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

Background Despite the initial response to combination chemotherapy in CLL/SLL patients, disease relapse and minimal residual disease (MRD) remain major issues in treatment of these diseases. Therefore, developing more effective treatments for CLL/SLL patients is a necessity. One strategy is to eliminate persistent disease using radioimmunotherapy (RIT), such as 131I-tositumomab (Bexxar®), as consolidation after an objective complete (CR) or partial response (PR) after an induction regimen. In this study we investigated the tolerability and efficacy of standard non-myeloablative doses of 131I-tositumomab following primary induction chemotherapy in CLL/SLL patients in first remission. Patients and Methods Patients older than 18 with CLL/SLL with indication for treatment were included if they were in first CR or PR from prior treatments and had <25% bone marrow involvement and acceptable peripheral counts. 131I-tositumomab (75 cGy total-body dose) was delivered between days 90 and 180 from the first day of the last chemotherapy treatment. The dose was reduced to 65 cGy in cases of thrombocytopenia (between 100,000-150,000/µL). Three months after the treatment dose, efficacy and response criteria were specified per NCI working group guidelines and toxicity assessments were recorded based on the CTCAEv3.0. Rituximab levels were determined using ELISA with a monoclonal anti-rituximab idiotype antibody. Results 16 patients (CLL11, SLL 5) received consolidative 131I-tositumomab in first remission between 2005-2012. The median age was 61 (38-78). Seven patients (43.7%) had high-risk disease based on cytogenetics or molecular profile. Two patients (12.5%) had 11q deletion and one had mutated TP53 (6.25%). Increased CD38 and ZAP-70 expression was present in 3 of 11 and 6 of 7 patients who were tested and unmutated IgVH was detected in 1 of 3 patients. Twelve patients (75%) were in PR when entered the study while 4 (25%) were in CR. Eight patients (50%) had minimal residual disease (MRD) assessed by multiparametric flow cytometry (MFC). Prior chemotherapy consisted of FR in 9 patients (56.2%), FCR in 4 patients (25%), BR in 2 patients (12.5%) and R-CHOP in 1 patient (6.2%). The median time from the first day of the last treatment cycle to the RIT dose was 15.4 weeks (10 - 29). 7 patients (43.7%) needed dose reduction. At 3 months, CR was achieved or sustained in 12 patients (80%). Conversion from PR to CR following RIT occurred in 4 of 8 patients (50%). Likewise, 131I-tositumomab eliminated MRD in 4 of 8 patients (50%) by negative MFC at 3 months. One patient (6.6%) had PR, one (6.6%) had nodular PR and one had disease progression (6.6%) after administration of 131I-tositumomab. Lymphadenopathy was improved in 83% (5 of 6) of the patients with measureable disease prior to 131I-tositumomab. Overall, the patients with CR at 3 months had significantly higher levels of pre-treatment Rituximab levels (11.0 vs. 2.32 µg/ml, p = 0.01. There was no difference in the pre-treatment levels in patients with pre-treatment MRD who had a negative MFC analysis at 3 months compared to the ones to had residual MRD (12.5 vs. 7.6 µg/ml, p = 0.50) or in patients with PR before receiving 131I-tositumomab who achieved CR at 3 months compared to the ones who did not (11.7 vs. 5.8 µg/ml, p = 0.19). These Results suggest that the levels of Rituximab may be blocking CD20 sites at the lymph node and/or marrow level. The median follow-up was 9.4 months (2.7-54.3). Hematologic toxicities at 3 months were grade 3 anemia in 1 patient (6.2%), grade 3 or 4 neutropenia in 13 (81%), and grade 3 or 4 thrombocytopenia in 8 (50%). Six patients (37.5%) required blood or platelet transfusions. Two patients (12.5%) needed myeloid growth factor support. One patient was hospitalized within 3 months of RIT for neutropenia-related sepsis/typhlitis. Two patients (12.5%) had disease progression and dysplastic changes were found in one. One patient died 3 years after treatment for an unrelated medical reason. Persistent cytopenias were reported in 4 patients (25%) during the follow-up period. Conclusion Overall, consolidation RIT with 131I-tositumomab after first remission appears to be a feasible approach and may provide the potential benefit of converting PR to CR or eliminating MRD in CLL/SLL patients. Further long–term follow-up to assess possible prolonged side effects and clinical effectiveness of this approach remain on-going. Disclosures: Off Label Use: Bexxar is not FDA approved for consolidation of CLL. Gopal:GSK : Research Funding. Becker:Pfizer: Consultancy. Maloney:GSK: Consultancy. Press:Roche/Genentech: Consultancy.

Incidence and Characteristics of Therapy-Related Myeloid Neoplasms in Patients with Non-Hodgkins Lymphoma Treated with Radioimmunotherapy

Abstract 4924 Purpose: Radioimmunotherapy (RIT) delivers targeted radiation to tumor cells using cancer-specific monoclonal antibodies. Two agents, 90Y-ibritumomab tiuxetan (Zevalin®) and 131I-tositumomab (Bexxar) have been approved for the treatment of relapsed or refractory CD20 positive low-grade, follicular, or transformed NHL. With increasing use of RIT, it is important to elucidate short and long-term toxicities of treatment, particularly the development of therapy-related myelodysplastic syndrome and/or acute myelogenous leukemia (t-MDS/AML). We are reporting on the incidence and characteristics of t-MDS/AML in 149 patients with NHL treated at a single institution. Methods: We conducted a retrospective chart review of 149 patients with NHL treated with radioimmunotherapy at our institution. Incidences of t-MDS/AML, along with patient and disease characteristics were investigated. Results: 149 patients with NHL were included in this analysis: All patients had received at least one cytotoxic chemotherapy regimen prior to RIT. Regimens most commonly included purine analogues, anthracyclines, alkylating agents, and topoisomerase II inhibitors. Seven out of 149 patients developed t-MDS/AML with an estimated incidence of 4. 69%, (t-MDS: 5, t-AML: 2). Five patients had follicular lymphoma, 1 with mantle cell lymphoma, and 1 with diffuse large B-cell lymphoma. Three patients received 131I-tositumomab and 4 patients received 90Y-ibritumomab tiuxetan. The median age at RIT, and at diagnosis of t-MDS/AML, was 71. 3 and 73. 1 years respectively. The median time from RIT to diagnosis of t-MDS/AML was 1266 days (3. 47 years). The median time from initial NHL treatment to t-MDS/AML was 1680 days (4. 60 years). Two patients developed t-AML without a preceding t-MDS; one of whom had received topoisomerase II inhibitors. Six patients had cytogenetic abnormalities, with complex karyotype present in 4 patients. The majority of the karyotypic abnormalities involved chromosomes 5, 7, 11, and 20. The median time from diagnosis of t-MDS/AML to death was 278 days (0. 76 years). Conclusion: Therapy –related myeloid neoplasms develop after exposure to cytotoxic agents and carry a worse prognosis than de novo disease as is shown in our series. Incidence varies according to underlying disease, specific agents received, timing of exposure, and dose. The incidence rate of 4. 69% observed in this study is within the range previously described for NHL patients treated with conventional-dose chemotherapy (Armitage J. O. et al., 2003). Most patients received fludarabine, an agent linked to a high incidence of t-MDS/AML (Carney D. A. et al., 2010). Roboz et al., 2007, noted that the median time to t-MDS/AML after standard initial therapy is approximately 6 years, which is slightly longer than our study (4. 60 years). This difference may be attributed to differences in chemotherapeutic agents utilized in that analysis for NHL therapy. T-AML without antecedent t-MDS was likely related to etoposide as has been observed in previous studies (Ratain M. J. et al., 1987, 1992). Chromosome 5 and 7 abnormalities were seen with the greatest frequency, a finding typical of t-MDS/AML (Armitage J. O. et al., 2003). This study provides an estimate of 4. 69% for the development of t-MDS/AML after NHL therapy which included chemotherapy/RIT, and suggests that RIT may not contribute to an increased risk of developing t-MDS/AML beyond what is expected with chemotherapy alone. Longer follow-up of NHL patients treated with RIT alone is necessary to determine the precise role of RIT in the development of t-MDS/AML. Disclosures: No relevant conflicts of interest to declare.

Phase 1 Study of Radiosensitization Using Bortezomib in Patients with Relapsed Non-Hodgkin's Lymphoma Receiving Radioimmunotherapy

Abstract 1636 Background: Radioimmunotherapy (RIT) is effective treatment for relapsed and refractory indolent lymphomas. Results in aggressive lymphomas such as diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) have been less impressive, with lower response rates and short duration of response. We hypothesized that administration of the proteasome inhibitor bortezomib as a radiosensitizer in patients receiving RIT would be tolerable and potentially improve efficacy in both aggressive and indolent lymphomas. Methods: We performed a Phase 1 dose escalation study to evaluate the maximum tolerated dose (MTD) of bortezomib in combination with 131I-tositumomab. The study underwent review and was approved by each institution's Institutional Review Board. Dose escalation proceeded using a Time to Event-Continuous Reassessment Model (TiTE-CRM). Patients with relapsed or refractory DLBCL, MCL or indolent B cell non-Hodgkin's lymphoma were eligible if they had not undergone prior stem cell transplant, organ function was preserved, and bone marrow involvement by lymphoma was less than 25% of the intertrabecular space. Neutrophil count at least 1500/uL and platelet count at least 150 × 103/uL were required. A dosimetric dose of 131I-tositumomab was administered on day 1, followed by three whole body gamma camera scans for purposes of dose calculation and evaluation of biodistribution. After an initial cohort received a reduced whole-body dose of 50 cGy 131I-tositumomab, patients received RIT at the standard dose of 75 cGy on day 8. Patients were treated with escalating doses of bortezomib (0.3 to 1.2 mg/m2) on days 6, 10, 13, 16 and 20. Dose limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematologic toxicity, or grade 4 hematologic toxicity. Results: The study has completed enrollment, with 25 patients having received study treatment. These include 8 patients with DLBCL, 5 with MCL, 11 with follicular lymphoma (FL), and one with marginal zone lymphoma (MZL). Median age is 68 (range 40–81). Median number of prior therapies is 2 (range 1–4), and all but one had received prior rituximab. Twenty-three patients are evaluable for response, while two patients have not yet undergone restaging. Twenty-four patients are evaluable for the primary endpoint of MTD. One treated patient was not evaluable for toxicity due to early progression of disease and need for further therapy prior to the end of the observation period. Of 24 patients evaluable, 4 experienced DLT (Table), all at dose level 5 (1.2 mg/m2). These events included grade 3 hyponatremia, herpes zoster, and grade 4 thrombocytopenia. Grade 3 hematologic toxicities included two patients with leukopenia, three with neutropenia, one with anemia, and five with thrombocytopenia. Dose level 4 (0.9 mg/m2 bortezomib, 75 cGy 131I-tositumomab) was well tolerated, and this dose was identified as the MTD. Fourteen of 23 (61%) patients evaluable for response have responded, including 3/8 with DLBCL, 3/5 with MCL, and 8/9 with FL. Ten patients have achieved complete remission, including one patient with DLBCL, one with MCL, and 8 with FL. At median follow up of 8 months, median progression free survival is 6 months, and seven patients (50% of responders) remain in remission at 2 to 28 months. Conclusions: Bortezomib can be safely administered in combination with 131I-tositumomab. Responses were seen in a majority of patients, including those with aggressive histology. The MTD has been defined as 0.9 mg/m2 bortezomib plus 75 cGy 131I-tositumomab. This strategy of radiosensitization using bortezomib shows promise, and efficacy should be further evaluated in a Phase 2 trial. Disclosures: Off Label Use: Azacitidine is approved for use in MDS. Discussion here is off label. Leonard:Glaxo SmithKline: Consultancy, Honoraria. Martin:Cephalon: Consultancy; Celgene: Consultancy; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lebovic:Genentech: Speakers Bureau. Coleman:Celgene Corp: Speakers Bureau. Kaminski:GlaxoSmithKline: Patents & Royalties, Research Funding.

Phase 1 Study of Radiosensitization Using Bortezomib in Patients with Relapsed Non-Hodgkin's Lymphoma Receiving Radioimmunotherapy,

Abstract 3712 Background: Radioimmunotherapy (RIT) is effective treatment for relapsed and refractory indolent lymphomas. Results in aggressive lymphomas such as diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) have been less impressive, with low response rates and short duration of remission. We hypothesized that administration of the proteasome inhibitor bortezomib as a radiosensitizer in patients receiving RIT would be tolerable and potentially improve efficacy in both aggressive and indolent lymphomas. Methods: We performed a Phase 1 dose escalation study to evaluate the maximum tolerated dose (MTD) of bortezomib in combination with 131I-tositumomab. The studies underwent review and was approved by each institution's Institutional Review Board. Dose escalation proceeded using a Time to Event-Continuous Reassessment Model (TiTE-CRM) design. Patients with relapsed or refractory DLBCL, MCL or indolent B cell non-Hodgkin's lymphoma were eligible if they had not undergone prior stem cell transplant, organ function was preserved, and bone marrow involvement by lymphoma was less than 25% of the intertrabecular space. Neutrophil count at least 1500/uL and platelet count at least 150 × 103/uL were required. A dosimetric dose of 131I-tositumomab was administered on day 1, followed by three whole body gamma camera scans for purposes of dose calculation and evaluation of biodistribution. After an initial cohort received a step down dose level of 50 cGy 131I-tositumomab, patients received RIT at the standard dose of 75 cGy on day 8. Patients were treated with escalating doses of bortezomib (0.3 to 1.2 mg/m2) on days 6, 10, 13, 16 and 20. Dose limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematologic toxicity, or grade 4 hematologic toxicity. Results: Twenty patients have been enrolled, of whom 15 have received study treatment. These include 5 patients with DLBCL, 5 with MCL and 5 with follicular lymphoma (FL). Median age is 68 (range 48–80). Median number of prior therapies is 2 (range 1–3), and all but one had received prior rituximab. Fourteen patients are evaluable for response, while one patient has not yet undergone restaging. Of the 5 enrolled patients that were not treated, three patients were deemed ineligible due to excessive bone marrow involvement by lymphoma or inadequate organ function, one patient had abnormal biodistribution of 131I-tositumomab, and one patient was not treated due to lack of drug availability. Fourteen patients are evaluable for the primary endpoint of MTD. One treated patient was not evaluable for toxicity due to early progression of disease and need for further therapy prior to the end of the observation period. Of 14 patients evaluable, 3 experienced DLT (Table), all at dose level 5 (1.2 mg/m2). These events included grade 3 hyponatremia, herpes zoster, and grade 4 thrombocytopenia. Grade 3 hematologic toxicities included two patients with leukopenia, one with neutropenia, one with anemia, and three with thrombocytopenia. Three patients treated at dose level 4 (0.9 mg/m2) have not experienced DLT, and enrollment is continuing at this dose level to ensure tolerability and to expand efficacy data. Nine of 14 (64%) evaluable patients have responded, including 3/5 with DLBCL, 3/5 with MCL, and 3/4 with FL. Five patients have achieved complete remission, including one patient with DLBCL, one with MCL, and 3 with FL. Conclusions: Bortezomib can be safely administered in combination with 131I-tositumomab. Responses were seen in a majority of patients, including those with aggressive histology. This strategy of radiosensitization using bortezomib shows promise, and efficacy should be further evaluated in a Phase 2 trial. Disclosures: Elstrom: GlaxoSmithKline: Research Funding. Off Label Use: bortezomib and 131I-tositumomab. Leonard:GlaxoSmithKline: Consultancy; Millennium: Consultancy. Furman:GlaxoSmithKline: Speakers Bureau. Kaminski:GlaxoSmithKline: Consultancy, Patents & Royalties, Research Funding.