Iodine-131 Tositumomab Research Articles

Phase 2 Study of Iodine-131 Tositumomab Plus Chemotherapy in Patients With Previously Untreated Mantle-Cell Lymphoma

BackgroundMantle-cell lymphoma (MCL) is sensitive to radiotherapy, and the CD20 antigen is relatively highly expressed in MCL. Therefore, radioimmunotherapy using radiolabeled anti-CD20 monoclonal antibodies has the potential to treat MCL. The objective of this study was to investigate the efficacy, pharmacokinetics, and safety of tositumomab (TST) and iodine-131 tositumomab (I-131 TST) followed by 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with previously untreated MCL (ClinicalTrials.govNCT00022945). Patients and MethodsIn this phase 2 open-label study, patients received dosimetric (day 0: 450 mg TST, then 35 mg I-131 TST [5 mCi]) and therapeutic (between days 7 and 14: 450 mg TST, then an individualized dose of I-131 TST [65-75 cGy]) TST/I-131 TST, with CHOP treatment commencing approximately 13 weeks after the therapeutic dose. The primary end point was the MCL response rate to treatment; secondary end points included confirmed complete response rate and total body residence time. ResultsTwenty-six patients were enrolled, and 25 were included in the intent-to-treat population. The overall unconfirmed response rate was 84%, and the confirmed complete response rate was 44%. The median progression free-survival was 27.6 months. The median total body residence time was 94.5 hours. No new or unexpected safety signals were identified. ConclusionPatients with previously untreated MCL who received radioimmunotherapy with TST/I-131 TST followed by CHOP had a high response rate and a long duration of response, indicating that radioimmunotherapy is a therapeutic option in this patient population.

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

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

CHOP Chemotherapy Followed by Tositumomab and Iodine-131 Tositumomab for Previously Untreated Diffuse Large B-cell Lymphoma.

The efficacy and safety of tositumomab/iodine-131 tositumomab (TST/I-131 TST) were evaluated in diffuse large B-cell lymphoma patients who responded to first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Fifteen patients (median age, 52 years) received dosimetric and therapeutic doses of TST/I-131 TST. The most common Grade 3/4 hematologic adverse events were decreased absolute neutrophil count (47%), white blood cell count (40%), platelet count (27%), and hemoglobin (20%). The complete response (CR) rate increased from 60% post-CHOP to 80% post TST / I-131 TST. With a median follow-up of 120.0 months (range, 14-130 months), median duration of response (95% confidence intervals) was 58.4 months (12.0-not reached [NR]) for patients with confirmed complete response and 58.4 months (20.9-NR) for all confirmed responders. Median progression-free survival and time to treatment failure were 63.0 months (16.1-NR). Median overall survival was not reached; 2 patients died on study. CHOP and TST/I-131 TST demonstrated clinical activity with acceptable toxicity.

Low Serum Vitamin D Levels Are Associated With Inferior Survival in Follicular Lymphoma: A Prospective Evaluation in SWOG and LYSA Studies.

Recent literature reports a potential association between high vitamin D and improved lymphoma prognosis. We evaluated the impact of pretreatment vitamin D on follicular lymphoma (FL) outcome. SWOG participants were previously untreated patients with FL enrolled onto SWOG clinical trials (S9800, S9911, or S0016) involving CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab) between 1998 and 2008. Participants included in our second independent cohort were also previously untreated patients with FL enrolled onto the Lymphoma Study Association (LYSA) PRIMA trial of rituximab plus chemotherapy (randomly assigned to rituximab maintenance v observation) between 2004 and 2007. Using the gold-standard liquid chromatography-tandem mass spectrometry method, 25-hydroxyvitamin D was measured in stored baseline serum samples. The primary end point was progression-free survival (PFS). After a median follow-up of 5.4 years, the adjusted PFS and overall survival hazard ratios for the SWOG cohort were 1.97 (95% CI, 1.10 to 3.53) and 4.16 (95% CI, 1.66 to 10.44), respectively, for those who were vitamin D deficient (< 20 ng/mL; 15% of cohort). After a median follow-up of 6.6 years, the adjusted PFS and overall survival hazard ratios for the LYSA cohort were 1.50 (95% CI, 0.93 to 2.42) and 1.92 (95% CI, 0.72 to 5.13), respectively, for those who were vitamin D deficient (< 10 ng/mL; 25% of cohort). Although statistical significance was not reached in the LYSA cohort, the consistent estimates of association between low vitamin D levels and FL outcomes in two independent cohorts suggests that serum vitamin D might be the first potentially modifiable factor to be associated with FL survival. Further investigation is needed to determine the effects of vitamin D supplementation in this clinical setting.

Radioimmunoconjugates for the Treatment of Cancer

Radioimmunotherapy (RIT) has been developed for more than 30 years. Two products targeting the CD20 antigen are approved in the treatment of non-Hodgkin B-cell lymphoma (NHBL): iodine 131-tositumomab and yttrium 90-ibritumomab tiuxetan. RIT can be integrated in clinical practice for the treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy. High-dose treatment, RIT in first-line treatment, fractionated RIT, and use of new humanized monoclonal antibodies (MAbs), in particular targeting CD22, showed promising results in NHBL. In other hemopathies, such as multiple myeloma, efficacy has been demonstrated in preclinical studies. In solid tumors, more resistant to radiation and less accessible to large molecules such as MAbs, clinical efficacy remains limited. However, pretargeting methods have shown clinical efficacy. Finally, new beta emitters such as lutetium 177, with better physical properties will further improve the safety of RIT and alpha emitters, such as bismuth 213 or astatine 211, offer the theoretical possibility to eradicate the last microscopic clusters of tumor cells, in the consolidation setting. Personalized treatments, based on quantitative positron emission tomography (PET), pre-therapeutic imaging, and dosimetry procedures, also could be applied to adapt injected activity to each patient.

Phase III Randomized Study of Rituximab/Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) Compared With Iodine-131 Tositumomab/BEAM With Autologous Hematopoietic Cell Transplantation for Relapsed Diffuse Large B-Cell Lymphoma: Results From the BMT CTN 0401 Trial

This clinical trial evaluated standard-dose radioimmunotherapy with a chemotherapy-based transplantation regimen followed by autologous hematopoietic cell transplantation versus rituximab with the same regimen in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Patients with chemotherapy-sensitive persistent or relapsed DLBCL were randomly assigned to receive iodine-131 tositumomab (dosimetric dose of 5 mCi on day -19 and therapeutic dose of 0.75 Gy on day -12), carmustine 300 mg/m(2) (day -6), etoposide 100 mg/m(2) twice daily (days -5 to -2), cytarabine 100 mg/m(2) twice daily (days -5 to -2), and melphalan 140 mg/m(2) (day -1; B-BEAM) or rituximab 375 mg/m(2) on days -19 and -12 and the same chemotherapy regimen (R-BEAM). Two hundred twenty-four patients were enrolled, with 113 patients randomly assigned to R-BEAM and 111 patients assigned to B-BEAM. Two-year progression-free survival (PFS) rates, the primary end point, were 48.6% (95% CI, 38.6% to 57.8%) for R-BEAM and 47.9% (95% CI, 38.2% to 57%; P = .94) for B-BEAM, and the 2-year overall survival (OS) rates were 65.6% (95% CI, 55.3% to 74.1%) for R-BEAM and 61% (95% CI, 50.9% to 69.9%; P = .38) for B-BEAM. The 100-day treatment-related mortality rates were 4.1% (95% CI, 0.2% to 8.0%) for R-BEAM and 4.9% (95% CI, 0.8% to 9.0%; P = .97) for B-BEAM. The maximum mucositis score was higher in the B-BEAM arm (0.72) compared with the R-BEAM arm (0.31; P < .001). The B-BEAM and R-BEAM regimens produced similar 2-year PFS and OS rates for patients with chemotherapy-sensitive relapsed DLBCL. No differences in toxicities other than mucositis were noted.

Fractionated 90y Ibritumomab Tiuxetan (Zevalin™) Radioimmunotherapy As An Initial Therapy of Follicular Lymphoma – First Results From a Phase II Study in Patients Requiring Treatment According to GELF/BNLI Criteria

Abstract 102 Background:Radioimmunotherapy (RIT) has proven to be highly active in relapsed follicular lymphoma (FL) and the best single agent efficacy results in frontline therapy of FL were obtained with Iodine-131 Tositumomab (Bexxar™) (Kaminski et al NEJM 2005); albeit half of the patients had low tumor burden. In patients with higher tumor burden, using more than one fraction of RIT increases the overall radiation dose over that of a single fraction of treatment, thereby potentially improving both the response rates and survival (Illidge et al, Blood 2009). Methods:We conducted an international, multicenter phase 2 trial to evaluate the efficacy and toxicity of Fractionated 90Y Ibritumomab tiuxetan (Zevalin™) RIT as an initial therapy of Follicular Lymphoma. Eligible patients had untreated follicular lymphoma (grade 1, 2, or 3a) and at least one criterion of high tumour burden - one lymphoma lesion greater than 7 cm or three separate nodes of 3 cm or more; symptomatic splenic enlargement; raised serum concentrations of either lactate dehydrogenase or β2-microglobulin; compressive syndrome; or the presence of B symptoms. Treatment consisted of two doses of 90Y-ibritumomab tiuxetan (11.1 MBq/kg) given 8–12 weeks apart. Patients with greater than 20% bone marrow involvement (BM) with lymphoma received 4 weekly infusions Rituximab (375 mg/m2) and proceeded to fractionated RIT only if a repeat BM biopsy demonstrated clearing of lymphoma with less than or equal to 20% involvement. The primary endpoint was end of treatment response (EOR) of the intent-to-treat (ITT) population according to IWC 1999, assessed 12 weeks after last 90Y Ibritumomab tiuxetan infusion (21 weeks after treatment start). Secondary objectives were safety and progression free survival (PFS). Results:74 patients with a median age of 61 years (28−80), including 58 (78%) with stage III–IV stage, 23 (31%) intermediate risk FLIPI 2 and 34 (46%) with high risk FLIPI 3–5; were included between June 2007 and June 2010 in 7 centres. Thirteen (18%) patients with >20% BM involvement required rituximab pre-treatment, 2/74 did not qualify for RIT, meaning 72 received the first 90Y Ibritumomab tiuxetan infusion and 55 (76%) completed the full treatment schedule. The 2nd infusion of RIT was withheld secondary to hematologic toxicity with 1st infusion (n=12, 17%) or human anti murine antibodies positive testing (n = 4; 5.6%) or other (n = 1, 1.4%). Two out of 72 patients did not have recorded response data and the EOR was 95.7% (67/70) with CR/CRu of 57.1% (40/71). Six patients subsequently improved response making an ORR of 97.1% (68/70) (95% CI 90.0% – 99.7%), and CR/CRu of 64.3%% (45/70) (95% CI 51.9% – 75.4%). For the subset of 17 patients who only received a single 90Y Ibritumomab tiuxetan infusion, ORR (CR/CRu) was 100% (76,5%). At a median follow-up of 1.52 years (range 0.13 – 3.69 years) the PFS is 67 %, 20 patients have progressed and 12 of these have required further treatment (8 chemotherapy, 2 radiotherapy, 2 other). Updated data with median follow-up of more than 2 years will be presented.Ten patients experienced at least one SAE during the treatment period, with 3 related to study treatment (one case of rigors associated with the first infusion of rituximab and 2 cases of neutropenic sepsis both associated with the second RIT dose. The most common toxicity was hematologic: after the first 90Y Ibritumomab tiuxetan dose, related G3-4 hematological AEs were transient neutropenia (20.8%, 18 days median duration) and thrombocytopenia (20.8%; 20 days median duration). After the second 90Y Ibritumomab tiuxetan dose, related G3-4 hematological AEs increased to 36.4% for neutropenia (31days median duration), 14% for anemia (8/55 required transfusion) and 56.4% for thrombocytopenia (40 days median duration). There has been one case of MDS diagnosed 26 months after treatment and one death due to metastatic breast cancer diagnosed 9 months post last dose of 90Y Ibritumomab tiuxetan Conclusion:Fractionated RIT using 90Y-ibritumomab tiuxetan is an effective frontline treatment of advanced-stage follicular lymphoma in patients with high tumor burden requiring treatment and delivers high response rates. The treatment was well tolerated by patients with few infectious episodes and AE's and manageable hematologic toxicity. Disclosures:Illidge:Bayer Schering Pharma: Honoraria, Research Funding, Speakers Bureau. Morschhauser:Roche: Consultancy, Honoraria.

R-CHOP with Iodine-131 Tositumomab Consolidation for Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL): Southwest Oncology Group Protocol S0433

AbstractAbstract 590 Background:Although the majority of patients (pts) with DLBCL have durable remissions following R-CHOP chemotherapy, a substantial proportion of pts with advanced stage disease and other clinical risk factors are not cured. Low toxicity options are required for the majority of pts who are over age 60, or have medical comorbidities. Radioimmunotherapy, a low-toxicity option, is active in relapsed DLBCL (Blood 110:54), and improves PFS when used as consolidation after chemotherapy in follicular lymphoma (JCO 26:5156). We therefore evaluated consolidative radioimmunotherapy with iodine-131 tositumomab in pts with previously untreated DLBCL. Methods:Eligible pts had bulky stage II, or advanced stage DLBCL with measurable disease and adequate organ function. Treatment was 6 cycles of R-CHOP-21, followed by 2 cycles of CHOP-21 (no rituximab), followed by iodine-131 tositumomab (65 cGy if platelet count between 100 and 150/mm3 or 75 cGy if normal platelet count) 4–12 weeks after last dose of CHOP. Results:Eighty six pts (84 eligible; 45 females) were enrolled. Median age was 64 years; International Prognostic Index risks were low (n=20, 24%), low intermediate (n=27; 32%), high intermediate (n=27, 32%) and high (n=10, 12%). Five pts died of toxicities possibly related to therapy including one case each of febrile neutropenia, acute myeloid leukemia, and renal failure; there were two deaths from cardiac ischemia including one following a GI bleed in setting of thrombocytopenia after iodine-131 tositumomab. With a median follow-up of 12 months, 26 pts have progressed or died, with a 1-year progression-free survival (PFS) estimate of 75% (95%CI: 64%-85%), and 1-year overall survival (OS) estimate of 83% (95% CI:74%-93%). Based on prior studies, the estimated historical 1-year PFS rate with R-CHOP alone in this population is 74%. Complete data on iodine-131 tositumomab treatment is available for 73 of 84 eligible patients: 23 pts (32%) did not receive iodine-131 tositumomab due to early progression (n=3), other adverse event (n=6), refusal (n=6), death (n=3), or other reasons (n=5). Conclusions:A consolidation strategy utilizing iodine-131 tositumomab after 8 cycles of CHOP chemotherapy (6 with rituximab) for DLBCL does not appear to be promising in regard to 1 year PFS or OS. Unlike follicular lymphoma, in this population of DLBCL, early progressions, deaths, and declining performance status during CHOP chemotherapy limits the number of pts who ultimately can benefit from a planned consolidation approach. These current results suggest that the incorporation of novel agents earlier in therapy may ultimately have greater impact in DLBCL than consolidation or maintenance approaches. (Supported by 5U10CA32102-31, 5U10CA38926-25, and GlaxoSmithKline). Disclosures:Friedberg:Genentech: Honoraria. Off Label Use: Iodine-131 tositumomab for large cell lymphoma. Gopal:GlaxoSmithKline: Research Funding. Press:Trubion Pharmaceuticals: Consultancy, Equity Ownership; PhaseRx: Equity Ownership; Algeta: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Genentech: Honoraria; Spectrum: Honoraria.

Cyclophosphamide, Vincristine, and Prednisone Followed by Tositumomab and Iodine-131–Tositumomab in Patients With Untreated Low-Grade Follicular Lymphoma: Eight-Year Follow-Up of a Multicenter Phase II Study

The efficacy and safety of cyclophosphamide, vincristine, and prednisone (CVP) followed by tositumomab and iodine-131 ((131)I) -tositumomab therapy were evaluated in a multicenter phase II study in patients with untreated low-grade follicular lymphoma. Patients received six cycles of CVP followed by one cycle of tositumomab and (131)I-tositumomab (one dosimetric dose and one therapeutic dose). The treatment was evaluated for efficacy and safety. All 30 patients enrolled completed CVP as well as tositumomab and (131)I-tositumomab therapy. The overall response rate after completion of therapy was 100%, with 28 patients (93%) achieving a complete response (CR) and two patients achieving a partial response. Of the 17 patients with bone marrow involvement at enrollment, 15 achieved a confirmed CR. Fourteen of 15 patients with bulky disease (> or = 5 cm) had a CR after treatment completion. After a median follow-up of 8.4 years, the median response duration had not been reached (range, 3 to 111+ months). Five-year progression-free and overall survival rates were 56% and 83%, respectively. The most common grade > or = 3 hematologic adverse events were neutropenia (87%) and thrombocytopenia (37%). Nineteen patients received growth factor support, and three required blood product transfusions. No patients developed human antimurine antibodies. Two patients developed myelodysplastic syndrome/acute myeloid leukemia. These mature data demonstrate that sequential therapy with a non-anthracycline-containing regimen comprising CVP followed by one cycle of tositumomab and (131)I-tositumomab produced high response rates with adequate safety and durable remissions and that this regimen represents a highly active treatment for first-line therapy of follicular non-Hodgkin's lymphoma.

Radioimmunotherapy of Lymphoma: A Treatment Approach Ahead of Its Time or Past Its Sell-By Date?

The US Food and Drug Administration (FDA) registration of rituximab (anti-CD20 monoclonal antibody [mAb]) in 1997 was a landmark event, not only because that is when the first antibody for the treatment of cancer was licensed but also because a new era of targeted therapies in the treatment of B-cell malignancies had begun. Although responses with single-agent rituximab were rather modest, the addition of rituximab to chemotherapy (Rchemo) as immunochemotherapy has resulted in impressive improvements in response rates and outcome in patients with a range of B-cell malignances. In contrast, radioimmunotherapy (RIT) is the administration of mAb or mAb-derived constructs that are chemically conjugated to therapeutic radioisotopes targeted to tumors. A wide variety of different mAbs, delivery schedules, radioisotopes, and doses of radioactivity have been tested in RIT, resulting in impressive responses in the treatment of non-Hodgkin’s lymphoma (NHL). For more than a decade, targeting the CD20 antigen has dominated clinical RIT of lymphoma, and a number of pivotal clinical studies ultimately led to FDA approval of two radioimmunconjugates, iodine-131 (I)tositumomab (Bexxar; GlaxoSmithKline, Research Triangle Park, NC) and yttrium-90 (Y) –ibritumomab tiuxetan (Zevalin; Cell Therapeutics Inc, Seattle, WA). Y–ibritumomab tiuxetan was subsequently approved within the European Union in 2004, and in September 2009, it was approved by FDA as a first-line treatment for NHL. The recent approval by the FDA, applauded in the national press by the US Society of Nuclear Medicine, received little or no attention in the clinical community. Despite the fact that both drugs clearly have unique non–cross-reactive mechanisms of action with proven high clinical efficacy in patients resistant to both chemotherapy and rituximab and are arguably the most active drug approaches ever developed for NHL, this treatment modality has failed to be widely adopted by the hemato-oncology community. So what progress has been made with RIT and why is this “designer” targeted therapy so underused? During the last decade, the defining features of RIT using the two licensed radioimmunoconjugates applied to indolent lymphomas have emerged. These features include high response rates, durable remissions, and safe, predictable, and manageable toxicity. Both Itositumomab and Y–ibritumomab have demonstrated high clinical efficacy in heavily pretreated populations, including patients with disease refractory to both chemotherapy and rituximab underlying their unique mechanisms of action of RIT. An analysis of the long-term follow-up of patients who were heavily pretreated for indolent lymphoma with I-tositumomab demonstrated overall response rates (ORRs) of 47% to 68% and complete response (CR) rates of 20% to 38%. At the time of publication, with a median follow-up of 5.3 years, the 5-year progression-free survival (PFS) was 17%, and 81 (32%) of 250 patients had a time to progression of 1 year. For the durable response population, the median duration of response was 45.8 months and, impressively, the median duration of response had not been reached at 5 years for those who had achieved a CR. Interestingly, many of the patients who enjoyed these long durable responses had poor prognostic characteristics, including bone marrow involvement (41%), bulky disease 5 cm (49%), and transformed histology (23%). Forty-three percent of the patients had been treated with more than four prior therapies, and 36% had not responded to their most recent therapy. These durable responses have also been observed after Y–ibritumomab tiuxetan, with about 70% of patients who achieve a CR remaining in remission for years. RIT has also shown highly promising results in the first-line treatment of previously untreated follicular lymphoma as a single treatment or as consolidation therapy after initial chemotherapy. For 76 patients treated with I-tositumomab after a median follow-up of 5.1 years, the actuarial 5-year PFS for all patients was 59%, with a median PFS of 6.1 years. Hematologic toxicity was moderate, with no patients requiring transfusion or granulocyte colony-stimulating factor. Initial US-based phase II studies using RIT as consolidation therapy demonstrated high rates of conversion from partial response (PR) to CR, leading to impressive overall CR rates and PFS. However, these highly encouraging data from phase II studies have been insufficient to change practice, and the clinical community demanded phase III studies. More recently, results were published on a large, phase III randomized European and Canadian intergroup study (n 414) in previously untreated patients with follicular lymphoma. This study confirmed the high conversion rate from PR to CR (53.3% to 87.4%) seen in the early phase II US studies for patients treated with Y– ibritumomab tiuxetan. This high CR rate was almost identical in all subgroups of pretreatment chemotherapy, despite the difference in CR rate between the initial chemotherapy regimens such as chlorambucil (CR rate, 31%) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; CR rate, 56%). This consistently high CR among all of the groups after Y–ibritumomab tiuxetan suggests that JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 18 JUNE 2

Treatment strategies for nodal and gastrointestinal follicular lymphoma: Current status and future development

In recent years, therapies for follicular lymphoma (FL) have steadily improved. A series of phase III trials comparing the effect of rituximab with chemotherapy vs chemotherapy alone in treating FL have indicated significant improvements in progression-free survival (PFS) and overall survival. Recent studies have found that prolonged response durations and PFS were obtained with maintenance therapy using rituximab or interferon after completion of first line therapy. For patients with relapsed or refractory FL, phase II studies have assessed the effectiveness of combination therapies using a Toll-like receptor-9 agonist (1018ISS), oblimersen sodium (a Bcl-2 antisense oligonucleotide), bendamustine, and rituximab, as well as veltuzumab, a new humanized anti-CD20 antibody, and epratuzumab. In addition, the effectiveness of yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab as radioimmunotherapies has been reported. Furthermore, three phase III studies on an idiotype vaccine are near completion. Unfortunately, these vaccines, which appeared highly effective in phase I and II trials, do not appear to result in prolonged PFS. This report will summarize the current knowledge on therapies for treatment of FL, and will conclude with a brief discussion of feasible future options for effective treatments. Lastly, we added descriptions of the management of gastrointestinal FL, which is considered to be controversial because it is rare.

Tositumomab and Iodine I-131 Tositumomab (Bexxar® therapeutic regimen) for Non-Hodgkin's Lymphoma Patients Who Progressed After Treatment with Rituximab: Long Term Follow-up of a Multi-Center Phase II Study.

Abstract 2732Poster Board II-708 PURPOSE:Patients with indolent lymphoma generally require a number of therapies to address the relapsing course of disease and it is therefore important to provide long-term safety and efficacy data for novel therapeutics. We evaluated such data from the original phase II trial of the tositumomab and iodine-131 tositumomab therapeutic regimen in patients with indolent, follicular large-cell, or transformed B-cell lymphoma, progressive after rituximab METHODS:From July 1998 to November 1999, 40 patients with a median age of 57 years (24 rituximab nonresponders: 11 with response <6 months, and five with response 36 months) received a therapeutic dose (0.65 to 0.75 Gy) of iodine-131 tositumomab based on total-body dosimetry. Adverse prognostic characteristics included elevated lactic dehydrogenase in 31% and high or high-intermediate International Prognostic Index score in 21% of patients. Thirteen patients (32%) had tumor masses >7 cm and 20 patients (50%) had tumor masses >5 cm. The median number of prior treatments was 4 (range 1–11); 59% of patients were chemotherapy-resistant. Histology included follicular grade 1–2 (26), grade 3 (2), other indolent (2), and transformed (10). After 2 years on study or after disease progression, long term follow-up was conducted every 6 months for 10 years with CT and laboratory studies. This report presents an update, with investigator-assessed tumor evaluation, from the J Clin Oncol 23:712, 2005. RESULTS:The median duration of follow-up from the dosimetric dose was 54 (range 1–119) months. The overall response rate was 72% (28 of 39 evaluable patients with 9 complete responders). The median duration of overall response was 18.9 months; the proportion of patients maintaining response at 5 years is estimated at 40% with just two known relapses after two years. Five of 9 complete responders have been continuously maintained. For all 40 study patients, the median progression-free survival (PFS) was 10.4 months (95% CI: 5.7, 18.6) and the estimated 5 year PFS is 28%. The estimated median overall survival for all patients is 80.0 months. To date, 20 deaths have been reported, 10 without documented disease progression. Six second cancers have occurred: 2 acute leukemia, 1 prostate, 2 skin (1 squamous, 1 Merkel cell) and 1 primary hepatic. The incidence of secondary leukemia remains the same as previously reported in 2005 at 5% (2 of 40 patients). Seven of the 40 patients enrolled in this study had elevated thyroid stimulating hormone (TSH) levels prior to receiving the therapeutic dose of iodine-131 tositumomab and 2 patients did not have baseline TSH data. Of the 31 patients with normal baseline TSH levels prior to treatment, 3 developed elevated TSH as of July 2009 and as reported previously (J Clin Oncol 23:712, 2005). There were no cases of hypothyroidism reported as an adverse event by investigators as of July 2009. CONCLUSIONS:The group of extensively pretreated (median = 4) patients participating in this phase II study survived a median of 6.7 years after receiving the BEXXAR® therapeutic regimen. No additional cases of leukemia were seen and no unexpected toxicities were observed. Of the 72% of patients responding to treatment, about 40% were estimated to continue their response at 5 years, including 5 of 9 complete responders. These data demonstrate durable efficacy of BEXXAR® in an indolent lymphoma population with disease progression after rituximab. Disclosures:Horning:GlaxoSmithKline: Honoraria, Research Funding. Podoloff:GE Healthcare: Honoraria, Research Funding. Horner:GlaxoSmithKline: Employment. Williams:GlaxoSmithKline: Employment. Vleisides:GlaxoSmithKline: Employment.

Update on the rational use of tositumomab and iodine-131 tositumomab radioimmunotherapy for the treatment of non-Hodgkin&amp;rsquo;s lymphoma

Targeted radioimmunotherapy in non-Hodgkin's B-cell lymphoma (NHL) offers an efficacious therapy and minimal toxicity compared to conventional chemotherapy. Iodine 131 tositumomab ((131)I-TST) is a murine monoclonal antibody against the CD20 cell surface protein and is directly covalently conjugated to (131)I, a radioactive beta and gamma emitter. While initially approved for use in relapsed, refractory, or transformed low grade B-cell NHL, investigational uses with promising results include autologous stem cell transplant, intermediate grade NHL, and the frontline management of indolent NHL. This review summarizes the (131)I-TST literature on mechanism of action, treatment indications, treatment delivery, efficacy, investigational uses, and future prospects.

Effect of Prior Rituximab on Residence Time of I131 Tositumomab Consolidation Therapy in Patients (pts) with Non Hodgkin's Lymphoma (NHL): Analysis of SWOG Clinical Trials.

Backround: Anti CD-20 radioimmunotherapy (RIT) is effective therapy for indolent B-cell NHL, and under investigation in more aggressive histologies. Most data on safety and efficacy of RIT is from the pre-rituximab era, and the effect of rituximab exposure on RIT in pts with NHL is unknown. Gopal et al recently demonstrated that exposure to rituximab correlated with inferior tumor response and alteration in tumor: organ dosimetry ratio both in vitro and in mouse models following therapy with iodine-131 tositumomab (Blood 112:830). Two ongoing SWOG trials evaluating RIT consolidation therapy provide a unique opportunity to evaluate the impact of prior rituximab on pharmacodynamics of iodine-131 tositumomab in humans. S0016 enrolls previously untreated pts with follicular NHL, and iodine-131 tositumomab consolidation is administered after 6 cycles of CHOP. S0433 enrolls previously untreated pts with DLBCL, and iodine-131 tositumomab is administered after 6 cycles of CHOP with rituximab, and 2 additional cycles of CHOP alone. As rituximab leads to B-cell depletion for 6 months or more, we hypothesized the residence time of iodine-131 tositumomab would differ in pts exposed recently to rituximab compared to no prior rituximab.Methods: Prospective pts at the University of Rochester enrolled in S0016 and S0433 were analyzed. Residence times of iodine-131 tositumomab were calculated using serial imaging on a Picker XP 2000 gamma camera. Rituximab levels were performed within one week prior to dosimetric iodine-131 tositumomab administration using ELISA. Medians were used to summarize the data, and the 2-tailed Mann-Whitney-Wilcoxon test was used for hypothesis testing.Results: 16 pts (6 female) on S0016 and 12 pts (6 female) on S0433, were identified, with median ages of 54.5 and 69.5 respectively. All pts had advanced stage disease, and median BMI and creatinine were similar for both groups. Pts on S0433 had a median time from rituximab to RIT of 78.6 days (range 58–98 days). Despite this, rituximab levels were present at time of iodine-131 tositumomab in all pts measured (N=9; median rituximab level 37.2 ug/ml, range 15.6–61.69). Median absolute lymphocyte count appeared lower in the S0433 group compared to the S0016 group (600 vs 1050 /ul), but this difference was not significant (p=0.12). Pts on S0433 (all had received rituximab prior to iodine-131 tositumomab consolidation) had significantly longer RIT residence times when compared to those on S0016, (not treated with prior rituximab): 115 hours vs. 107 hours; p=0.02. Therapeutic doses of iodine-131 tositumomab were not significantly different between the two studies (S0433: 72 mCi vs. S00016: 78 mCi p=0.59).Conclusions: Our results indicate that prior therapy with rituximab results in a longer residence time of iodine-131 tositumomab when used as consolidation after chemotherapy. Measurable rituximab levels at time of RIT suggest that rituximab-induced B-cell depletion decreases clearance of RIT, possibly allowing for longer exposure times. The significance of this longer residence time is unknown but it could be associated with greater toxicity to normal organs, and could be indicative of decreased tumor binding. If confirmed in larger studies, these findings could have profound implications on RIT administration in the context of rituximab. Rituximab-induced B-cell depletion could obligate the need for unlabeled antibody dosing prior to RIT, and may affect dosimetry of RIT. Prospective studies of RIT in the rituximab era should evaluate the impact of prior rituximab and RIT residence time on toxicities and outcomes in pts treated with RIT.

Consolidation radioimmunotherapy of follicular lymphoma: a step towards cure?

Radioimmunotherapy (RIT) of non-Hodgkin’s lymphoma was pioneered at the end of the 1980s [1, 2]. This clinical indication was chosen because of the availability of appropriate antibodies and of the relative radiosensitivity of lymphoma cells: Even moderate absorbed doses were expected to translate into some tumor response. In the meantime, rituximab, a naked chimeric anti-CD20 antibody, became a real clinical and commercial success and is now part of the standard treatment of CD20 positivediffuse large B cells and follicular non-Hodgkin’s lymphoma. However, it is clear that rituximab administered in combination with chemotherapy is not a curative treatment of follicular lymphoma. Thus, radiolabelled anti-CD20 antibodies have been introduced with the aim of improving the efficacy of naked antibodies. Multiple clinical studies were performed first with tositumomab/iodine-131 tositumomab (Bexxar; GlaxoSmithKline, Philadelphia, PA, USA) then with rituximab/yttrium-90 ibritumomab tiuxetan (Zevalin; Biogen Idec, Cambridge, MA, USA), which demonstrated both their safety and efficacy with overall response rates between 50% and 80% and complete response (CR) rates between 20% and 40% in patients with relapsed, refractory or transformed follicular nonHodgkin’s lymphoma. Subsequently, both products have been approved in the US (tositumomab/iodine-131 tositumomab and rituximab/yttrium-90 ibritumomab tiuxetan) and one in Europe (rituximab/yttrium-90 ibritumomab tiuxetan). In the absence of randomised trials, it is difficult to compare the safety and efficacy of both products. Nevertheless, it appears from the literature that they are roughly comparable in terms of response rates and progression-free survival (PFS) even if tositumomab/ iodine-131 tositumomab using a patient-specific dosing regimen seems to induce less bone marrow toxicity than rituximab/yttrium-90 ibritumomab tiuxetan using weightbased dosing regimen [3]. However, from the time of approval, their routine use has not been very successful, with sales showing a much slower progression than expected. Several reasons to this limited commercial performance have been put forward. First, RIT needs a close coordination between haematologists and nuclear medicine physicians. Some referring physicians or haematologists have certainly considered that such coordination was too difficult and RIT too cumbersome even if it is quite simple in a routine practice in most institutions [4]. A stronger reason of the limited success was probably the nonsignificant difference of time to progression (TTP) between patients treated with RIT and those treated with rituximab, making haematologists rather disappointed [5]. In routine clinical practice, both radiopharmaceuticals have been mainly used as a last-line, salvage treatment in patients who had often high tumor burden and had been heavily pretreated, whereas clinical trials had clearly shown that TTP was significantly longer when RIT was used at an earlier stage, after only one prior therapy [6]. There is a relative consensus to consider that the best indication of RIT is the treatment of residual disease characterised by small-sized or microscopic tumors, which are still rather well vascularised and consequently accessible to circulating radiolabelled antibodies. Moreover, the small size of the tumors fits well with the short path length of electrons emitted by iodine-131 (<2 mm) and by yttrium-90 (<5 mm). This favourable situation of residual disease prompted investigators to use RIT as a consolidation Eur J Nucl Med Mol Imaging (2008) 35:1236–1239 DOI 10.1007/s00259-008-0727-z

Radioimmunotherapy (RIT) in non-Hodgkin lymphoma

Radio-labeled anti-CD20 antibodies are a relatively novel technique that uses monoclonal antibodies to target CD20-positive cells and administer complex antibody-mediated and/or complement-dependant cytotoxicity in combination with systemic radiotherapy to targeted cells and adjacent cells via the “crossfire” effect. There are currently two main agents in clinical practice—yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) and iodine-131 (131I) tositumomab (Bexxar)—with other agents in clinical development. Studies have been performed looking into the use of radioimmunotherapy (RIT) in indolent non-Hodgkin lymphoma (NHL), initially in patients with relapsed, treatment-refractory and transformed disease (overall response rates [ORR] 74–92% with complete response [CR] 15–51%), and also in patients not suitable for transplant (i.e., the elderly population [CR 23%]) and in isolation in the first-line setting (comparable response rates to RCHOP) and combination with chemotherapy in the first-line setting (ORR 90–100%). The use of RIT in diffuse large B cell aggressive (DLBC) NHL has been assessed initially in patients with relapsed disease, both rituximab naive (ORR 44%) and refractory (ORR 19%), and more recently as consolidative treatment following primary chemotherapy (early results 5-year overall survival 60% vs 37%), or in combination with primary chemotherapy. The main side effects are infusion related and hematological with a delayed nadir (4–6 weeks in DLBC NHL, 6–8 weeks in indolent disease) and correlate with bone marrow reserve.

Safe Administration of Iodine-131 Tositumomab After Repeated Infusion-Related Reactions to Rituximab

Infusion-related reactions during administration of monoclonal antibody therapy are often mild and unlikely to recur with subsequent treatment. If patients experience another severe reaction upon reattempting treatment, future treatments with the same agent are typically not pursued. It is unclear whether different monoclonal antibodies that bind the same tumor cell or antigen are likely to induce similar infusion reactions. Here, we report the case of a patient with repeated severe infusion reactions with rituximab who subsequently safely received treatment with iodine-131 tositumomab and discuss the relevant literature.

Radioimmunotherapy of Non-Hodgkins Lymphomas

The availability of active monoclonal antibodies has altered the treatment paradigms for patients with non-Hodgkin's lymphomas (NHL). Nevertheless, some patients do not respond, while almost all of the others eventually relapse and require additional treatment. Thus, more effective alternatives are needed. Radioimmunotherapy (RIT) is an attractive option because of the inherent radiosensitivity of most NHL. Yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab are the first two radioimmunoconjugates currently available for clinical use. These agents appear comparably active in patients with follicular and low-grade NHL after failure following chemotherapy and/or rituximab. Activity has also been demonstrated against other histologies, including diffuse large B-cell NHL, mantle cell NHL, and transformed NHL. Toxicities primarily include myelosuppression, with a potential risk of treatment-associated myelodysplastic syndrome and acute myelogenous leukemia. Current clinical trials are attempting to optimize the use of these agents by evaluating them earlier in the course of the disease, and sequenced with a variety of chemotherapy regimens. Hopefully, the rational development of RIT will lead to a prolongation of survival for patients with NHL.

Iodine-131 tositumomab (Bexxar) in a radiation oncology environment

Iodine-131 (I-131) tositumomab (Bexxar; GlaxoSmithKline, Research Triangle Park, NC) is one of two recently approved radiolabeled antibodies directed against the CD20 surface antigen found on normal B cells and in more than 95% of B cell non-Hodgkin's lymphoma. The compound itself is formulated as an IgG2a immunoglobulin radiolabeled with the mixed beta/gamma emitter I-131. Multicenter clinical trials have repeatedly shown impressive clinical responses (20-40% complete response rates and 60-80% overall response rates) in the patient groups for whom this treatment is indicated. Treatment-related toxicity is generally extremely mild and typically involves only reversible hematopoietic suppression and (in some cases) a risk of treatment-induced hypothyroidism. Owing to the radiation safety concerns necessitated by the clinical use of this targeted radiopharmaceutical, it is important for radiation oncology departments wishing to participate in the care of these patients to establish methodologies and standard operating procedures for safe and efficient departmental use. This summary reviews the pertinent background information related to the current clinical experience with I-131 tositumomab and highlights some of the major opportunities for the participation of radiation oncology in the patient evaluation and treatment process. I-131 tositumomab provides an excellent example of the way in which the increasingly important new field of "targeted therapy" intersects with the practice of clinical radiotherapy. The author contends that it will be worth the time and effort involved in establishing a firm basis for the development of a comprehensive program for systemic targeted radiopharmaceutical therapies (STaRT) within the radiation medicine domain.

Ongoing investigations and new uses of radioimmunotherapy in the treatment of non-Hodgkin’s lymphoma

Studies in radiation oncology are focusing on the optimal use of systemic targeted radionuclide therapy (STaRT) in the treatment of patients with cancer. The two approved radioimmunotherapy agents, yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab, are being studied in a range of lymphoid malignancies, from low-grade to aggressive B-cell non-Hodgkin's lymphomas. Studies of standard- and escalated-dose radioimmunotherapy with or without stem cell support are reviewed, as are radioimmunotherapy with other therapeutic modalities in these settings. The results of these trials have important implications for clinical practice, and it is hoped that they will further clarify the optimal timing and dosing of these agents.