Yttrium-90 Ibritumomab Tiuxetan Research Articles

The asymptomatic follicular lymphoma (AFL) trial: single-agent rituximab immunotherapy versus 90Y-ibritumomab tiuxetan radioimmunotherapy (RIT) for patients with new, untreated follicular lymphoma

Patients with asymptomatic follicular lymphoma (AFL) are candidates for observation or immunotherapy. Given the effectiveness of radiation therapy in FL, another option is 90Yttrium-ibritumomab tiuxetan radioimmunotherapy (RIT). We conducted a trial where untreated AFL patients were randomized to rituximab 375 mg/m2 weekly × 4 or rituximab 250 mg/m2 days 1, 8, and 0.4 mCi/kg (maximum 32 mCi) of RIT day 8. Twenty patients were enrolled before the study was halted due to unavailability of RIT. The ORR for rituximab and RIT were 90% and 80%, respectively; the CR rate at 6 months was 30% and 60%, respectively. After a median follow-up of 67 months, eight patients have progressed—three in the rituximab arm and five in the RIT arm and five have required systemic therapy. All patients remain alive. Both agents are highly active for AFL. The 1-week treatment with RIT and sparing of T-cells make combination therapy with newer agents attractive.

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

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

Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine+Rituximab in Low-grade Lymphomas.

Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immunotherapeutic agent. It has shown an excellent therapeutic activity with high tolerability against previously untreated follicular lymphoma (FL) and marginal zone B cell lymphoma (MZL). It is an attractive therapeutic option as the treatment schedule is short and convenient. The aim of our study is to determine the cost-effectiveness of (90)Y-IT in comparison to the standard-of-care bendamustine+rituximab (BR) in the first-line treatment of low-grade FL (LG-FL) and MZL in the real world. We included all patients who were treated with standard-dose (90)Y-IT for previously untreated LG-FL and MZL at the Mayo Clinic Cancer Center (N=51). A comparator arm with a historical cohort of previously untreated LG-FL and MZL patients who received BR was used (N=92). Inverse propensity weighting was utilized to balance the 2 study arms. There were no differences in terms of overall response rate (100% vs. 98%, P=.18), complete response rate (94% vs. 95%, P=.91), or 5 years progression-free survival (76% vs. 75%, P=.63) between patients who received (90)Y-IT and BR, respectively. Within the first year, patients who received (90)Y-IT required an average of 4.5 fewer oncology clinic visits (P < .001), an average of 10 fewer days of therapeutic use (P < .001), and 40% less use of growth factors (P < .001) as compared to the BR group. The direct therapeutic cost of (90)Y-IT treatment was 54% less than that of 6 cycles of BR. The findings suggest that (90) Y-IT is more cost-effective than BR and is a viable alternative in up-front management of LG-FL and MZL.

Real-world data from yttrium-90 ibritumomab tiuxetan treatment of relapsed or refractory indolent B-cell non-Hodgkin's lymphoma: J3Zi Study.

Yttrium-90 ibritumomab tiuxetan (90YIT) is a radioimmunotherapy agent in which the radioisotope yttrium-90 is bound to ibritumomab via tiuxetan as a chelating agent, and is used for relapsed or refractory low-grade B-cell non-Hodgkin's lymphoma (rr-B-NHL). We conducted a joint study to evaluate the clinical outcome of 90YIT. The J3Zi study is composed of data from patients receiving 90YIT for rr-B-NHL from the top three institutions with 10years of 90YIT treatment experience from October 2008 to May 2018 in Japan. The efficacy, prognostic factors and safety of 90YIT were retrospectively evaluated. Data from 316 patients were analyzed; the mean age was 64.6years and the median number of prior treatments was 2. The median PFS was 3.0years, the final OS rate was over 60%, and the median OS was not reached during the study period. Significant factors influencing PFS were sIL-2R ≤ 500 (U/mL) and no disease progression within 24months of first treatment. Significant factors influencing OS were number of prior treatments ≤ 2 and sIL-2R ≤ 500 (U/mL). The PFS and OS rates were found to be significantly higher in the late half era (2013 to 2018) than in the early half era (2008 to 2013) during the study period. Prognosis following 90YIT treatment was improved in the late half era compared to the early half era. As treatment using 90YIT increased, administration of 90YIT shifted to the earlier treatment line. This may have contributed to the improvement of prognosis found in the late era. (UMIN000037105).

Real World Long-term Follow-up Experience with Yttrium-90 ibritumomab tiuxetan in Previously Untreated Patients with Low-Grade Follicular Lymphoma and Marginal Zone Lymphoma

IntroductionYttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immuno conjugate. Clinical trials of (90)Y-IT as a first-line stand-alone treatment in follicular lymphoma (FL) and/or marginal zone lymphoma (MZL) showed high efficacy. However, long-term survival outcomes and toxicities are not well-defined. MethodsWe report a retrospective single-institution, multi-center study of (90)Y-IT in previously untreated low grade (LG)-FL and MZL at Mayo Clinic Cancer Center between January 2000 and October 2019. We selected patients with LG-FL and MZL who received standard-dose (90)Y-IT as a single agent in the first line setting. ResultsThe cohort (n = 51) consists of previously untreated LG-FL (n = 41) or MZL (n = 10). Median follow-up was 5.3 years (95% CI; 4.2, 6.2). Overall response rate (ORR) was 100% with complete response rate (CR) of 94%. Continuous CR was observed in 59% patients who had more than 2 years of follow-up. Long-term CR (>7 years) was seen in 25% of patients. Median progression free survival (mPFS) for the whole cohort was not reached (NR) (95% CI; 4.9, NR). Bulky disease was associated with shorter median PFS of 3.5 years (CI 95%; 0.8, 4.9) compared to non-bulky disease NR (CI 95%; 5.8, NR), P = .02. The incidence of grade 3 or higher thrombocytopenia, neutropenia and anemia were 47%, 37%, and 4% respectively. No therapy-related myelodysplasia or acute myeloid leukemia were observed. ConclusionLong real-life follow-up showed that single-agent (90)Y-IT is highly efficacious with durable long-term survival in previously untreated LG-FL and MZL without significant risk for secondary malignancies.

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

BackgroundYttrium-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.MethodsWe 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.ResultsOur 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.ConclusionRadio-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. [Display omitted] DisclosuresCerhan: 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

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

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

Initial report of a phase II study with R-FND followed by ibritumomab tiuxetan radioimmunotherapy and rituximab maintenance in patients with untreated high-risk follicular lymphoma

R-FND (rituximab, fludarabine, mitoxantrone, and dexamethasone) can induce molecular remissions in indolent lymphoma. The addition of 90yttrium ibritumomab tiuxetan (90YIT) radioimmunotherapy following first-line induction treatment in patients with advanced follicular lymphoma (FL) may improve remission rates. We now report 10-year follow-up results from our sequential treatment approach with an abbreviated regimen of R-FND followed by 90YIT consolidation and rituximab maintenance. Forty-nine patients were enrolled; 47 received treatment. Patients had high-risk (FLIPI score ≥3) FL of grade 1–3A and stage III/IV with adequate hematologic function. Following R-FND, the complete and partial response rates were 91% and 8.5%, respectively. After 90YIT consolidation, the CR rate increased to 97%. The 10-year PFS rate was 49%. The most common non-hematologic, grade 3 or 4 adverse events were fatigue, dyspnea, and myalgia. Five developed myelodysplastic syndrome (MDS). This treatment approach is most appropriate in FLIPI-based high-risk patients whose outlook with standard therapy is inadequate.

Efficacy and safety of yttrium-90 ibritumomab tiuxetan in the treatment of non-Hodgkin lymphoma.

103 Background: Yttrium 90-labeled ibritumomab tiuxetan (Zevalin) is a radioimmunotherapy agent which combines the action of a beta-emitting isotope, yttrium-90, with the anti-CD20 monoclonal antibody, rituximab. The purpose of this study was to evaluate the efficacy of Zevalin in the treatment of Non-Hodgkin Lymphoma (NHL) in terms of response to therapy, overall survival (OS) and progression free survival (PFS). Methods: A total of 171 patients with NHL referred for treatment with Zevalin between September 2005 and January 2017 were identified for retrospective analysis. Clinical characteristics, treatments, and outcomes were extracted from clinical chart review. Survival rates and survival curves were generated using Kaplan-Meier analysis. Chi-square and independent student t test were used for comparison of categorical variables. Multivariate analysis (MVA) Cox proportional hazards ratios (HR) model was used to assess OS and PFS. Results: Of the 171 patients referred for treatment, median age was 70 years old, 54% were male (n = 93), and each patient had received a median of 2 prior chemotherapy regimens. The majority of patients were treated for follicular lymphoma (n = 107) and diffuse large B-cell lymphoma (n = 34). Seventy-three patients (53%) achieved complete response, and 23 patients achieved partial response (17%). One-year progression free survival was 71%, and median PFS was 31 months. Adverse events included cytopenic events, GI side effects, and mucocutaneous toxicity. Conclusions: Use of Zevalin for treatment of NHL demonstrated a significant improvement in PFS. In addition to improved efficacy, Zevalin was well-tolerated in this study and demonstrated an adequate safety profile. Further considerations will be given as to which treatment factors are associated with a complete response and improved PFS.

Long-Term Outcome of Patients with Low-Grade Follicular Lymphoma Treated with Yttrium-90 Ibritumomab Tiuxetan: The Mayo Clinic Experience

Background Follicular lymphoma (FL) is the second most common lymphoma accounting for approximately 15% of all non-Hodgkin's lymphoma (NHL). Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. It is approved in relapsed/refractory low-grade NHL and as consolidation after upfront induction chemoimmunotherapy for FL. This study analyzed patients with previously untreated (UFL) or relapsed/refractory low-grade FL (RFL) treated at our institution with (90)Y-IT. It represents the largest reported cohort for therapeutic use of (90)Y-IT in low-grade FL. Methods Medical records of patients with low-grade FL (WHO grade 1-2) who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2003 and December 2018 were analyzed. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Our cohort consists of 137 patients - 29% (40/137) with UFL and 71% (97/137) with RFL. The median age at diagnosis was 60 years (range, 18-86) with 54% (74/137) males. The median number of previous treatments in RFL patients was 1 (range, 1-5). ECOG performance status at the time of treatment was 0 in 90% and 1 in 10% of patients. 87% (119/137) had stage III/IV disease at the time of (90)Y-IT therapy. The median follow up from the time of (90)Y-IT therapy was 10.2 years (95% CI; 8.8, 11.6); 69% (95/137) of patients are alive. The ORR was 100% in UFL with 93% (37/40) CR while ORR in UFL was 93% (90/97) with 73% (71/97) CR. 45% (48/108) of the CR patients remain in continuous CR (CCR) with a median follow-up of 7 years (95% CI; 5.2, 9.9). CCR was observed in 55% (22/40) of UFL patients compared to 27% (26/97) of RFL patients. 63% (86/137) of patients had relapsed. More relapses occurred in the RFL group (69/97; 71%) compared to the UFL group (17/40; 43%), (p=0.002). In the entire cohort, the median PFS was 2.5 years (95% CI; 2.1, 3.5) and TTNT was 3.6 years (95% CI; 2.5, 4.7). Median PFS was significantly higher in UFL group compared to RFL group- 4.1 years (95% CI; 2.3, NR) vs 2.2 years (95% CI; 1.6, 3.1), respectively (Figure 1-A). Median TTNT was higher in UFL group compared to RFL group- NR (95% CI; 4.1 years, NR) vs 2.4 years (95% CI; 2, 3.6), respectively (Figure 1-B). Median OS (entire cohort) was 18 years (95% CI; 15.8, NR) with no statistically significant difference between UFL group and RFL group; NR (95% CI; NR, NR) vs 18 years (95% CI; 12.3, 20.5), respectively (Figure 1-C). Transformation to high grade lymphoma was seen in 19% (18/97) in RFL group compared to 2.5% (1/40) in UFL group, (p=0.005). Median time to transformation was 4.3 years (range, 1-11). More patients developed therapy-related myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in the RFL group 14% (14/97) compared to 2.5% (1/40) in the UFL group (p= 0.02). Median time to develop MDS/AML was 3.3 years (range, 0-9.7). Grade ³3 neutropenia was observed in 46% of patients with median time to recovery of 21 days (range, 2-706). Grade ³3 thrombocytopenia was observed in 47% of patients with median time to recovery of 23 days (range, 7-548). Eighteen patients required growth factors support and 14 required transfusions. Non-hematologic AEs included mild to severe fatigue in 35 patients. Conclusion Radio-immunoconjugate therapy with (90)Y-IT is an effective single-agent regimen for low-grade FL. The response and survival data in this large real-world cohort is superior to the pivotal trials of this agent conducted nearly 20 years ago. The data in untreated FL is also of interest and provides the rationale for our current randomized phase 2 trial in untreated FL (https://clinicaltrials.gov/show/NCT02320292). Long-term complete remission (&gt;7 years) was seen in 35% of the study population. Based on these promising results, clinical trials combining RIC with novel agents that could potentiate its effects are warranted. Figure 1 (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UFL) and patients with relapsed/refractory FL (RFL), (B) Time to next therapy; comparing time to starting next line of treatment after (90)Y-IT treatment between UFL and RFL, (C) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UFL and RFL. Figure 1 Disclosures Tun: DTRM Biopharma: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; Curis: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. It is approved in relapsed/refractory low-grade NHL and as consolidation after upfront induction chemoimmunotherapy for FL. We are discussing its use as a frontline therapy in low grade FL.

Nonmyeloablative Allogeneic Transplantation (NMAT) Confers an Overall Survival Benefit with Similar Non-Relapse Mortality When Compared to Autologous Stem Transplantation (ASCT) for Patients (pts) with Relapsed Follicular Lymphoma (FL)

Nonmyeloablative Allogeneic Transplantation (NMAT) Confers an Overall Survival Benefit with Similar Non-Relapse Mortality When Compared to Autologous Stem Transplantation (ASCT) for Patients (pts) with Relapsed Follicular Lymphoma (FL)

Long-Term Outcome of Patients with Marginal Zone Non-Hodgkin Lymphoma (MZL) Treated with Yttrium-90 Ibritumomab Tiuxetan: The Mayo Clinic Experience

Background MZL is a low-grade non-Hodgkin's lymphoma (NHL) which involves lymph nodes, extranodal sites, or spleen. It is sensitive to radiation therapy, which is used in localized disease with curative intent. Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) that targets CD20. It is approved for relapsed/refractory low grade and follicular NHL. The data on its use in MZL is limited. We present long-term outcome of the largest reported cohort of MZL patients who received (90)Y-IT. Methods Medical records of patients who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2004 and December 2018 were analyzed. We selected patients with MZL and reviewed clinical data including age, gender, MZL type, clinical stage (Ann Arbor Staging System), treatment response, (90)Y-IT related adverse effects (AEs), as well as lymphoma and treatment related events. All patients received (90)Y-IT according to the standard treatment guidelines. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Twenty-one patients were identified (Table 1). The median age at diagnosis was 60 years (range, 11-81) and 71% (15/21) were female. 52% (11/21) were previously-untreated (UMZL) while 48% (10/21) were relapsed (RMZL). The median number of pretreatments in RMZL patients was 2 (range, 1-3). ECOG performance status at the time of treatment was 0 in 90% (19/21) and 1 in 10% (2/21). 62% (13/21) were stage III/IV disease at the time of (90)Y-IT therapy. The median follow-up was 8.5 years (95% CI; 4.5, 12.4); 17 (81%) patients remain alive. The ORR was 91% (19/21) with the two non-responders being in the RMZL group. The CR rate was 81% (17/21) and 65% (11/17) remain in CR at a median follow-up of 5.7 years (95% CI; 1.4, 11). Nine (43%) patients had a relapse during the study period. More relapses occurred in the RMZL group (7/10; 70%) compared to (2/11; 18%) in the UMZL group. Median PFS (whole cohort) was 10 years (95% CI; 2.1, NR) and TTNT (whole cohort) was not reached (NR) (95% CI; 2.1 years, NR). Median PFS was significantly higher in UMZL group compared to RMZL group NR (95% CI; 2.5 years, NR) vs 2.1 years (95% CI; 0.17, 9.9), respectively (Figure 1-A).Median OS (whole cohort) was 19.3 years (95% CI; 8.9, 19.3) without statistical difference in between UMZL group and RMZL group NR (95% CI; NR, NR) vs 16.6 years (95% CI; 9, 19.4), respectively (Figure 1-B). None of the 11 UMZL patients died at median follow up of 4.7 years (95% CI; 1.6, 9.2). All 4 deaths were in the RMZL group with 3 dying of transformation to high-grade lymphoma at 8, 22, and 25 months post-(90)Y-IT treatment. One patient died of myelodysplastic syndrome 7.3 years post-(90)Y-IT treatment while in CR. Toxicities were primarily hematologic. Grade ³3 neutropenia was observed in 6/21 (29%) patients with median time to nadir of 48.5 days (range, 19-70) and median time to recovery to normal absolute neutrophil count of 39.5 days (range, 7-476). Grade ³3 thrombocytopenia was observed in 3 (14%) patients with median time to nadir of 35 days (range, 19-357) and median time to recovery of 21 days (range, 2-538). Grade ³3 anemia was observed in only one patient. Only two patients required transfusions and growth factor support. Non-hematologic AEs included mild to severe fatigue in 4 patients. Conclusion RIC with (90)Y-IT is efficacious and well-tolerated in patients with previously untreated as well as relapsed MZL. As expected it appears to be more efficacious in previously untreated patients. Long-term complete remission (&amp;gt;5 years) was observed in 52% of the study population (43% of UMZL and 9% of RMZL). Combination of efficacy, tolerability, and treatment schedule most convenient for patients makes (90)Y-IT a reasonable alternative to systemic therapy with immunotherapy, chemotherapy, or chemo-immunotherapy in management of MZL. Figure 1: (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UMZL) and patients with relapsed MZL (RMZL), (B) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UMZL patients and RMZL patients. Disclosures Tun: Curis: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: The use of Yttrium-90 ibritumomab tiuxetan as a first line treatment for marginal zone lymphoma

Yttrium-90 ibritumomab tiuxetan consolidation versus rituximab maintenance therapy for indolent non-Hodgkin lymphoma

Abstract Background Indolent non-Hodgkin lymphoma is a common B-cell lymphoma that is considered incurable. Post-remission therapies seek to prolong survival. Rituximab (R) maintenance and yttrium-90 ibritumomab tiuxetan (90Y-IT) consolidation are promising post-remission therapies. However, until now, no trials have compared their efficacy and adverse effects. Method To this effect, we retrospectively examined 75 patients with consecutive indolent lymphoma with complete response or partial response after initial chemotherapy between January 2008 and December 2018. Patients received either 90Y-IT consolidation (27 patients) or R maintenance therapy (2 years, every 2 months, 48 patients). Progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT) from the start of post-remission therapies were estimated using the Kaplan-Meier Method, and adverse effects were evaluated. Result After a median follow-up of 3.6 years (range, 0.5-13.1 years), 5-year PFS of 90Y-IT consolidation and R maintenance therapy were 75.5% and 82.4%, respectively (log-rank test, p = 0.839). OS of 90Y-IT consolidation and R maintenance therapy were 100% and 97.8%, respectively (log-rank test, p = 0.465). Median TTNT of 90Y-IT consolidation and R maintenance therapy were not achieved (log-rank test, p = 0.804). The most common adverse event with 90Y-IT consolidation was hematotoxicity, whereas lower rates and grades of cytopenia were observed in patients who received R maintenance therapy. Secondary malignancies were observed in 1 patient (4%) who received 90Y-IT consolidation and in 2 patients (4.2%) who received R maintenance therapy (Fisher’s exact test, p = 1.00). Conclusion 90Y-IT consolidation and R maintenance therapy were similar with respect to PFS, OS, and TTNT. However, the features and grades of adverse effects were significantly different. Patient-specific characteristics should be considered while choosing between these post-remission therapies.

Safety and Efficacy of Myeloablative Conditioning Autologous Stem Cell Transplantation, Targeted Immunotherapy, and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation in Children, Adolescents, and Young Adults with Relapsed/Refractory Mature B-Cell Non-Hodgkin Lymphoma

Background Despite high cure rates for children, adolescents and young adults (CAYA) with mature B-cell non-Hodgkin lymphoma (B-NHL) (Cairo, JCO, 2012), the results are dismal in those with relapsed/refractory (r/r) disease following reinduction therapy with myeloablative conditioning (MAC) and autologous stem cell transplantation (AutoSCT) (Cairo, BBMT, 2013). Sequential MAC AutoSCT and reduced intensity conditioning (RIC) allogeneic stem cell transplantation (AlloSCT) has achieved 59% 10-year event-free survival (EFS) in CAYA with Hodgkin (Satwani/Cairo, Leukemia, 2015). The addition of Y-ibritumomab tiuxetan to an RIC based regimen prior to AlloSCT in a cohort of adults with high risk B-NHL was proven to be safe and efficacious (Boubdallah, Annals of Oncology, 2015) and may further improve outcomes. Objective To investigate the safety and efficacy in CAYA with poor risk r/r B-NHL of sequential MAC AutoSCT followed by RIC AlloSCT with or without targeted radioimmunotherapy. Design/Methods CAYA patients with poor risk r/r mature B-NHL who underwent MAC AutoSCT followed by RIC AlloSCT ± targeted radioimmunotherapy are included in this study. Twelve of thirteen patients with chemo-sensitive disease underwent sequential MAC AutoSCT followed by RIC AlloSCT (Fig 1). Six patients received radioimmunotherapy with Yttrium-90 ibritumomab tiuxetan prior to MAC. In addition to EFS, patients were assessed for time to hematological recovery, graft failure, whole blood chimerism, aGVHD ≥ Gr 2 and extensive chronic GVHD. Results Thirteen patients with a mean age of 15.3 years and mean follow-up of 48 months were analyzed. Median time to neutrophil and platelet engraftment is 18.8 and 36.4 days, respectively (Fig. 2). Whole blood chimerism at D+100 is 98.4 ± 1.5 %. Eleven patients are in complete remission with an EFS of 91% (Fig. 3). The transplant-related mortality was 0% and no graft failures developed. Conclusions CAYA with r/r B-NHL receiving MAC AutoSCT, targeted radioimmunotherapy, and RIC AlloSCT can achieve long-term EFS. The combination of radioimmunotherapy comprised of Yttrium-90 ibritumomab tiuxetan with MAC AutoSCT was safe and effective in our cohort. A potential graft versus lymphoma effect may explain the favorable outcomes in this cohort of patients with otherwise dismal outcomes.

Yttrium-90 ibritumomab tiuxetan consolidation versus rituximab maintenance therapy after induction chemotherapy in patients with indolent non-Hodgkin lymphoma: a single-institution experience

ABSTRACTOBJECTIVES: Indolent B-cell non-Hodgkin lymphomas (iNHLs) are considered incurable. Rituximab maintenance and yttrium-90 ibritumomab tiuxetan (90Y-IT) consolidation are promising post-remission therapies. However, only one randomized phase II trial has compared their efficacies and adverse effects. Here, we compared the efficacy and safety of 90Y-IT consolidation and rituximab maintenance in iNHL patients.METHODS: We retrospectively examined 75 iNHL patients with complete or partial response after initial chemotherapy between January 2008 and December 2018. Twenty-seven patients received 90Y-IT consolidation and 48 received rituximab maintenance (every 2 months for 2 years). Progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT) were estimated from the start of the treatment, and adverse effects were evaluated.RESULTS: After a median 3.6-year follow-up, the 5-year PFSs of the 90Y-IT consolidation and rituximab maintenance groups were 75.5% and 82.4%, respectively (log-rank test, p = 0.839), and the 5-year OSs were 100% and 97.8%, respectively (log-rank test, p = 0.465). The corresponding median TTNTs were not reached (log-rank test, p = 0.804). The commonest adverse effect with 90Y-IT consolidation was hematotoxicity; lower rates and grades of cytopenia were observed in patients who received rituximab maintenance. Secondary malignancies were observed in 1 patient (4%) who received 90Y-IT consolidation and 2 patients (4.2%) who received rituximab maintenance (Fisher’s exact test, p > 0.99).CONCLUSION: 90Y-IT consolidation and rituximab maintenance were similar with respect to PFS, OS, and TTNT. However, the features and grades of adverse effects significantly differed. Patient-specific characteristics should be considered when deciding post-remission treatments.

Durability Results of Non-Myeloablative (NMA) Allogeneic Stem Cell Transplantation (alloSCT) for Relapsed Follicular Lymphoma: 17- Year Experience

Abstract Purpose: We have previously reported the outcomes of NMA alloSCT in 47 patients with relapsed/chemosensitive follicular lymphoma (FL) who received a matched sibling donor (MSD) after FCR conditioning (Khouri, Blood 2008;111:5530). In subsequent trials, eligibility was expanded to include transplants from matched unrelated donors (MUDs) using a 90yttrium ibritumomab tiuxetan (90YIT)-based regimen (Khouri, Blood 2012 ;119:6373) or, more recently, BFR (bendamustine, fludarabine, rituximab; Khouri, Blood 20014;124:2306) conditioning. Herein we report on long-term outcomes in 98 FL patients treated on these 3 consecutive trials between 1999-2017. Methods: The BFR regimen (N=20) consisted of bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, thus substituting for the cyclophosphamide in the FCR regimen (N=47) . The dose and schedule of fludarabine (30 mg/m2 IV daily x3) and rituximab (375 mg/m2 IV on day -13 and 1000 mg/m2 on days -6, +1, and +8) were similar in both regimens. 90YIT-regimens (N=31) : A diagnostic dose of 111In-ibritumomab was administered on day-14, followed by a fixed dose of 0.4 mCi/kg 90YIT on day -7; FC or BF chemo was then administered at the same dose and schedule (days -5 to -3) as described above. Tacrolimus and methotrexate was used for GVHD prophylaxis. In addition, thymoglobulin of 1 mg/kg was given on days -2, -1 in patients receiving a MUD transplant. Results: Median age was 53 years (range, 29-71) and 24 patients (24%) were &gt;60 years. Twenty-eight patients (29%) had a HCT-CI of ≥ 3. The median prior number of treatments was 3 (range, 2-9); 51 patients (52%) had rituximab-chemo induction at diagnosis. Seventy-one patients (72%) relapsed within 2 years of their induction treatment and median duration of last remission prior to alloSCT was &lt; 1 year in 61% of patients. At transplant, 82 patients (84%) had chemosensitive disease (46% CR, 38% PR); 16% had refractory disease; 22% were PET+; and 20% had elevated serum LDH. Seventy patients (71%) had a transplant from a MSD and 28 (29%) from MUDs; 15 (15%) transplants had female-to-male donors, and 42 (43%) were ABO-mismatched. In addition, CMV was reactive in 80% of patients/ and or donors. Most patients (94%) had alloSCT from peripheral blood. Median number of CD34-positive cells infused was 4.9 x 106/kg. A significant difference in ANC recovery between the 3 conditioning regimens was observed. Neutrophil counts recovered to &gt; 0.5 x 109/L a median of 0 days (range 0-16) for the BFR groups vs. 10 days (range, 0-17) and 11 days (range, 5-17) for the FCR and 90YIT-regimen groups, respectively (p&lt;0.0001). This difference was consistent for each transplant type. With a median follow-up time for all patients of 98 months (range, 3-208 months), the overall survival (OS) and progression-free-survival (PFS) rates at 98 months were 82% (95%CI, 73-89) and 74% (95% CI, 64-82), respectively (Figure 1) . The cumulative incidence (CI) of grade II-IV and III-IV acute GVHD was 22% and 9%, respectively. The CI of chronic GVHD was 38%. Treatment-related mortality at 1 year was 9%. Patient demographic, disease characteristics, and transplant characteristics and their correlation with outcomes were evaluated. Disease status of &gt; 1st relapse, &gt;2 prior chemotherapies, duration of last remission prior to alloSCT &lt; 1 year, ≥ 3 comorbidities, elevated LDH, acute II-IV GVHD, chronic extensive GVHD were associated with inferior OS. By multivariable analysis (MVA), duration of last remission prior to alloSCT (&lt;1year) [HR 6.48 (1.28, 32.69); p=0.024]) and acute II-IV GVHD [HR 8.61 (2.99, 24.83); p&lt;0.001] were associated with inferior OS. No significant prognostic factors on MVA for PFS, or risk for acute or chronic GVHD were noted for this cohort of patients. Conclusions: Nonmyeloablative allogeneic transplant can induce complete responses lasting over a decade in most patients with relapsed FL. Our initial findings published in 2008 were thus confirmed in a larger number of patients including those who received MUD transplants. BFR conditioning has been associated with significantly lesser myelosuppression and a faster neutrophil recovery than other regimens used, validating our initial observation in earlier reports. Disclosures Jabbour: Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Abbvie: Research Funding; Takeda: Consultancy, Research Funding. Oran:AROG pharmaceuticals: Research Funding; ASTEX: Research Funding; Celgene: Consultancy, Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

Radio-pharmaceuticals for cancer treatment: are they ready for prime time yet?

Radio-pharmaceuticals for cancer treatment: are they ready for prime time yet?

Updated Results of Rituximab Pre- and Post-BEAM with or without 90Yttrium Ibritumomab Tiuxetan during Autologous Transplant for Diffuse Large B-cell Lymphoma.

Purpose: We evaluated the effect on long-term survival of adding rituximab (R) to BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning with or without yttrium-90 ibritumomab tiuxetan (90YIT) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (ASCT).Experimental design: Patients were enrolled on three consecutive phase II clinical trials. Patients received two doses of rituximab (375 and 1,000 mg/m2) during mobilization of stem cells, followed by 1,000 mg/m2 on days +1 and +8 after ASCT with R-BEAM or 90YIT-R-BEAM (90YIT dose of 0.4 mCi/kg) conditioning.Results: One hundred thirteen patients were enrolled, with 73 receiving R-BEAM and 40 receiving 90YIT-R-BEAM. All patients had a prior exposure to rituximab. The median follow-up intervals for survivors were 11.8, 8.1, and 4.2 years in the three trials, respectively. The 5-year disease-free survival (DFS) rates were 62% for R-BEAM and 65% for 90YIT-R-BEAM (P = 0.82). The 5-year overall survival rates were 73% and 77%, respectively (P = 0.65). In patients with de novo DLBCL, survival outcomes of the germinal center/activated b-cell histologic subtypes were similar with 5-year OS rates (P = 0.52) and DFS rates (P = 0.64), irrespective of their time of relapse (<1 vs. >1 year) after initial induction chemotherapy (P = 0.97).Conclusions: Administering ASCT with rituximab during stem cell collection and immediately after transplantation induces long-term disease remission and abolishes the negative prognostic impact of cell-of-origin in patients with relapsed DLBCL. The addition of 90YIT does not confer a further survival benefit. Clin Cancer Res; 24(10); 2304-11. ©2018 AACR.

Management of newly diagnosed high-risk and intermediate-risk follicular lymphoma with 90 Y ibritumomab tiuxetan in a phase II study.

Five-year overall survival for high-risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high-risk follicular lymphoma. Front-line treatment with chemo-immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio- immunotherapy with 90-Yttrium ibritumomab tiuxetan consolidation, and 2years of rituximab maintenance. The 5-year overall survival for intermediate and high-risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio-immunotherapy. Three months post radio-immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo-immunotherapy and converted to complete response after radio-immunotherapy. The 5-year progression-free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow-up of 48months (range 3-84months). Post radio-immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%-36% and 10%-24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4years post treatment. Whereas many patients had prolonged B-cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov: NCT01446562.

Risk of histological transformation and therapy-related myelodysplasia/acute myeloid leukaemia in patients receiving radioimmunotherapy for follicular lymphoma.

Histological transformation (HT) of follicular lymphoma (FL) to an aggressive lymphoma after chemotherapy remains a key issue. The incidence of HT after radioimmunotherapy (RIT) is unknown. This single institution study analysed the risk of HT in FL after treatment with yttrium-90 ibritumomab tiuxetan in 115 consecutive patients treated during 1987-2012. RIT was administered for progressive FL in 111 (97%) patients and as first-line therapy in the remaining 4. 28% (n=32) had HT, occurring at a median of 60months from diagnosis and 20months after RIT. 48% (12/25) of patients who received fludarabine developed HT. The estimated 10-year risk of HT in the fludarabine and non-fludarabine groups was 67% and 26% respectively (P=0·015). Only prior fludarabine was significantly associated with predicting the risk of HT after RIT. 8% (9/115) of patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (tMDS/AML) at a median of 41·4months (range, 5-89). The estimated 10-year risk of tMDS/AML in non-fludarabine treated patients (n=90) versus fludarabine treated (n=25) was 13% and 29%, respectively. The estimated overall risk of FL undergoing HT at 10years without fludarabine exposure appears similar to patients reported in the literature that have not received RIT. Patients with prior purine-analogue therapy are at significantly higher risk of HT.