Groupe d'Etude Des Lymphomes Folliculaires Research Articles

Loncastuximab tesirine with rituximab in patients with relapsed or refractory follicular lymphoma: a single-centre, single-arm, phase 2 trial.

Preliminary data suggest promising activity of loncastuximab tesirine in follicular lymphoma, and synergistic activity between rituximab-induced cytotoxicity and loncastuximab tesirine. In this study, we evaluated loncastuximab tesirine combined with rituximab for second-line and later treatment of follicular lymphoma. We did a single-arm, investigator-initiated, phase 2 trial at Sylvester Comprehensive Cancer Center in Miami, FL, USA. We recruited patients aged 18 years or older with histologically confirmed relapsed or refractory follicular lymphoma (grade 1-3A) treated with one or more lines of therapy and presenting with progression or relapse of disease within 24 months (POD24) after the first line of treatment, one or more Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria, or second relapse, and with an Eastern Cooperative Oncology Group performance status of 0-2. Intravenous loncastuximab tesirine was administered on day 1 of a 21-day cycle, at 0·15 mg/kg for two cycles, then 0·075 mg/kg thereafter. Intravenous rituximab was administered on day 1 of cycle 1, at 375 mg/m2 for four once-weekly doses, followed by one dose every 8 weeks on cycles 5, 6, and 7. At week 21, patients with a complete response discontinued loncastuximab tesirine and received two more doses of rituximab once every 8 weeks. Patients with a partial response at week 21 continued both agents for 18 more weeks. The primary endpoint was complete response rate at week 12 assessed by the Lugano 2014 classification in patients who had received at least three doses of loncastuximab tesirine. The safety analysis included all patients who received one or more doses of loncastuximab tesirine. The trial is registered with ClinicalTrials.gov, NCT04998669, and is ongoing (open to recruitment); the data cutoff for this analysis was Sept 13, 2024. Between Jan 28, 2022, and June 3, 2024, we enrolled 39 patients (median age 68 years [IQR 58-77]; 21 [54%] male patients and 18 [46%] female patients). All patients presented with one or more GELF criteria (n=36 [92%]) or POD24 after the first line of treatment (n=20 [51%]) at baseline. As of Sept 13, 2024, the median follow-up was 18·2 months (95% CI 12·0-19·3). Week 12 complete response rate was 67% (n=26 of 39). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) were lymphopenia (eight [21%] of 39 patients) and neutropenia (five [13%] patients; one of whom had a serious grade 3 TEAE of febrile neutropenia that was considered to be related to study treatment). Generalised and peripheral oedema was predominantly grade 1-2 and all cases of oedema were treatable with diuretics. Serious TEAEs that were considered to be related to study drugs occurred in four (10%) of 39 patients. No fatal TEAEs occurred. Loncastuximab tesirine with rituximab showed clinically meaningful activity in relapsed or refractory follicular lymphoma, and had a manageable safety profile. ADC Therapeutics and Sylvester Comprehensive Cancer Center.

COMBINING BASELINE TOTAL METABOLIC TUMOR VOLUME AND BETA‐2‐MICROGLOBULIN LEVELS PREDICTS OUTCOMES IN HIGH BURDEN FOLLICULAR LYMPHOMA

Introduction: Follicular lymphoma (FL) usually presents an indolent course with repeated events of disease progression but treatment-free time intervals and patients’ survival are reduced at each relapse. Many prognostic scores exist but few are used in practice due to their complexity. Total metabolic tumor volume (TMTV) has demonstrated a strong prognostic value in FL and its routine use is increasing in academic centers. We aim to explore the predictive value of a simple prognostic score based on TMTV and beta-2-microglobulin (B2M) levels at baseline in high tumor burden FL to identify patients with the highest unmet medical need. Methods: In this monocentric retrospective analysis, we enrolled adult patients admitted to our hospital between 2006 and 2018 and fulfilling the following inclusion criteria: grade 1 to 3A FL with at least one high tumor burden criteria defined by the Groupe d'Etude des Lymphomes Folliculaires (GELF), available PET-CT images collected before first-line standard immunochemotherapy start and suitable for TMTV assessment. Baseline TMTV was determined using the 41% SUVmax threshold method. B2M levels were routinely measured at diagnosis. Primary endpoints were progression-free survival (PFS) and overall survival (OS) according to a score combining TMTV and B2M. Results: We included 126 FL patients in this analysis. Median age at time of treatment was 61 years (55; 57). Patients displayed advanced-stage disease (n = 112, 88.9%), intermediate (n = 51, 40.8%) or high (n = 62, 49.6%) FLIPI and intermediate (n = 40, 33.3%) or high (n = 31, 25.8%) PRIMA-PI scores. Median baseline SUVmax and TMTV were 12.1 (10; 17) and 606 mm3 (268;1219), respectively. Baseline B2M levels were measured for 125 (97%) patients and >3 mg/L in 30 (24%). Treatment regimens used were mostly R-CHOP like (n = 109, 86.5%) and R-lenalidomide (n = 9, 7.1%). 80 patients (63.5%) received a maintenance therapy during 24 months. We defined three risk categories : (i) Low risk (n = 45, 36%): TMTV ≤510 mm3 and B2M ≤3 mg/L; (ii) Intermediate risk (n = 57, 45.6%) : TMTV >510 mm3 or B2M >3 mg/L ; (iii) High risk (n = 23, 18.4%) : TMTV >510 mm3 and B2M >3 mg/L. With a median follow-up of 83 (52; 116) months, the 5-year PFS was 81.7% (95% CI: 71–94), 53.7% (95% CI: 41.8–69) and 38.6% (95% CI: 23–65) in the low, intermediate and high risk groups, respectively (p < 0.0001). Five-year OS was based on 14 deaths and estimated at 96.1% (95% CI: 91–100), 89.1% (95% CI: 81.2–97.7) and 73.7% (95% CI: 57.6–94.2) in the low, intermediate and high risk groups, respectively (p = 0.003). Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, PET-CT No conflicts of interests pertinent to the abstract.

A phase 2 trial of mosunetuzumab with lenalidomide augmentation as first-line therapy for follicular (FL) and marginal zone lymphoma (MZL).

TPS7588 Background: First-line therapy for high-burden FL and MZL includes immunochemotherapy (most commonly rituximab with bendamustine), which is associated with toxicities, is not curative, and leads to a prolonged T-cell depletion. The alternative of rituximab with full-dose lenalidomide did not improve efficacy or toxicity [Morschhauser et al., NEJM 2018]. However, lower-dose, short-course lenalidomide (15mg) may enhance cytotoxic T-cell immunity and efficacy of rituximab [Zucca et al, Blood 2019]. Mosunetuzumab is a CD20xCD3-binding, T-cell-engaging bispecific antibody approved for relapsed/refractory FL after 2 lines of therapy. It results in a complete response (CR) rate of 60% in that setting [Budde et al., Lancet Oncol, 2022], despite prior exposure to immunosuppressive therapies. This trial proposes a novel therapeutic approach to first-line treatment of FL/MZL, exploring 3 hypotheses: 1) that mosunetuzumab will lead to a high rate of CR, and possibly eradication, of FL/MZL when applied before exposure to immunosuppressive modalities; 2) that low-dose lenalidomide can augment the cytotoxic T-cell response when CR is not achieved with mosunetuzumab alone, and 3) that baseline host immune environment measured in treatment-naïve state can predict CR to bispecific antibody therapy. Methods: The Brown University Oncology Research Group BrUOG-401/ML43251 ( NCT04792502 ) is an investigator-initiated, multi-center, single-arm, phase 2 clinical trial for patients (pts) with FL and MZL in need of first-line systemic therapy. Pts with FL must meet the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria of high-burden disease, whereas pts with MZL must require therapy in the investigators’ opinion. As of January 2023, 7 of the planned 52 pts have been enrolled. The trial uses a response-adapted design: pts start with 4 courses of subcutaneous mosunetuzumab monotherapy, using step-up dosing during Cycle 1 (5mg → 45mg → 45mg) to mitigate the risk of cytokine release syndrome (CRS). Pts attaining CR (by Lugano criteria) after Cycle 4 continue for a total of 8 cycles of mosunetuzumab monotherapy. Pts attaining partial response or stable disease receive 4 additional cycles of mosunetuzumab with low-dose lenalidomide augmentation (10mg daily), with further 4 cycles of mosunetuzumab/lenalidomide if CR after C8 is still not attained. The primary endpoints include the ORR and CR rate at final assessment, and rates of toxicities, particularly CRS, tumor flare, and immune-mediated events. PFS and rate of progression of disease at 24 months (POD24) are among secondary endpoints. The study uses Simon’s two-stage design, with the null hypothesis that the CR rate is 53% (based on prior RELEVANCE trial). Correlative studies aim at determining predictive biomarkers of response, including immune signatures and dynamics of circulating tumor DNA during study therapy. Clinical trial information: NCT04792502 .

Zanubrutinib plus obinutuzumab versus obinutuzumab in patients with relapsed/refractory follicular lymphoma: Updated analysis of the ROSEWOOD study.

7545 Background: In an early-phase study, the combination of zanubrutinib plus obinutuzumab (ZO) was well tolerated and associated with an early signal of efficacy in patients (pts) with follicular lymphoma (FL) (Tam et al. Blood Adv 2020). ROSEWOOD (NCT03332017) is a phase 2, randomized study designed to assess efficacy and safety of ZO vs obinutuzumab (O) in pts with relapsed/refractory (R/R) FL. Here, we present an updated analysis with a median follow-up of 20.2 mo. Methods: Pts with R/R FL (grade 1–3a) who received ≥2 lines of therapy including an anti-CD20 antibody and alkylating agent were randomized 2:1 to receive ZO or O. Zanubrutinib was given at 160 mg twice daily until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and safety. Results: A total of 217 pts were randomized (145 for ZO; 72 for O). Median age was 64 years. Of the 217 pts, 114 (52.5%) had a high Follicular Lymphoma International Prognostic Index (FLIPI) score at screening and 123 (56.7%) pts had high tumor burden criteria according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Median number of prior lines of therapy was 3 (range, 2–11). A total of 114 (52.5%) pts were refractory to rituximab; 214 (98.6%) pts received prior immunochemotherapy. Prior exposure to anticancer drugs included anthracyclines (80.6%), cyclophosphamide (94.0%), and bendamustine (54.8%). ORR was 69.0% (ZO) vs 45.8% (O) ( P = 0.0012). Complete response rate was 39.3% (ZO) vs 19.4% (O); 18-mo DOR rate was 69.3% (ZO) vs 41.9% (O); median PFS was 28.0 mo (ZO) vs 10.4 mo (O) (hazard ratio [HR], 0.50 [95% CI: 0.33, 0.75]; P = 0.0007). Median TTNT was not evaluable for ZO and 12.2 mo for O (HR, 0.34 [95% CI: 0.22, 0.52]; P &lt; 0.0001). Estimated OS rate at 24 mo was 77.3% (ZO) and 71.4% (O), with median OS not reached in either arm. Nonhematologic treatment-emergent adverse events of any grade that occurred more frequently for ZO vs O ( &gt; 5% difference) were petechiae (6.3% vs 0%) and herpes zoster infection (6.3% vs 0%); in contrast, pyrexia (13.3% vs 19.7%) and infusion-related reaction (2.8% vs 9.9%) occurred more frequently in pts on O. When adjusted for duration of treatment exposure, incidences of infection and cytopenia were similar, and incidence of all grades of hemorrhage was 2.4 (ZO) vs 1.3 (O) persons per 100 person-months. Two pts in each treatment group reported major hemorrhage. Incidences of atrial fibrillation and hypertension were low and similar in both treatment arms. Conclusions: ZO demonstrated meaningful activity and a manageable safety profile in pts with heavily pretreated R/R FL, representing a potential novel therapy. Clinical trial information: NCT03332017 .

A Phase 2, Open-Label, Multicenter Study of Tazemetostat in Combination with Rituximab for the Treatment of Relapsed or Refractory Follicular Lymphoma

Background: Patients with follicular lymphoma (FL) who do not achieve a response after 2 or more prior lines of systemic therapy have a poor prognosis when treated with salvage chemotherapy alone or PI3K inhibitors. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that supports germinal center (GC) formation and suspends differentiation during B-cell development by silencing genes that limit proliferation and promote exit from the GC. Throughout the pathogenesis of FL, EZH2 plays a consistent underlying role in maintaining the GC and B-cell proliferation, regardless of the oncogenic drivers. Dysregulation of EZH2 or gain-of-function mutations in EZH2 can lead to accumulation of malignant B cells and may contribute to the development of FL. Tazemetostat, a first-in-class oral EZH2 inhibitor, recently gained approval by the US Food and Drug Administration in patients with relapsed or refractory (R/R) FL after demonstrating single-agent, antitumor activity in patients with mutant (MT) or wild-type (WT) EZH2 R/R FL. Here we examine the efficacy and safety of tazemetostat in combination with rituximab for the treatment of R/R FL. Study Design and Methods: This trial is a phase 2, single-arm, open-label, multicenter study of tazemetostat in combination with rituximab in patients with R/R FL who have received at least 2 prior lines of systemic therapy, including an anti-CD20-based regimen. Patients eligible for inclusion are aged ≥18 years with grade 1 to 3A FL who have met Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria to receive treatment, have an Eastern Cooperative Oncology Group (ECOG) score ≤2, have &amp;gt;5.0 x 109/L circulating malignant cells, and have not received any prior treatment with EZH2 inhibitors. Patients with transformed FL, a history of clinically significant gastrointestinal conditions, or any uncontrolled illness are excluded from this study. EZH2 mutation testing will be performed during patient screening. Patients will receive tazemetostat 800 mg by mouth twice daily beginning on cycle 1 day 1 for continuous 28-day cycles until the end of cycle 24, for a total of 24 months of therapy. Patients will also receive rituximab 375 mg/m2 intravenously (IV) on cycle 1 day 1, then 375 mg/m2 IV or 1400 mg subcutaneously on days 8, 15, and 22 of cycle 1, and on day 1 of cycles 3, 4, 5, and 6, for a total of 8 doses of rituximab. The primary endpoint is the objective response rate (ORR; the proportion of patients with complete or partial response) in patients with WT EZH2. Key secondary endpoints include median progression free survival (PFS) in patients with WT EZH2; median PFS in all patients, regardless of mutational status; ORR in patients with MT EZH2; efficacy outcomes in rituximab-refractory patients; and incidence of adverse events. Efficacy and safety analyses will be performed on all patients who receive ≥1 dose of study drug. The evaluation of ORR will be based on Lugano 2014 response criteria and will be presented with corresponding 2-sided Clopper-Pearson 95% confidence intervals. The Kaplan-Meier method will be used to estimate PFS. Survival follow-up will be done following the study treatment period every 6 months for 2 years or until disease progression or death for all patients who complete the 24 months of tazemetostat therapy. Disclosures Patel: Adaptive Biotechnologies, AstraZeneca, Pharmacyclics, Janssen, Genentech, Celgene/BMS, BeiGene, Kite: Consultancy. Pagel:Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy.

Analyzing Efficacy Outcomes from the Phase 2 Study of Single-Agent Tazemetostat As Third-Line Therapy in Patients with Relapsed or Refractory Follicular Lymphoma to Identify Predictors of Response

Analyzing Efficacy Outcomes from the Phase 2 Study of Single-Agent Tazemetostat As Third-Line Therapy in Patients with Relapsed or Refractory Follicular Lymphoma to Identify Predictors of Response

IBCL-094: Combination of Ibrutinib with Rituximab Versus Placebo with Rituximab for First-Line Treatment of Follicular Lymphoma: PERSPECTIVE, a Randomized Phase 3 Study

Context: Few first-line chemotherapy-free treatment options are available for patients with follicular lymphoma (FL) who are elderly or have comorbid conditions. Single-agent rituximab has been used to treat previously untreated elderly, frail patients or those with low tumor burden. Ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor, is approved in the US and EU for the treatment of various B-cell malignancies. The combination of once-daily ibrutinib with 4 weekly doses of intravenous rituximab was evaluated in a phase 2 study as a first-line treatment option for patients with FL. At a median follow-up of 34 months, an overall response rate of 85% and complete response of 40% were reported. At 30 months, the progression-free survival (PFS) and overall survival rates were 67% and 97%, respectively (Fowler, BJH. 2020). Based on these promising results, the phase 3 PERSPECTIVE study was designed to further evaluate ibrutinib-rituximab combination therapy in previously untreated patients with FL. Objective: To compare PFS outcomes between: (1) ibrutinib-rituximab and placebo-rituximab, and (2) continuous versus fixed-duration ibrutinib treatment. Design: Phase 3, multicenter, randomized, double-blind, placebo-controlled study (PCYC-1141-CA, NCT02947347 ). Patients or other participants: Eligible patients are enrolled if they meet ≥1 Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion, and are aged ≥70 years or 60–69 years with ≥1 comorbidities (creatinine clearance 30–59 mL/min or ECOG performance status of 2). Patients who received any prior treatment for FL or showed evidence of CNS involvement or transformed lymphoma are excluded. Enrollment of approximately 440 patients is planned. Interventions: In Part 1, patients will be randomized to receive either: (1) once-daily oral ibrutinib-rituximab, or (2) once-daily oral placebo-rituximab. Patients in both arms will receive rituximab in 4 weekly doses, followed by rituximab maintenance therapy. In Part 2, patients receiving ibrutinib-rituximab and remaining on ibrutinib treatment for ≥2 years will be randomized again to either receive once-daily oral ibrutinib or switch to once-daily oral placebo. Main outcome measures: The primary endpoint is PFS for both parts. Conclusions: The study is currently enrolling patients at participating sites in the US, EU, and Asia Pacific. Funding: Pharmacyclics LLC, an AbbVie Company.

A multicenter, randomized, double-blind, placebo-controlled phase III study of the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, in combination with rituximab versus placebo in combination with rituximab in patients with treatment-naive follicular lymphoma (PERSPECTIVE).

TPS7576 Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. A limited number of chemotherapy-free options exist for patients with treatment-naïve (TN) FL who are older or who have comorbidities. Single-agent rituximab is considered a treatment option for elderly or infirm patients. In a phase 2 study, frontline treatment with ibrutinib in combination with rituximab for 4 weekly doses without maintenance resulted in an ORR of 85% (CR, 35%) with a median follow-up of 22 months and an 18-month PFS rate of 87% (Fowler Blood 2016). The phase 2 study serves as the basis for the randomized, double-blind, placebo-controlled phase 3 PERSPECTIVE (PCYC-1141-CA) trial. PERSPECTIVE will be conducted in two parts and will uniquely test (1) whether frontline treatment with ibrutinib in combination with rituximab results in prolongation of PFS compared to rituximab alone, and (2) whether continuous versus finite treatment with ibrutinib affects PFS outcomes. Methods: In the ongoing PERSPECTIVE trial, approximately 440 patients with TN FL meeting at least one Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion will be randomized if they also meet one of the following criteria: age ≥70 years or age 60 to 69 with one or more comorbidities (creatinine clearance 30-59 mL/min or ECOG performance status of 2). Patients will be randomized to receive either ibrutinib or oral placebo once daily. All patients will be given rituximab for 4 weekly doses followed by maintenance. After at least 2 years of treatment in Part 1, patients randomized to ibrutinib who still remain on ibrutinib will be re-randomized in Part 2 to continue ibrutinib or switch to placebo. Key exclusion criteria include any prior treatment for FL, evidence of CNS involvement, or transformation. Analyses will be conducted in two distinct parts, both with a primary endpoint of PFS. The study is open for enrollment with sites planned in the US, EU, and Asia Pacific. Clinical trial information: NCT02947347.

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

Advanced Stage Follicular Lymphoma - Watch and Wait or Immunochemotherapy?

BACKGROUNDThe outcome of patients with advanced stage Follicular Lymphoma (FL) has improved over the last decade, with the use of monoclonal antibodies (mAbs). The watch and wait approach (WW) in FL with low tumor burden was assumed when treatment options were limited and less effective than nowadays. In FL patients with indolent disease characterized by multiple relapses evolution, the therapeutic strategy should take into consideration the quality and duration of response and the impact on overall survival (OS) versus the risk of long-term toxicity. AIMSEvaluation of the impact of WW approach compared with chemotherapy (CT) in time to next treatment (TNT), progression-free survival (PFS) and OS. METHODSRetrospective study of 213 patients with FL, followed in a cancer care center between 2000-2012. Of these, 79 asymptomatic patients at diagnosis, with Ann Arbor stage III-IV were included and divided in 2 subgroups: 58 patients received the first-line treatment and 21 remained in surveillance. Tumor burden defined according to criteria of the Groupe d’Etude des Lymphomes Folliculaires (GELF). Survival analysis using the Kaplan-Meier method. Type of response defined according to NCCN criteria. RESULTSMedian follow-up of 48 months (12-147). 41 of the 58 patients submitted to 1st line treatment [median age 57 years (38-72), 36.2% male], underwent CT regimen containing Rituximab. The majority of these patients presented with follicular pattern and histological grade 1/2 (89.7%), 34.5% had FLIPI ≥ 3 and 50 % high tumor burden (GELF), 15.5% bulky mass, 53.4% had > 4 nodal areas involved and 6.9% > 1 extranodal area involved. 52 of the treated patients (89.7%) achieved CR and in 4 progression occurred (6.9%). 50 patients (86.2%) were alive without evidence of disease at the end of study (86.2%). In the group of patients undergoing surveillance, 11 suffered disease progression (52.4%), of which 10 (47.6%) stayed alive without evidence of disease. The TNT was higher in patients undergoing 1st CT regimen, compared to patients on WW (median 1480.5 vs. 765 months, p <0.001) with significant impact on PFS (p <0.001) but not on OS. Analyzing the treated subgroup, the addition of immunotherapy resulted in better TNT and PFS compared to WW (p <0.001), without affecting the OS. In univariate Cox regression analysis, the number of areas and extranodal tumor burden (GELF) were independent predictors of PFS and TNT (p <0.05). CONCLUSIONIn asymptomatic patients with FL stage III-IV and high tumor burden, the CT especially when combined with immunotherapy, showed significant improvement on TNT and PFS compared to a WW approach, with no impact on OS. Despite a small sample group with retrospective data, our results are in agreement with the published literature. DisclosuresNo relevant conflicts of interest to declare.

Fractionated 90Y-Ibritumomab Tiuxetan Radioimmunotherapy As an Initial Therapy of Follicular Lymphoma: An International Phase II Study in Patients Requiring Treatment According to GELF/BNLI Criteria

We report an international, multicenter phase II trial to evaluate the efficacy and toxicity of fractionated (90)Y-ibritumomab tiuxetan ((90)Y-IT) as initial therapy of follicular lymphoma (FL). A total of 74 patients, with a median age of 61 years (range, 28 to 80 years), were recruited requiring initial therapy by Groupe d'Etude des Lymphomes Folliculaires (GELF)/British National Lymphoma Investigation (BNLI) criteria. Among them, 78% had stage III-IV disease, 32% intermediate, and 44% high-risk (according to FL International Prognostic Index). Treatment consisted of two doses of (90)Y-IT (11.1 MBq/kg) administered 8 to 12 weeks apart. Patients with more than 20% lymphoma infiltration of bone marrow (BM) received one infusion per week for 4 consecutive weeks of rituximab (375 mg/m(2)) and proceeded to fractionated radioimmunotherapy (RIT) only if a repeat BM biopsy demonstrated clearing of lymphoma to less than 20% involvement. The primary end point was end of treatment response of the intention-to-treat population. Secondary objectives were safety and progression-free survival (PFS). Initial overall response rate (ORR) was 94.4% (68 of 72 patients) with combined complete response (CR/CRu) of 58.3% (42 of 72 patients). Nine patients subsequently improved response making an ORR of 95.8% (69 of 72 patients) and CR/CRu of 69.4% (50 of 72 patients). At a median follow-up of 3.1 years (range, 0.2 to 5.2 years) estimated 3-year PFS is 58%, treatment-free survival 66%, and overall survival 95%. Median PFS is 40.2 months. Thirty patients have experienced disease progression and 24 have required further treatment. The treatment was well tolerated with few (2.8%) grade 3 or 4 infectious episodes or adverse events and manageable hematologic toxicity. Fractionated RIT using (90)Y-IT is an effective initial treatment for advanced-stage FL in patients with higher tumor burden requiring treatment.

A Multicenter Phase II Study Of Bortezomib (VELCADE®) Combined With Rituximab For Untreated High Tumor Burden (HTB) Indolent Non-Hodgkin Lymphoma (NHL): Long-Term Follow-Up Of Outcomes and Examination Of Prognostic Factors

BackgroundStandard therapy for patients (pts) with untreated HTB indolent NHL includes rituximab combined with cytotoxic chemotherapy. There remains a deficiency of prospective data examining non-cytotoxic options. We examined long-term outcomes and prognostic factors for indolent NHL patients with HTB treated with front-line rituximab and bortezomib therapy. MethodsWe conducted a multicenter prospective phase II clinical trial for untreated indolent NHL pts (NCT 00369707). All pts were required to have HTB as defined by Groupe D'Etude des Lymphomes Folliculaires (GELF) criteria. Induction therapy consisted of 3 cycles of: rituximab at 375 mg/m2 x 4 weekly doses for cycle 1, then only day 1 for cycles 2 and 3 combined with bortezomib 1.6 mg/m2 days 1, 8, 15, and 22 given q35 days for all 3 cycles. This was followed by an abbreviated maintenance with both drugs given once q2 months x 8 months. Staging was done via CT with international workshop1999 criteria. All efficacy endpoints and survival rates were analyzed by intent-to-treat (ITT). Additionally, we examined prognostic factors for associations with survival on univariate analyses. Results42 pts were enrolled and all pts were evaluable for toxicity and efficacy. Histologies were follicular lymphoma (FL) (n=33, 79%), marginal zone lymphoma (MZL) (n=6, 12%), small lymphocytic lymphoma (SLL) (n=2, 7%), and Waldenstroms (n=1, 2%). Median age was 62 years (40-86) with 21% of pts age >70 years; 91% of pts had advanced-stage disease (67% stage IV). Additional characteristics included: B symptoms in 31%, 38% with bulky disease (>7cm), and malignant ascites or effusions were present in 19%. The median FLIPI was 3 (61% were 3-5). Overall, therapy was well tolerated with minimal cytopenias noted. Most adverse events (AEs) occurred during the 3 induction cycles. Grade 3 AEs were: fever (5%), infusion reaction (5%), infection (5%), cardiac (5%), and fatigue (5%), as well as diarrhea, hypokalemia, and bowel obstruction each at 2%. The only grade 4 AEs were neutropenia (5%) and thrombocytopenia (2%); 3 pts were taken off study early (each after 1 cycle of induction) due to grade 3 diarrhea, fatigue, and cardiac AEs (latter due to CHF exacerbation, deemed unrelated to therapy [pt autonomously stopped cardiac medications]). Following the 3 induction cycles, the overall response rate (ORR) on ITT was 69% for all pts with a complete remission (CR) rate of 24% (FL ORR 70%, CR 23% on ITT). The ORR at end of therapy for all pts was 69% with 39% CR, while for FL, the end of therapy ORR was 75% and CR 44%. With a median follow-up of 48 months (10-78) and on ITT, the 4-year progression-free survival (PFS) for all pts was 44% with a 4-year overall survival (OS) rate of 87%. The 4-year PFS and OS rates for FL patients were 44% and 97%, respectively (Figure 1). Further, the 4-year OS rate for FL pts was significantly better compared with non-FL pts (97% (95% CI 80%, 99%) versus 43% (95% CI 6%, 78%), respectively, P=0.003). The time-to-treatment failure rate at 4 years for all pts was 26%, which was primarily due to the aforementioned AEs resulting in study removal and several non-progressing pts taken off study at physician discretion. Analyzing predictors of survival on univariate analysis, there was a trend for FLIPI to impact PFS of FL pts (HR: 1.48, 95% CI 0.95-2.32, P=0.08) as well as OS (HR: 3.34, 95% CI 0.89-12.56, P=0.08). Further, OS was similar, but PFS rates for FL pts were significantly different by low and high-risk FLIPI groups (Figure 2); 4-year PFS for FLIPI 0-2 was 57% (95% CI 29%, 77%) vs 28% (95% CI 8%, 53%) for FLIPI 3-5 (P=0.02). In addition, FL histology had a significant effect favoring lower risk of death vs non-FL histology (OS HR: 0.07, 95% CI 0.01-0.70, P=0.02). ConclusionsIn pts with untreated HTB NHL, therapy with rituximab/bortezomib was well tolerated and survival rates for FL pts approximated that of prior rituximab/cytotoxic chemotherapy series that have reported long-term outcomes of this pt population (e.g., R-CVP induction: Marcus R et al J Clin Oncol 2009). Moreover, OS for FL pts here was excellent, while OS for non-FL pts was sub-optimal. Continued strategies to incorporate novel therapeutic agents into frontline FL are warranted in part to delineate untreated HTB indolent NHL pt populations that may achieve long-term survival without use of cytotoxic therapy. [Display omitted] [Display omitted] Disclosures:Evens:Millennium: Consultancy, Honoraria. Off Label Use: Bortezomib in follicular lymphoma.

A Multicenter Phase II Clinical Trial of Rituximab Combined with Bortezomib (VELCADE®) Therapy for Untreated “High Tumor Burden” Indolent Non-Hodgkin Lymphoma (NHL)

AbstractAbstract 1642Standard therapy for patients (pts) with untreated high tumor burden indolent NHL includes rituximab combined with cytotoxic chemotherapy. There remains a paucity of prospective data examining non-chemotherapeutic options. We hypothesized that frontline treatment with rituximab and bortezomib therapy for “high tumor burden” indolent NHL would be well tolerated and effective. Methods:We conducted a prospective phase II clinical trial for untreated indolent NHL (registered at clinicaltrials.gov [NCT 00369707]). All pts were required to have “high tumor burden” as defined by Groupe D’Etude des Lymphomes Folliculaires (GELF) criteria. ‘Induction therapy' consisted of 3 cycles: rituximab at 375 mg/m2 × 4 weekly doses for cycle 1, then only day 1 for cycles 2 and 3 combined with bortezomib 1.6 mg/m2 days 1, 8, 15, and 22 given q35 days for all 3 cycles. This was followed by an abbreviated consolidation phase with rituximab and bortezomib both given once q2 months × 8 months. Responses were assessed by CT according to IWG criteria (JCO 1999). To our knowledge, this represents one of the first clinical trials to examine a ’non-chemotherapeutic’ program for the specific population of high-tumor burden indolent NHL. Results:42 pts (41 response-evaluable) were enrolled. Histologies were follicular lymphoma (FL) (n=32, 79%), marginal zone lymphoma (MZL) (n=5, 12%), small lymphocytic lymphoma (SLL) (n=3, 7%), and Waldenstroms (n=1, 2%). Median age was 61 years (40–86) and 91% of patients had advanced-stage disease at study entry (67% stage IV). All pts had high tumor burden by GELF, while the median FLIPI was 3 (61% 3–5). Therapy was overall well tolerated. The vast majority of toxicities occurred during induction therapy. Grade 3 adverse events (AEs) were fever (5%), infusion reaction (5%), infection (5%), cardiac events (5%), and fatigue (5%), as well as diarrhea, hypokalemia, and bowel obstruction all at 2% each. The only grade 4 AEs were neutropenia (5%) and thrombocytopenia (2%). Responses according to cycle number and histology are shown in the Table. A reduction in measurable tumor size was observed in 100% of all pts following cycle 1; however, the objective response rate (ORR) was only 22%. Following 3 induction cycles, ORR was 59% among all pts, while the ORR for FL pts was 62%. Notably, from cycle 1 to cycle 3, 63% of FL pts improved their response (17 pts from SD to PR and 3 pts from PR to CR). Further, after consolidation treatment, 2 SDs converted to PR and 1 PR to CR. Accounting for all pts who responded, the best ORR was 71% with CR rate of 39% (FL best ORR 75%, CR 46%). However, these data were tempered by several early treatment failures due to toxicity or physician discretion as well as several early disease progressions (i.e., from induction cycle 1 to 3: 2 SD to PD; and from induction to maintenance: 2 SD to PD, 2 PR to PD, and 1 CR to PD). With a median follow-up of 41 months (10–59), the 3-year PFS for all pts, as well as the FL subgroup, were 33%. The 3-year PFS for FL pts who achieved CR was 54%. Median progression-free survival (PFS) for all pts was 22 months (2–59), while the median overall survival (OS) was not reached. Finally, 3-year OS for all pts was 88% (94% for FL). Conclusions:In high tumor burden FL, therapy with rituximab/bortezomib resulted in successive conversions of response over time, however, responses altogether appeared less durable and PFS was lower than expected compared with historical chemotherapy-based induction series. Continued strategies to incorporate novel agents into frontline FL are warranted, although more protracted dosing schedules should be considered in high tumor burden pt populations in order to maintain adequate duration of response. Further, drug-specific biomarker studies predictive of response/outcome are critically needed.TableResponse according to time and NHL histologyAfter Cycle 1After Cycle 3*After ConsolidationBest ORRFL (n=32)CR/CRu 6% PR 13% SD 81%CR/CRu 9% PR 53% SD 19%CR/CRu 13% PR 41% SD 6%ORR 75% CR 46%Non-FL histology (n=9)CR/CRu 0% PR 44% SD 66%CR/CRu 11% PR 33% SD 11%CR/CRu 11% PR 33% SD 11%ORR 56% CR 11%CR, complete remission; CRu, CR unconfirmed; PR, partial remission; SD, stable disease; PD, progressive disease.*4 pts were removed after 1 to 2 cycles of induction due to toxicity (1 in CR, 1 in PR, 2 in SD), while 2 pts were taken off study at physician discretion (both with SD). [Display omitted] Disclosures:Off Label Use: Bortezomib in untreated follicular lymphoma.

Efficacy and safety of the combination of rituximab, fludarabine, and mitoxantrone for rituximab‐naive, recurrent/refractory follicular non‐Hodgkin lymphoma with high tumor burden

This phase 2 trial was undertaken to evaluate the efficacy and safety of rituximab combined with intravenous fludarabine and mitoxantrone (R-FM) for patients with recurrent/refractory follicular lymphoma who had high tumor burden according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Fifty patients were enrolled who had received a maximum of 2 previous regimens, including 1 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/CHOP-like regimen but no previous exposure to rituximab, fludarabine, or mitoxantrone. At baseline, 58% of patients had bulky disease (lesion > 7 cm), 56% had high-risk Follicular Lymphoma International Prognostic Index (FLIPI) scores (range, 3-5), and 22% were refractory. Treatment consisted of 4 courses of R-FM (rituximab 375 mg/m(2) intravenously on Day 1, fludarabine 25 mg/m(2) intravenously on Days 2 through 4, and mitoxantrone 10 mg/m(2) intravenously on Day 2, recycling at Day 28) and consolidation with 2 courses of fludarabine and mitoxantrone (the same regimen without rituximab). The best response (84% overall response rate including 68% complete response/complete response unconfirmed) was achieved after 4 courses of R-FM. Response rates were high regardless of age, refractoriness to last previous therapy, and FLIPI score. After a median follow-up of 4 years, the 3-year progression-free survival rate was 47%, the event-free survival rate was 41%, and the 3-year overall survival rate was 66%. Grade ≥ 3 neutropenia and infections were the most common toxicities and occurred in 72% and 14% of patients, respectively. Cytoreduction with 4 courses of R-FM was safe and highly efficient in patients with recurrent/refractory follicular lymphoma who had high tumor burden; however, better consolidation than FM is needed to further improve outcome.

A Phase II Trial of Combination Bortezomib (Velcade®) and Rituximab for Untreated “High Tumor Burden” Indolent Non-Hodgkin Lymphoma (NHL).

Traditional therapy for patients with symptomatic and/or high-risk indolent NHL most commonly includes rituximab combined with multiagent cytotoxic chemotherapy. However some patients are not able to tolerate chemotherapy due to advanced age and/ or co-morbidities. Further, combination of novel, targeted agents (non-chemotherapeutic) have been infrequently tested in newly diagnosed indolent NHL patient populations. Overall response rate (ORR) with single-agent rituximab in prior data for untreated indolent NHL was 73% with a complete remission (CR) rate of 37% following maintenance therapy (JCO 2002; 20: 4261), although a good portion of patients in that series had low tumor burden at study entry. We hypothesized that frontline bortezomib and rituximab therapy would be effective and well tolerated for untreated “high tumor burden” indolent NHL. We have conducted a Simon 2-stage phase II trial for untreated indolent NHL. All patients were required to have “high tumor burden” as defined by Groupe D'Etude des Lymphomes Folliculaires (GELF) criteria. Induction therapy consisted of 3 cycles: bortezomib given at 1.6 mg/m2 days 1, 8, 15, and 22 q35 days for all 3 cycles and rituximab at 375 mg/m2 x 4 weekly doses for cycle 1, then day 1 only for cycles 2 and 3. Abbreviated consolidation therapy was subsequently given with 1 dose of each drug q2 months x 8 months. Responses were assessed by computerized tomography (CT) according to Cheson criteria (JCO 1999). We report here the results of the first stage of this 2-stage trial. Twenty-two patients have enrolled, of whom 17 were in the 1st stage. There were 9 women and 8 men; median age was 63 years (range 46–78 years). 14 patients had follicular lymphoma (FL), 2 marginal zone lymphoma, and 1 small lymphocytic lymphoma. 13 of 17 patients had stage IV disease and 4 had stage III. The median Follicular Lymphoma International Prognostic Index (FLIPI) was 3 (range 1–4) and the median follow-up was 13 months (range 1–24 months). Responses according to cycle number are shown in Table 1. After only 1 cycle, the ORR was 29% (all partial remissions (PRs)) with 71% stable disease (SD). Following cycle 3, ORR was 59% (24% CR). From cycle 1 to 3, 4/5 PRs converted to CR, 6 SDs converted to PR, while 1 PR and 4 SDs progressed or were removed from the study at physician discretion. 8 of 12 eligible patients have completed consolidation therapy. Following consolidation, 1 PR converted to CR and 2 SDs converted to PR for an ORR of 71%. According to histology, the ORR among FL patients after consolidation therapy was 86% (CR 36%, PR 50%). Therapy was very well tolerated. Grade 3 toxicities seen were lymphopenia, partial small bowel obstruction, and fatigue (all in 1 patient); no grade 4 toxicities occurred. Furthermore, no cytopenias or neurotoxicity was seen. Accrual to the 2nd stage is being completed. In summary, we found in the 1st stage of this phase II trial that bortezomib/rituximab combination therapy for untreated high tumor burden indolent NHL is well tolerated and active. Response rates improved throughout therapy (i.e., from cycle 1 through consolidation), although the CR rate achieved was low compared with chemotherapy-based regimens. Chemotherapy-based therapy should be considered standard therapy for frontline “high tumor burden” indolent NHL, although non-chemotherapy options may be considered for patients not anticipated to tolerate intensive therapy. Furthermore, responses seen here with bortezomib/rituximab, in a uniform high tumor burden patient population, were similar to rituximab alone in lower tumor burden populations. Analysis of clinical trials/reports in indolent NHL should include critical assessment of patient selection and future trials in high tumor burden should incorporate novel therapies into rituximab-chemotherapy based regimens.Table 1. Response according to cycle/treatment.After Cycle 1After Cycle 3*Following consolidation therapy**ORR29% (5/17)59% (10/17)71% (12/17)CR0%24% (4/17)30% (5/17)PR29% (5/17)35% (6/17)41% (7/17)SD71% (12/17)12% (2/17)0%PD/off trial0%29% (5/17)29% (5/17)*Three patients had PD, while 2 patients were taken off study (without PD) at physician discretion.**Eight of 12 eligible patients have completed post-induction therapy.

Impact of Rituximab and/or High-Dose Therapy With Autotransplant at Time of Relapse in Patients With Follicular Lymphoma: A GELA Study

The treatment of patients with follicular lymphoma has changed with the introduction of high-dose therapy (HDT) with autologous stem-cell transplant then with rituximab. The effect of these two strategies on the outcome of relapsing patients with follicular lymphoma has never been compared. We analyzed two cohorts of patients treated in two successive randomized studies with the same treatment, cyclophosphamide, doxorubicin, teniposide, and prednisolone plus interferon, to evaluate the role of rituximab and HDT in salvage therapy after first disease progression or relapse. Of the 364 patients included in these two studies, 254 progressed or relapsed and constitute the population of this analysis. Among them, 98 had been treated with HDT, including 33 of them after rituximab-containing salvage regimen, and 69 with rituximab alone or combined with chemotherapy but without HDT. Patients' characteristics at diagnosis were similar in all subgroups. If event-free survival was identical for patients treated within Groupe d'Etude des Lymphomes Folliculaires (GELF) -86 or GELF-94 studies, overall survival was longer in GELF-94 study. HDT was associated with a statistically significant benefit in terms of event-free survival from relapse and survival after relapse (SAR). Rituximab was associated with a greater benefit than HDT for these two end points. When both treatments were combined, patients treated with rituximab-containing salvage regimen followed by HDT had 5-year SAR more than 90%. In follicular lymphoma, for patients treated with first-line chemotherapy the combination of a salvage regimen containing rituximab with or without HDT leads to a dramatic improvement of long-term outcome.

Efficacy of Fludarabine/Mitoxantrone/Dexamethasone Alternating with CHOP in Bulky Follicular Non-Hodgkin's Lymphoma

This phase II study investigated the efficacy of alternating fludarabine/mitoxantrone/dexamethasone (FMD) with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy for patients with high tumor burden, follicular non-Hodgkin's lymphoma. Maintenance interferon was given in a nonrandomized fashion, and a retrospective analysis of its impact was performed. A total of 87 patients were included (44 females and 43 males). The median age of patients was 56 years (range, 25–86 years). All patients had high tumor burden as defined by the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Eighty-four percent of patients (73/87) had stage III/IV disease and 99% of patients (86/87) had good performance status. The majority of patients had not been previously treated, with only 3 patients receiving prior oral alkylators or cyclophosphamide/vincristine/prednisone (COP). A total of 637 cycles of FMD/CHOP were administered and were well tolerated during this trial, the majority on an outpatient basis. The overall response rate was 95% (79 complete response/unconfirmed complete response/partial response) in the 83 evaluable patients. Event-free survival (EFS) was 28.7 months, with time to progression (TTP) at 29 months and time to treatment failure at 41 months. Overall survival was not reached. Patients had similar EFS and TTP as patients in the French GELF trial with a shorter duration of chemotherapy. Patients with a lower International Prognostic Index (IPI) score had better EFS when compared to those with a higher IPI score (median EFS not reached versus 22.6 months). Serum β2-microglobulin levels were not a significant predictive factor. An informal analysis of interferon maintenance therapy suggests that patients who tolerated the immune modifier did better than those who did not. Alternating FMD/CHOP is a feasible and effective therapeutic option for patients with high tumor burden, low-grade non-Hodgkin's lymphoma. While this regimen may not offer dramatic benefit over FMD alone, it is beneficial in those patients for whom a prompt treatment response is needed.

Cost-Effectiveness of Interferon Alfa-2b Added to Chemotherapy for High-Tumor-Burden Follicular Non-Hodgkin's Lymphoma

Recent data from GELF (Groupe d'Etude des Lymphomes Folliculaires) have shown that the addition of interferon alfa-2b (IFN) to a doxorubicin-containing regimen (CHVP: cyclophosphamide, doxorubicin, teniposide and prednisone) prolongs both progression-free survival and overall survival in high-tumor-burden follicular non-Hodgkin's lymphoma. This gain must be weighed against the incremental toxicity and cost of IFN over CHVP alone and the objective here was, to determine the marginal cost-effectiveness of additive IFN in the specific setting of high-tumor-burden follicular non-Hodgkin's lymphoma. Meta-analysis of GELF trial results employing a Markov model was used with three health states: No Progression, Progressive Disease, and Death. Treatment response, survival and toxicity data are drawn from the GELF study. The current study is based on the final analysis of 242 patients (J Clin Oncol 1998;16:2332–2338), with a six year median follow-up for overall survival (median overall survival: not reached for CHVP + IFN vs 5.6 years for CHVP Only, p = 0.008). Measurements: Quality of life data (utilities) are taken from studies with similar dosing of IFN, from Q-TwiST (quality adjusted time without symptoms or toxicity) analysis of the GELF data and from a panel of experts gathered to develop treatment models for high-tumor-burden follicular non-Hodgkin's lymphoma. Costs and quality-adjusted years of life saved were discounted at 3% per annum. Setting: Costs determined for university medical centers in the United States.Results showed that, at the median cohort age of 52, IFN add 9.9 quality-adjusted months at an added cost of $13,900 (marginal cost-effectiveness of $16,900 per quality-adjusted life year, or QALY). A more complex, two-stage model approximates the actual cohort survival curves much better than a simple, one-stage model, but both models yield essentially the same marginal cost-effectiveness. Sensitivity analysis to quality of life on IFN shows marginal cost-effectiveness ranging from $15,200/QALY (no penalty for IFN) to $21,300/QALY (20% quality adjustment, greater than that reported). The model is quite insensitive to the probability of IFN toxicity. The model is moderately sensitive to the efficacy of IFN in delaying progression, particularly in the first 18 months (pProgI), but the marginal cost-effectiveness does not rise to $50,000/QALY until pProgI increases 220% from the baseline. Although the model is moderately sensitive to the cost of IFN (cIFN), marginal cost-effectiveness is below $50,000/QALY for values of cIFN below $2580/month (baseline cIFN = $850/month, corresponding to a marginal cost-effectiveness of $16,900/QALY in the baseline case). If the model is modified to reflect the 14% overall survival advantage at five years found in trials utilizing more intensive initial chemotherapy (including the GELF trial), then the marginal cost-effectiveness drops to $11,900/QALY in the baseline case. In condusion, based on data from the GELF study, low-dose interferon alfa-2b is cost-effective when added to CHVP therapy in the treatment of high-tumor-burden follicular non-Hodgkin's lymphoma. The analysis is robust: the model employs very conservative assumptions, and additive IFN remains cost-effective over wide ranges of variables in sensitivity analyses. The marginal cost-effectiveness is best expressed as being in the range of $12,000/QALY to $17,000/QALY in the baseline case. A simple Markov model can be used to describe treatment regimens with distinct periods of therapy.

Quality-of-life-adjusted survival analysis of interferon alfa-2b treatment for advanced follicular lymphoma: an aid to clinical decision making.

To evaluate the trade-off of toxicity versus improved clinical outcome with interferon alfa-2b (IFN) administered concomitantly with a doxorubicin-containing regimen for the treatment of advanced follicular lymphoma. A quality-of-life-adjusted survival analysis (Quality-Adjusted Time Without Symptoms or Toxicity [Q-TWiST]) was applied to the Groupe d'Etude des Lymphomes Folliculaires (GELF) trial 86, which compared a regimen of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) versus CHVP plus IFN in 242 patients with confirmed follicular lymphoma. CHVP was administered monthly for 6 months then every other month for 12 months. The IFN dosage was 5 x 10(6) U three times weekly for 18 months. After a median follow-up duration of 72 months, the IFN group gained a mean of 12.3 months of progression-free survival (PFS) and 7.4 months of overall survival (OS), but also experienced additional time with grade 3 or worse toxicity compared with the CHVP group. Sensitivity analysis demonstrated that CHVP plus IFN provided a greater amount of quality-adjusted survival regardless of the relative quality-of-life valuations placed on time with toxicity due to CVHP alone, time with toxicity due to CHVP plus IFN, and time following disease progression. This gain was significant (P < .05) in all cases except for patients who consider time with toxicity to have a low relative value and time following disease progression to have a high relative value. In patients with advanced follicular lymphoma, the clinical benefits of concomitant IFN can significantly offset the associated grade 3 or worse toxic effects. The magnitude of this clinical benefit depends on an individual patient's relative quality-of-life valuations for time with toxicity and time following disease progression.