Extranodal Presentation in Limited Stage DLBCL As a Prognostic Marker in Three Sequential SWOG Trials S0014, S0313 and S1001 (NCT00005089, NCT00070018, NCT01359592)

Introduction Several recent pivotal trials have changed the standard of care for patients with limited stage (LS) diffuse large B-cell lymphoma (DLBCL) to minimize the number of chemoimmunotherapy cycles and/or eliminate the need for radiotherapy (RT) without compromising excellent long-term outcomes (Poeschel 2019; Persky 2020; Bologna 2021). However, there may be subsets of patients where an abbreviated treatment approach is insufficient. With this in mind, Bobillo (2021), retrospectively reviewed pts with LS DLBCL treated with RCHOP (4-6 cycles) +/- RT and reported an extranodal (EN) presentation had shorter PFS and OS compared with nodal presentation. In these pts, consolidative RT prolonged survival in pts with EN disease, especially those with a positive PET scan at the end of chemotherapy. We sought to validate these findings by analyzing patients with LS DLBCL treated on 3 consecutive SWOG studies (S0014, S0313, S1001). Methods From 4/1/00 - 6/1/16, 234 eligible patients with non-bulky (exception of 2 patients on S0014) LS DLBCL were accrued to S0014 (n=60), S0313 (n=43), or S1001 (n=131), Enrolled pts received therapy with RCHOP x 3 + involved field radiotherapy (IFRT; 26%); RCHOP x 3 + IFRT + ibritumomab tiuxetan (24%); or RCHOP x 4 (51%). In S1001, an interim PET (iPET) scan was performed after RCHOP x 3 and considered negative if the Deauville Score was ≤3. Fisher's exact test compared the distribution of the characteristics and treatments received at 2-sided a of .05. PFS was calculated from date of randomization until progression/relapse/death. OS was calculated from date of randomization until death. PFS and OS estimates were calculated using the Kaplan-Meier method. Results Median follow-up is 7 years (range 1.1 - 15.8 years). Median age was 62 (range 18 - 85) and 68% had stage-modified international prognostic index (sm-IPI) of 0-1. Of the 234 pts, 104 (44%) had EN disease. Most common sites of EN disease were head & neck (n=55; nasopharynx=14; oral cavity=17; orbit=2; parotid=4; sinus=7; submandibular gland=1; thyroid=9; vocal cord=1), skin/soft tissue/muscle (n=12), gastrointestinal tract (n=11), bone (n=6), and breast (n=6). Clinical characteristics (age, stage, LDH, sm-IPI) and treatments received between EN and nodal disease groups were not statistically different. For the whole group, estimated 10-year PFS and OS were 71% (95% CI: 64% - 77%) and 77% (95% CI: 69% - 83%), respectively. For patients with extranodal versus nodal disease, there was no difference in the estimated 10-year PFS (74% vs 68%; 2-sided logrank p-value=.51, Figure 1A) or 10-year OS (77% vs 77%; 2-sided logrank p-value=.65; Figure 1B). For the 55 pts with EN disease of the head & neck, estimated 10-year PFS and OS were 61% (44% - 74%) and 77% (63% - 87%). Among the 104 pts with EN disease who received versus did not receive IFRT, there was no difference in the estimated 5-year PFS (83% vs 87%; 2-sided logrank p-value=.52) or 5-year OS (85% vs 92%; 2-sided logrank p-value=.28). Of 55 pts with EN disease treated on S1001, 5 (9%) pts had iPET+, 47 (85.5%) pts had iPET-, and 3 (5.5%) pts did not have iPET. In the 5 pts with EN disease and iPET+, all received IFRT and 1 progressed. There were 50 pt deaths. Of these, cause of death was lymphoma in 16 (32%), second cancer in 6 (12%), other in 15 (30%), and unknown in 13 (26%). Conclusions Patients with LS DLBCL treated on 3 SWOG studies had excellent and prolonged PFS and OS regardless of EN versus nodal presentation, or whether they received consolidative IFRT or not. Our dataset does not support EN disease as an adverse prognostic factor for pts with LS DLBCL. As such, we do not recommend consolidation with radiotherapy in pts with non-bulky LS DLBCL presenting with EN disease. There were too few patients with EN disease treated on S1001 that had iPET+ to make a recommendation for PET-adapted IFRT. The majority of pts in our dataset had EN disease of the head & neck, which appears to have similar survival as nodal presentation. As seen in previous studies, there was a continuous rate of relapse without plateau of the PFS curves. Most common known cause of death in was lymphoma, which supports the need for long term follow-up. Figure 1 Figure 1. Disclosures Stephens: Celgene: Consultancy; Mingsight: Research Funding; Arqule: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; JUNO: Research Funding; Novartis: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy; Epizyme: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Kahl: Abbvie, ADCT, AstraZeneca, Beigene, Celgene, Teva, Janssen, MTEM, Bayer, InCyte, Adaptive, Genentech, Roche, MEI, KITE, TG Therapeutics, Epizyme, Takeda: Consultancy; Abbvie, BeiGene, AstraZeneca, Acerta: Research Funding; Research to Practice: Speakers Bureau. Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Friedberg: Bayer: Other: DSMC ; Novartis: Other: DSMC ; Acerta: Other: DSMC . OffLabel Disclosure: ibritumomab tiuxetan is not FDA approved for marketing in DLBCL

Utilization and Cost Effectiveness of First-Line Yttrium-90 Ibritumomab Tiuxetan in Low-Grade Follicular and Marginal Zone Lymphomas Compared to Standard of Care Bendamustine Plus Rituximab: A Real-World Experience

Background Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. This study evaluates the utilization and cost-effectiveness of (90)Y-IT in the first line treatment for patients with previously untreated low-grade FL (UFL) and marginal zone lymphoma (UMZL) treated at our institution with (90)Y-IT. Methods We utilized the Advanced Text Explorer (ATE) and the Lymphoma SPORE databases to identify two groups of patients with UFL, WHO grade 1-2, and UMZL who received treatment with either (90)Y-IT or bendamustine plus rituximab (BR) at Mayo Clinic Cancer Center between January 2003 and December 2019. We excluded all patients who had >25% bone marrow involvement with lymphoma for the BR group as this was a requirement for (90)Y-IT treatment. Inverse propensity weighting was utilized to balance the groups for baseline patients and disease characteristics. We use progression-free survival (PFS) as a denominator for the cost effectiveness/utilization evaluation. We identified meaningful and retrospectively measurable outcomes to compare between the groups. we extracted the following data; number of clinic visits in the first year after therapy, emergency room visits, number of hospital admissions, number of hospitalization days, numbers of days on the floor and ICU, number of infections, number of neutropenic fever hospitalizations, number of C-difficile events, number of blood products transfusions, overall use of growth factors due to therapy induced neutropenia, average number of times a growth factor was used, and the number of therapeutic use days. We defined days of therapeutic use as the number of days a treatment was administered on. We also calculated the average cost of the induction treatment when utilizing either (90)Y-IT or BR. The therapeutic cost included only the cost of the medications/therapies and their administration. Results Our cohort consists of a total of 143 patients - 64% (92/143) received BR and 36% (51/143) received (90)Y-IT (see Table-1 for clinical characteristics).The median follow-up from the time of therapeutic administration for the (90)Y-IT group was 5.3 years (95% CI; 4.2, 6.2) with one death and 4.7 years (95% CI; 3.9, 4.9) for the BR group with 6 deaths. The ORR was 100% in (90)Y-IT group with 94% achieving complete response (CR) while ORR in the BR group was 98% with 95% achieving CR. Rituximab maintenance was utilized in 33% of BR patients compared to only 6% in patients who received (90)Y-IT, p=0.002. After utilizing inverse propensity weighting (Figure-1), 5 years PFS was 76% for the (90)Y-IT group and 75% for the BR group, p=0.63 (Figure-2). We evaluated the average treatment effect of (90)Y-IT compared to BR on utilization outcomes, Table-2. (90)Y-IT required an average of 4.5 clinic visits less within the first year after treatment compared to BR group, p<0.001. (90)Y-IT patients had an average of 10 days less of therapeutic use days compared to the BR group, p<0.001. Patienta had similar admission rates to the hospital in both groups. However, when patients were admitted to the hospital in the first year after treatment, those who received (90)Y-IT spent an average of 1.5 days less in the hospital compared to the BR group, p=0.046. The overall use of growth factors was 40% less in the (90)Y-IT group as compared to the BR group, p<0.001. The therapeutic cost of induction of (90)Y-IT was 54% less than that of 6 cycles of BR. Transformation to a high grade of lymphoma was seen in 4 patients in the BR group and 2 patients in the (90)Y-IT group. There was only one case of myelodysplastic syndrome in the BR group and none in the (90)Y-IT group. Conclusion Radio-immunoconjugate therapy with (90)Y-IT is a very convenient and cost-effective treatment for low-grade UFL and UMZL. This is especially important amidst the COVID-19 pandemic as it requires less contact with the health system with decreased number of therapeutic days, clinic visits, use of growth factors and number of hospitalization days. The cost of the therapeutic agents and their administration was also significantly lower for the (90)Y-IT which could help reducing the burden on the health system. Figure 1 Figure 1. Disclosures Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding. Tun: Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding; Gossamer Bio, Acrotech: Consultancy. OffLabel Disclosure: We are describing the use of Yttrium-90 ibritumomab tiuxetan in the first line setting in comparison to the bendamustine plus rituximab which is the standard of care

Mega-dose 90Y-Ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCL), though outcomes are worse in aggressive disease and most patients will still experience relapse. Radioimmunotherapy (RIT) using 90Y-Ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that mega-doses of 90Y-Ibritumomab tiuxetan with reduced-intensity conditioning (RIC) could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-Ibritumomab tiuxetan (1.5mCi/kg, maximum 120mCi), fludarabine, then 2Gy total body irradiation (TBI) prior to HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y activity of 113.6 mCi (range 71.2-129.2) was administered delivering a median of 552cGy to liver (range 499-2411cGy). The estimated 1 and 5-year PFS was 55% (95% CI, 31-73%) and 50% (95% CI, 27-69%) with a median PFS of 1.57 years. The estimated 1- and 5-year overall survival (OS) was 80% (95% CI, 54-92%) and 63% (95% CI, 38-81%) with a median OS of 6.45 years. Sixteen patients (80%) experienced grade ≥3 toxicities, although nonrelapse mortality was 10% at 1-year. No patients developed secondary AML/MDS. Mega-dose 90Y-Ibritumomab tiuxetan, fludarabine, and low-dose TBI followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified endpoint while producing nonhematologic toxicities comparable to standard RIC regimens. (Registered at ClinicalTrials.gov as NCT01434472).

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

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