOG S0016) that enrolled 554 patients with previously untreated, advanced-stage FL between March 1, 2001, and September 15, 2008. Patients were eligible for the study if they had advanced-stage (bulky stage II, III, or IV) evaluable FL of any grade (1, 2, or 3) and had not received previous therapy. In one arm of the study, patients received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy at 3-week intervals with six doses of rituximab (CHOP-R). In another arm of the study, patients received six cycles of CHOP followed by consolidation with tositumomab/iodine I-131 tositumomab radioimmunotherapy (RIT). After a median follow-up period of 4.9 years, the 2-year estimate of progression-free survival (PFS) was 76% on the CHOP-R arm and 80% on the CHOP-RIT arm (P = .11). The 2-year estimate of overall survival (OS) was 97% on the CHOP-R arm and 93% on the CHOP-RIT arm (P = .08). There was no evidence of a significant improvement in PFS comparing CHOP-RIT with CHOP-R. However, PFS and OS were outstanding on both arms of the study. Future studies are needed to determine the potential benefits of combining CHOP-R induction chemotherapy with RIT consolidation and/or extended rituximab maintenance therapy.

Consolidation Anti-CD22 Fractionated Radioimmunotherapy with 90y-Epratuzumab Tetraxetan Following R-CHOP in Elderly DLBCL Patients: A Lysa Phase II Prospective Trial

AbstractAbstract ▪906▪This icon denotes a clinically relevant abstract Background:Consolidation using radioimmunotherapy (RIT) is a promising approach for elderly patients with diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem-cell transplantation. RIT using fractionated injections of 90Y-epratuzumab tetraxetan (Immunomedics, Inc.), a radiolabeled humanized anti-CD22 antibody, has been evaluated in relapsed patients with indolent or aggressive non-Hodgkin lymphoma (NHL), providing long-term disease control with manageable hematologic toxicities (Morschhauser et al., J Clin Oncol. 2010;28(23);3709-16). A French phase II trial sponsored by the LYSA group now assessed front-line treatment using fractionated RIT with 90Y-epratuzumab tetraxetan as consolidation therapy after R-CHOP in previously untreated elderly (age >60 years) patients presenting with stage I/II bulky or stage III/IV DLBCL. Methods:The trial included 6 courses of R-CHOP delivered q2wks followed by 2 infusions of 90Y-epratuzumab tetraxetan (2 × 15 mCi/m2 [555 MBq/m2], 7 days apart), 8 wks later. Patients were enrolled at time of diagnosis. Results:From October 2008 to December 2010, 75 patients (41 males, 34 females) have been accrued prospectively at 19 French institutions. The median age was 69 (range, 60–79 years); 57 patients (76.0%) were Ann Arbor stage III/IV. Seventy-one of the 75 completed 6 courses of R-CHOP-14 and 61/75 (81.2%) were eligible for RIT. Thus, 14 patients were considered ineligible for RIT because of R-CHOP toxicity (N= 5), progressive disease (PD, N=3), patient refusal (N=3), or concomitant illness (N=3). RIT toxicity consisted of grade 3–4 hematologic toxicity in 51/61 patients (83.6%): grade 3–4 neutropenia in 46 (75.4%), grade 3–4 anemia in 15 (24.6%), and grade 3–4 thrombocytopenia in 47 (77.0%), with a nadir at 42, 48, and 43 days after RIT and a median duration of 18, 5, and 17 days, respectively. Following RIT, RBC and/or platelet transfusions were given to 31 patients (50.8 %). Serious febrile neutropenia was observed in 13 cases (17.3 %) after R-CHOP and in 3 patients (4.9%) following RIT. RIT’s severe non-hematologic toxicity consisted of grade 4 gastrointestinal in 1 patient (1.6 %) and grade 4 infection in 3 (4.9%). No patient had mucositis after RIT. In the follow-up, 2 patients (2.6%) developed myelodysplastic syndrome 5 and 20 months after RIT.Using the 1999 International Workshop for Response Criteria for NHL (Cheson 1999), the overall response rate (ORR) after 6 × R-CHOP14 was 94.6% (71/75); 52 patients (69.3%) achieved CR/CRu and 19 (25.3%) had a partial response (PR). Among the 4 remaining patients, one had stable disease and 2 had PD; no assessment was obtained in the other. In an intention-to-treat analysis, CR/CRu rate after 6 × R-CHOP14 followed by RIT was 72.0% (N=54). Seven patients (9.3%) remained in PR and 8 (10.7%) progressed (2 patients previously in PR with PET-positive findings, 3 previously in CRu, including 1 PET-positive, and 3 in PD before RIT and then ineligible for RIT). No response assessment was obtained in the 6 others ineligible for RIT. At a median follow-up of 24 months (range, 1–46), 18 patients experienced lymphoma progression and/or a related death, yielding an estimated 2-year event-free-survival (EFS) of 73.3% (60.7-82.5%) and an estimated 2-year overall survival (OS) of 83.2% (71.4-90.4%). For the 61 patients who received 6 courses of R-CHOP followed by RIT consolidation, ORR was 91.8% (56/61); 50 patients (81.9%) achieved CR/CRu. Eight of 16 patients (50.0%) who had less than a CR/CRu with R-CHOP converted to CR/CRu after RIT. According to a PET analysis (Cheson 2007; N=55), 12 of the 24 patients (50.0%) who were not PET-negative after R-CHOP improved their metabolic response after RIT, resulting in a CR rate of 72.7%. Among these 61 patients, 12 experienced progression and/or a related death, yielding an estimated 2-year EFS of 78.7% (65.1–87.4%) and an estimated 2–year OS of 90.1% (77.7–95.8%). Conclusions:This phase II study clearly shows that fractionated RIT with 90Y-epratuzumab as a consolidation therapy after 6 × R-CHOP-14 is feasible and tolerable in elderly untreated DLBCL patients with advanced disease. RIT markedly improved response status observed after 6 × R-CHOP14. EFS data achieved with R-CHOP plus RIT compare favourably with those achieved with R-CHOP alone in the same patient population. Disclosures:Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

A Systematic Literature Review and Meta-Analysis of Radioimmunotherapy Consolidation for Patients With Untreated Follicular Lymphoma

Follicular lymphoma (FL) is characterized by multiple relapses and progressively shorter response durations with subsequent therapies. Despite the development of numerous treatment strategies to reduce the risk of progression, optimal therapeutic strategies for patients with FL remain undefined. Radioimmunotherapy (RIT) with an anti-CD20 antibody linked to iodine-131 or to yttrium-90 has emerged as well-tolerated treatment after induction. We conducted a systematic literature review and meta-analyses to quantify the benefits of consolidative RIT. We searched the CENTRAL and MEDLINE libraries, and conference abstracts for reports on phase II/III clinical trials that assessed RIT consolidation for patients with untreated FL. Extracted data included pretreatment disease status, patient characteristics, treatment regimen, response rates, progression-free survival (PFS), and overall survival (OS). Pooled estimates of complete response (CR), overall response (OR), 2- and 5-year PFS and OS rates were computed by using random effects models. Eight studies (n = 783) were included in the meta-analyses. CR rates after RIT ranged from 69.0% to 96.5%, 2-year PFS ranged from 64.8% to 86.1%, and 5-year PFS ranged from 47.0% to 67.3%. The pooled estimates of the CR rate and OR rate were 82.7% (95% CI, 67.4%-91.7%) and 96.2% (95% CI, 90.4%-98.6%), respectively. The pooled estimates for 5-year PFS and OS were 57.6% (95% CI, 47.8%-66.9%) and 90.1% (95% CI, 83.9%-94.1%), respectively. We believe that these aggregated data can further the discussion on RIT as a consolidation therapy and inform decisions on future study designs Additional studies are needed to compare the benefits of RIT consolidation to maintenance therapy with rituximab.