90Y Ibritumomab Tiuxetan Research Articles

Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ)

Follicular lymphoma is the most common form of lymphoma in Europe and the USA. In this prospective, single-arm, open-labelled, multicentre non-randomised phase II trial (FLUMIZ [FLUdarabine, MItoxantrone, Zevalin] trial) we aimed to assess the efficacy and safety of fludarabine and mitoxantrone plus radioimmunotherapy in untreated patients with follicular non-Hodgkin lymphoma (NHL). Patients with stage III or IV untreated indolent follicular NHL were enrolled between June 1, 2004, and April 15, 2006, at 13 Italian institutions, and were treated with oral fludarabine (40 mg/m2 on days 1 to 3) and intravenous mitoxantrone (10 mg/m2 on day 1) every 28 days for six cycles. Patients who had at least a partial response (PR) with normal platelet counts (>100x10(9)/L) and granulocyte counts (1.5x10(9)/L), and bone-marrow infiltration less than 25% 4-6 weeks after completion of the sixth cycle of chemotherapy were deemed eligible for consolidation treatment 6-10 weeks after the sixth cycle with one course of yttrium-90 ((90)Y)-labelled ibritumomab tiuxetan (Zevalin), which consisted of an initial infusion of intravenous rituximab (250 mg/m2) on day 1 followed by a second 250 mg/m2 infusion on day 7, 8, or 9. The second infusion was followed by a weight-based dose of 90Y-ibritumomab tiuxetan, administered as a slow intravenous push over 10 min. Primary endpoints were complete response (CR) and haematological toxic effects and secondary endpoints were overall survival and progression-free survival. Responses were classified according to the International Workshop for Response Criteria for non-Hodgkin's lymphomas. Analysis was per protocol. This trial is registered as a European Standard Controlled Trial on the EudraCT website http://oss-sper-clin.agenziafarmaco.it, number 2004-002211-92. 61 patients were enrolled in the trial and received six cycles of fludarabine and mitoxantrone, after which an overall response was noted in 98% (60 of 61) of patients (43 of 61 patients had CR and 17 of 61 patients had PR). 57 patients (43 with CR and 14 with PR) were deemed eligible for subsequent (90)Y-ibritumomab tiuxetan. Of the 14 patients who had PR after the initial treatment, 12 obtained CR after (90)Y-ibritumomab tiuxetan. By the end of the entire treatment regimen 55 of 57 patients achieved CR. With a median follow-up of 30 months (range 21-48), 3-year progression-free survival was estimated to be 76% (95% CI 72.3-82.4) and 3-year overall survival 100%. 36 of 57 patients had grade 3 or 4 haematological toxic effects, and blood transfusions were given to 21 of 57 patients. This trial has provided evidence for the feasibility, tolerability, and efficacy of fludarabine and mitoxantrone plus (90)Y-ibritumomab tiuxetan in untreated patients with follicular NHL.

Efficacy of 90Y Ibritumomab-Tiuxetan Treatment in a Case of Resistant Gastric Malt Non Hodgkin's Lymphoma

Treatment modalities for resistant/relapsing gastric mucosa associated lymphoid tissue (MALT) non-Hodgkin’s lymphoma (NHL) are not yet well standardized. In the past, most patients were treated surgically with a gastrectomy, while, more recently, radiotherapy and systemic approaches (chemotherapy and immunotherapy) have been used with improving results.Here, we report the case of a patient affected by MALT NHL resistant to antibiotics, chemotherapy and immunotherapy, who achieved a durable complete remission after radio-immunotherapy treatment with Zevalin (90Y ibritumomab-tiuxetan), administered in a single-standard dose. This observation must be confirmed on a larger series but suggests that radio-immunotherapy may be a valid approach in treating relapsing MALT NHL patients, or those resistant to conventional therapies, so avoiding more aggressive and toxic approaches.

B-Cell Non-Hodgkin Lymphoma: PET/CT Evaluation after90Y–Ibritumomab Tiuxetan Radioimmunotherapy—Initial Experience1

To retrospectively compare fusion fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) imaging with CT imaging alone in the evaluation of yttrium 90 ((90)Y)-ibritumomab tiuxetan radioimmunotherapy treatment of B-cell non-Hodgkin lymphoma. This HIPAA-compliant study was performed with approval from the University of Southern California Institutional Review Board and with informed consent. Five men and five women (mean age, 52 years; range, 38-70 years) with relapsed or refractory non-Hodgkin lymphoma underwent FDG PET/CT imaging both 14-27 days before treatment with (90)Y-ibritumomab tiuxetan and 4-6 months after treatment. Response after treatment was measured with CT imaging as complete response, partial response, or stable or progressive disease, as defined according to published criteria from a National Cancer Institute-sponsored international workshop. Response after treatment was measured with PET as complete response, partial response, or stable or progressive disease, as defined according to published criteria of the European Organization for Research and Treatment of Cancer. Responses were determined by three interpreters in consensus. Interpretation of CT images alone resulted in classification of eight (80%) of 10 patients as responders to treatment, with two patients (20%) classified as having complete response. At reevaluation with fused PET/CT images, two patients (20%) had residual lesions at CT that did not show evidence of FDG avidity. These two patients, classified as partial responders according to CT criteria alone, were classified as complete responders at PET/CT. Both of these patients were free of evident disease at 18 or more months of follow-up. The use of combined FDG PET/CT may enable superior assessment of response to (90)Y-ibritumomab tiuxetan treatment than the use of CT alone, at which one may underestimate (90)Y-ibritumomab tiuxetan response by considering inactive residual CT masses to be residual disease.

A phase 2 trial of fludarabine and mitoxantrone chemotherapy followed by yttrium‐90 ibritumomab tiuxetan for patients with previously untreated, indolent, nonfollicular, non‐Hodgkin lymphoma

A prospective, single-arm, open-label, nonrandomized Phase 2 study of combined fludarabine and mitoxantrone (FM) plus radioimmunotherapy was conducted to evaluate efficacy and safety in patients with untreated, indolent, nonfollicular non-Hodgkin lymphoma (NHL). Between February 2005 and June 2006, at their institute, the authors treated 26 eligible patients with previously untreated, indolent, nonfollicular NHL (10 marginal zone lymphomas, 8 lymphoplasmacytic lymphomas, and 8 small lymphocytic lymphomas) using a novel regimen that consisted of 6 cycles of FM chemotherapy followed 6 to 10 weeks later by yttrium-90 (90Y) ibritumomab tiuxetan. After FM chemotherapy, the overall response rate was 80.5% and included a 50% complete remission (CR) rate (13 patients) and a 30.5% partial remission (PR) rate (8 patients). Of the 20 patients (13 with CR and 7 with PR) who were evaluable (at least a PR with normal platelet counts and bone marrow infiltration <25%) for subsequent 90Y ibritumomab tiuxetan, 100% obtained a CR at the end of the entire treatment regimen. At a median follow-up of 20 months, the estimated 3-year progression-free survival rate was 89.5%, and the estimated 3-year overall survival rate was 100%. The 90Y ibritumomab tiuxetan toxicity included grade >or=3 hematologic toxicity in 16 of 20 patients; the most common grade >or=3 toxicities were neutropenia (11 patients) and thrombocytopenia (16 patients) (adverse events were graded according to the World Health Organization criteria for toxicity). Transfusions of erythrocytes and/or platelets were given to 5 patients. The current study established the feasibility, tolerability, and efficacy of the FM plus 90Y ibritumomab tiuxetan regimen for the treatment of patients with untreated, indolent, nonfollicular NHL.

Comparison Between 2D and 3D Dosimetry Protocols in 90Y-Ibritumomab Tiuxetan Radioimmunotherapy of Patients with Non-Hodgkin's Lymphoma

We compared the radiation-absorbed dose obtained from a two dimensional (2D) protocol, based on planar whole-body (WB) scans and fixed reference organ masses with dose estimates, using a 3D single-photon emission computed tomography (SPECT) imaging protocol and patient-specific organ masses. Six (6) patients with follicular non-Hodgkin's lymphoma underwent a computed tomography (CT) scan, 5 2D planar WB, and 5 SPECT scans between days 0 and 6 after the injection of (111)In-ibritumomab tiuxetan. The activity values in the liver, spleen, and kidneys were calculated from the 2D WB scans, and also from the 3D SPECT images reconstructed, using quantitative image processing. Absorbed doses after the administration of (90)Y-ibritumomab tiuxetan were calculated from the (111)In WB activity values combined with reference organ masses and also from the SPECT activity values and organ masses as estimated from the patient CT scan. To assess the quantitative accuracy of the WB and SPECT scans, an abdominal phantom was also studied. The differences between organ masses estimated from the patient CT and from the reference MIRD models were between -10% and +98%. Using the phantom, errors in organ and tumor activity estimates were between -86% and 10% for the WB protocol and between -43% and -6% for the SPECT protocol. Patient liver, spleen, and kidney activity values determined from SPECT were systematically less than those from the WB scans. Radiation-absorbed doses calculated with the 3D protocol were systematically lower than those calculated from the WB protocol (29%+/-26%, 73%+/-26%, and 33%+/-53% differences in the liver, spleen, and kidney, respectively), except in the kidneys of 2 patients and in the liver of 1 patient. Accounting for patient-specific organ mass and using SPECT activity quantification have both a great impact on estimated absorbed doses.

Consensus conference: Implementing treatment recommendations on yttrium-90 immunotherapy in clinical practice – Report of a European workshop

Radiolabelled immunotherapy is a significant step forward in the treatment of non-Hodgkin’s lymphoma (NHL), with preliminary data suggesting long remissions in some patients. 90Y-ibritumomab tiuxetan is the only therapy approved for use after rituximab failure and is currently indicated in the EU for the treatment of adults with rituximab-relapsed or refractory CD20-positive follicular B-cell NHL. However, retrospective analyses confirm better responses when 90Y-ibritumomab tiuxetan is used earlier in the disease course. An expert panel of oncologists, haematologists and nuclear medicine physicians met at an European workshop to discuss proposed therapeutic algorithms for follicular lymphoma and the preliminary medical evidence supporting the incorporation of 90Y-ibritumomab tiuxetan as an early therapeutic option. Phase II data indicate that 90Y-ibritumomab tiuxetan either alone as primary therapy or as consolidation therapy following induction chemotherapy with or without rituximab achieves high response rates in follicular lymphoma, with complete remission rates of 62–80%. Phase III data are warranted, but based on preliminary observations the expert panel recommended incorporation of radiolabelled immunotherapy into national lymphoma treatment algorithms across Europe. This approach would maximise the therapeutic potential of this agent by encouraging its use early in the disease course of follicular lymphomas.

Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in primary cutaneous B-cell lymphomas: first results of a prospective, monocentre study

Radioimmunotherapy with Yttrium-90 (90Y) ibritumomab tiuxetan (IT) has been shown to be effective in systemic B-cell lymphomas. We conducted a pilot study to evaluate the outcome and assess complications of 90Y IT therapy in patients with primary cutaneous B-cell lymphomas (PCBCL). Ten patients, all but one, with relapsed PCBCL were included and treated with rituximab (250 mg m−2/body surface) on days 1 and 8 followed by a single dose of 90Y IT (11–15 MBq kg−1). The overall response rate was 100%. The complete response rate was 100%. The median time to relapse was 12 months. Ongoing remissions were achieved in four patients (median follow-up 19 months). Transient and reversible myelosuppression (grade 3–4) was the most frequent adverse event. Radioimmunotherapy with 90Y IT is an effective treatment in relapsed primary cutaneous follicle centre lymphomas and diffuse large B-cell lymphoma leg-type. Further investigations in controlled randomised clinical trials evaluating the role of 90Y IT versus rituximab in PCBCL are needed.

Radioimmunotherapy in relapsed follicular lymphoma previously treated by autologous bone marrow transplant: a report of eight new cases and literature review

Multicenter, retrospective study of standard-dose RIT in eight heavily pre-treated patients with CD20-positive follicular lymphoma who had relapsed after previous autologous bone marrow transplantation (ABMT). Patients underwent nine courses of 90Y-ibritumomab tiuxetan (0.3 or 0.4 mCi/kg body weight). Responses included five CR, two PR, one SD and one PD. Median DFS was 12 months with median follow-up of 17 months and 1-year OS was 83% (7/8 patients). Grade 4 thrombocytopenia occurred in 7/9 treatments, with no episodes of bleeding, and only two patients received a platelet transfusion. One patient, who had 20% bone marrow involvement at the time of relapse diagnosis, presented with Grade 4 thrombocytopenia and Grade 4 neutropenia and died of septic shock 6 months after RIT. One other case of Grade 4 neutropenia, without a serious infectious syndrome, was observed. Standard-dose RIT seems feasible and potentially effective after ABMT in correctly selected patients with follicular lymphoma.

Evaluation of different beta-counting systems involved in 90Y-Zevalin quality control

90Y-ibritumomab tiuxetan (90Y-Zevalin) is currently approved for radioimmunotherapy of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. The radioimmunoconjugate may be administered to the patient only if the radiolabelling yield is higher than 95%. To evaluate different methods of quality control testing for an accurate and rapid determination of radiolabelling yield in the clinical routine. Five beta-counting systems, involved in determining the yield of radiolabelled 90Y-Zevalin, were compared: an autoradiography system (AS), a thin-layer chromatography (TLC) scanner system, a dose calibrator (DC), a liquid scintillation analyser (LSA) and high-performance liquid chromatography (HPLC). These instruments were also analysed in terms of efficiency, spatial resolution, analysis time, operating procedure level, cost and availability. Radiolabelling yields were comparable among all instruments except for DC whose values were dubious. Efficiency was 1.5+/-0.11 MDLU.s for the AS (where DLU means digital light unit), 3.5+/-0.2 kcps for the TLC analyser, 0.74+/-0.02 MBq for the DC, 15+/-0.12 kcps for LSA and 180+/-0.07 kcps for HPLC. Spatial resolution was 1 mm for AS and 5 mm for the TLC analyser. The quality control test needed 8 min with AS and DC, 15 min with TLC and LSA, and 50 min with HPLC. The short analysis time, high sensitivity, simultaneous detection of multiple radioactive strips and low cost offered by AS make it a suitable tool for radioactivity analysis and quantification in a radiopharmacy laboratory.

Phase II Trial of a Transplantation Regimen of Yttrium-90 Ibritumomab Tiuxetan and High-Dose Chemotherapy in Patients With Non-Hodgkin's Lymphoma

This phase II trial evaluated the safety and efficacy of combining yttrium-90 (90Y) ibritumomab tiuxetan with high-dose carmustine, cytarabine, etoposide, and melphalan (BEAM) and autologous stem-cell transplantation in patients with non-Hodgkin's lymphoma who were considered ineligible for total-body irradiation because of older age or prior radiotherapy. Between May 2002 and January 2006, 14 days before autologous stem-cell transplantation, 41 patients with non-Hodgkin's lymphoma received standard-dose 90Y ibritumomab tiuxetan (14.8 MBq/kg [0.4 mCi/kg]) followed by high-dose BEAM. The median age was 60 years (range, 19 to 78 years), and the median number of previous therapies was two (range, one to six). Disease histologies were diffuse large B-cell (n = 20), mantle cell (n = 13), follicular (n = 4), and transformed lymphoma (n = 4). With a median follow-up of 18.4 months (range, 5.5 to 53.3 months) the estimated 2-year overall and progression-free survival were 88.9% (95% CI, 75.3% to 95.2%) and 69.8% (95% CI, 56.4% to 79.7%). The median time to WBC engraftment was 11 days (range, 9 to 26 days) and time to platelet engraftment was 12 days (range, 3 to 107 days). Adverse events were similar to those seen historically with high-dose BEAM alone, and included grade 3 or 4 pulmonary toxicity in 10 patients. Adding 90Y ibritumomab tiuxetan to high-dose BEAM with autologous stem-cell transplantation is feasible and has a toxicity and tolerability profile similar to that observed with BEAM alone. Rates of progression-free survival seen in these patients are promising and warrant additional study.

High Dose 90Yttrium Ibritumomab Tiuxetan with PBSC Support in Refractory-Resistant NHL Patients.

We present feasibility and toxicity results of a phase I/II study of High Dose (HD) 90Yttrium (90Y) Ibritumomab Tiuxetan with PBSC support in resistant-refractory NHL patients. From 04/04 to 08/07 25 patients were enrolled. Median age was 68ys (21–75). 21/25 patients had advanced stage disease (III/IV) at diagnosis. 14 patients had Diffuse Large B Cell Lymphoma (DLBCL), 7 Mantle Cell Lymphoma (MCL), 2 Follicular Lymphoma (FL) G3, 1 transformed FL, 1 transformed Marginal Zone Lymphoma (MZL). Median number of prior therapies was 3 (1–6), including Rituximab, RT and HD-CT. Three 90Y-Ibritumomab Tiuxetan activity levels were fixed: 30 MBq/kg, 45 MBq/kg and 56 MBq/kg; 4 patients at the 1st, 4 at the 2nd and 17 at the 3rd level. One week before treatment all patients underwent dosimetry with Indium-111 (111In) ibritumomab-tiuxetan in order to assess organ doses and plan the activity level. PBSC were reinfused 13 days after 90Y-Ibritumomab Tiuxetan. On day 28 from reinfusion engraftment was considered to be delayed if ANC<1.0×109/L or PLT<20.0×109/L.RESULTS: Dosimetry showed acceptable radiation-absorbed doses to normal organs in all cases except one: 1 patient showed an abnormal liver uptake still increasing up to 7 days post injection. The estimated absorbed dose to the liver was 11.3 Gy/GBq, meaning 50 Gy if the prescribed activity of 56 MBq/kg would be administered. Therefore, the patient was excluded from the treatment. The median (24 pts) adsorbed doses for 90Y-Ibritumomab Tiuxetan resulted (mGy/MBq): 0.80 (0.40–1.0), red marrow; 2.1 (1.1–5.4), heart wall; 1.7 (0.3–3.5), lungs; 2.8 (1.8–10.6), liver; 1.9 (0.8–5.0), spleen; 1.7 (0.6–3.8), kidneys; 2.8 (1.3–4.7), testes; 0.5 (0.4–0.8), total-body. Median activity of 90Y-Ibritumomab Tiuxetan delivered: 3.7 GBq, range 2.1–5.55 GBq. All patients engrafted promptly after PBSC transplantation. PLT and ANC-count nadirs were reached 8 and 4 days after transplantation, with median values of 11×109/L PLT (4–35) and 0.01×109/L ANC (0.01–1.09). The time of nadir did not change as a function of 90Y-ibritumomab tiuxetan dose. Median time to engraftment was 12 (0–22) and 20 (1–48) for PLT and ANC respectively. When data were analyzed per dose-level, no statistically significant differences in terms of hematological toxicity were observed. A drop in PLT-counts often occurs after engraftment as a sign of possible late toxicity, particularly in those patients who received more than 3 previous CT regimens. One transient acute G3 liver toxicity was observed at the 3rd level; 1pt died 4 months after treatment due to HCV reactivation; another pt died 2 months after 90Y-Ibritumomab Tiuxetan because of cerebral ischemia; finally we observed a myelodysplastic syndrome in 1pt who had received 45 MBq/kg 2 years after treatment. 22/24 patients are now evaluable for response: 9 CR, 4 PR, 1 SD, 8 PD.CONCLUSION: 90Y-Ibritumomab Tiuxetan at myeloablative activity is feasible with PBSC support and it could be safely delivered also in elderly pts. We suggest dosimetry in order to avoid unpredictable toxicity and an activity of 45 MBq/kg in heavily pretreated patients. Clinical efficacy and mild treatment-related toxicities suggest HD-90Y-Ibritumomab Tiuxetan is an interesting modality treatment to be further investigated as an alternative therapeutic option in ABMT setting.

Updated Results of High-Dose Yttrium 90 (90Y) Ibritumomab Tiuxetan with High-Dose Etoposide (VP-16) and Cyclophosphamide (CY) Followed by Autologous Hematopoietic Cell Transplant (AHSCT) for Poor-Risk or Refractory B-Cell Non-Hodgkin's Lymphoma.

Background: 90Y ibritumomab tiuxetan (Zevalin®) has been shown to be an effective therapy for patients with both follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). We have previously reported the feasibility of adding high-dose 90Y ibritumomab tiuxetan to high-dose VP-16 and CY followed by AHSCT without additional toxicity. Herein, we reported longer follow-up results of this high-dose regimen.Methods: Patients undergo dosimetry study (day-21) with 5 mCi 111In-ibritumomab tiuxetan following 250 mg/m2of rituximab, followed by 90Y ibritumomab tiuxetan (day-14) to deliver a target dose of 1000 cGy to highest normal organ and then VP-16 (day-4), and CY (day-2). Bone marrow biopsy is done on day-7 to estimate the radiation dose. Stem cells are re-infused when the radiation dose to re-infused stem cells is estimated to be <5 cGy.Results: Between 5/00 and 7/05, 53 patients were enrolled; 11 had an imaging study but did not proceed to treatment due to dosimetry ineligibility (7), progressive disease (2), reaction to 111In-ibritumomab tiuxetan (1) and reaction to rituximab (1). 42 patients (25 M: 17F), median age 51 yrs (range 25–59.6) with FL (n=13), DLBCL (n=20), mantle cell (MCL) (n=8) and transformed lymphoma (n=1) were treated. Disease status at AHSCT: 1stCR/PR=11, ≥2ndCR=13, REL=9 and IF=9. Twenty-three (55%) had prior BM involvement. Median number of prior chemo regimens was 2 (range 1–6). All but two had received rituximab. As part of phase I/II trial, 6 received VP-16 40mg/kg and the rest received 60 mg/kg. The median 90Y ibritumomab tiuxetan dose delivered was 70.8 mCi (range 37–105). The treatment was well tolerated with mucositis and neutropenic fever being the most common acute toxicities. All but one patient engrafted. The median time to reach ANC>500/μl and platelet>20,000/μl was 10 days (range 8–17) and 12.5days (range 8–123), respectively. The transplant-related mortality (TRM) at day 100 was 2%. There were 8 deaths due to relapse (3), second malignancies (2), graft failure (1), alcohol induced liver failure (1) and sudden death (1). Secondary malignancies occurred in 3 (7%) heavily pre-treated FL: pancreatic cancer at 3.8 yrs, acute myeloid leukemia at 5 years and one with abnormal chromosome but without morphologic evidence of MDS at 1 year. At a median follow-up of 55 months (range, 25–84) for the surviving patients, the 4-year estimated overall survival (OS) and disease-free survival (DFS) is 81% (95% CI, 67–89%), and 65% (95% CI, 54–74%), respectively (figure.1). The 4-year estimated DFS for FL, DLBCL and MCL is 71% (95% CI, 51–85%), 67% (95% CI, 49–79%) and 47% (95% CI, 29–63%), respectively.Conclusion: Our long-term results suggest that the combination of high-dose 90Y ibritumomab tiuxetan and high-dose VP-16 and CY is an effective high-dose regimen, especially for FL and DLBCL. Short term toxicities appear comparable to other conventional high-dose regimens. Further prospective studies are ongoing to determine the curability and long term toxicities of this preparative regimen. [Display omitted]

A Prospective Study Evaluating the Safety and Efficacy of Combination Therapy with Fludarabine Plus Mitoxantrone Followed by Yttrium-90 (90Y) Ibritumomab Tiuxetan (Zevalin®) and Maintenance Rituximab as Front Line Therapy for Patients with Intermediate or High Risk Follicular Non-Hodgkin's Lymphoma.

Background: The combination of fludarabine and mitoxantrone (FM) as a front line therapy for advanced follicular lymphoma (FL) has been shown to result in higher complete response rates when compared with standard-dose CHOP. We assessed the safety and efficacy of FM followed by 90Y ibritumomab tiuxetan (IT) and maintenance rituximab (MR) in previously untreated patients (pts) with FL.Methods: Pts with newly diagnosed stage III-IV FL and an intermediate or high FLIPI scores were eligible. Pts were required to have an expected survival of at least 3 months, a performance status ≤2, and adequate bone marrow (BM) function (ANC 1500/mm3, platelets 100,000/mm3), liver, and renal function. Initial treatment consisted of 4 cycles of FM (fludarabine 25 mg/m2 on days 1–3, mitoxantrone 12 mg/m2 on day 1 of each 28-day cycle). After restaging, complete and partial responders with ≤25% BM involvement proceeded to the IT therapeutic regimen. Partial responders with >25% BM involvement received 2 additional cycles of FM before IT. The 90Y IT dose (0.3 or 0.4 mCi/kg) was adjusted according to the patient's platelet count. MR (375 mg/m2 weekly× 4) was scheduled for every 6 months over 2 years.Results: Twenty patients have been enrolled. The median age was 53 years (range: 32–79), and 12 pts were male. 14 pts had stage IV with BM involvement and 6 had stage III. The median FLIPI score was 2 (range, 1–4). Only 1 pt had 6 cycles of FM. At the time of this analysis: 13 pts underwent therapy with IT, 3 of them finished MR cycles, 1 had 3 cycles, 5 had 2 cycles, 1 had 1 cycle, and 3 are still awaiting their first cycle of MR. 7 pts finished FM therapy but still awaiting treatment with IT. Overall response was achieved in 100% of pts; CR in 14/20 pts (70%) and PR in 6/20 pts (30%). The responses to FM were converted from PR to CR in 5 pts: 1 after IT, 1 after 2 cycles of MR, and 3 after completing MR. Grades 3 or 4 hematologic toxicities were encountered in 6/20 pts (30%); with grades 3 or 4 neutropenia in 5 pts (25%) and grades 3 or 4 thrombocytopenia in 5 pts (25%). Platelets, ANC, and hemoglobin nadirs occurred at 3–7 weeks following 90Y IT, and were reversible with median duration of nadirs of 4 weeks (range: 1–5). After median follow up of 16 months (range 3.5 – 39), only one pt developed progressive disease 14 months from registration, and after receiving IT therapy. Repeat BM biopsy at progression showed FL with focal areas of blastoid transformation. No death event has been reported to date.Conclusions: The initial results from this prospective study suggest: 1- FM followed by 90Y ibritumomab tiuxetan and maintenance rituximab regimen is safe and highly effective front line therapy for pts with intermediate or high risk FL (advanced stage with intermediate or high FLIPI scores at diagnosis). 2- The addition of IT and MR to the overall treatment strategy improves the quality of responses; and 3- Though the response rates are encouraging, longer follow-up will be required to evaluate the impact on progression-free survival and overall survival.

Efficacy of 90Y-Ibritumomab Tiuxetan in Marginal-Zone Lymphoma (MZL).

Radio-immunotherapy (RIT) is an effective approach for patients with relapse-refractory NHL. RIT targets radiation to the tumor bulk while limiting exposure of normal tissues. Toxicity is prevalently hematologic, but transient and reversible. 90Y-Ibritumomab Tiuxetan in particular has demonstrated activity in follicular (FL) and Diffuse Large B-Cell (DLBC) NHL, but data are still lacking in MZL. 90Y-Ibritumomab Tiuxetan could offer an alternative option to those pts who relapse or do not respond to conventional treatment. We report efficacy results of a pilot study of 90Y-Ibritumomab Tiuxetan delivered at conventional activity (0,4 mCi/kg) in MZL patients. From May 2004 to July 2007, 15 patients were enrolled. Median age was 57 ys (range 36–83 ys); 9 female and 6 male. Six out of 15 pts had Helicobacter Pylori-negative gastric MALT (mucosa-associated lymphoid tissue) NHL. The remaining 9 pts had non gastric extranodal MZL. At time of treatment 6/15 pts had limited disease (stage I/II), 9/15 disseminated disease (stage III/IV; Ann-Arbor Staging System); bone marrow biopsy showed disease localization in 3/15 pts. Median number of previous therapies received was 2 (0–4): all pts except one had received prior CT, 7 prior Rituximab, 3 prior RT. Toxicities were primarily haematological, as expected, and reversible. Response evaluation was performed two months after 90Y-Ibritumomab Tiuxetan administration by upper gastrointestinal endoscopy with multiple biopsy and endoscopic ultrasonography in gastric NHL and by CT scan in the remaining pts. Ten out of 15 patients are now evaluable for response: 6 CR, 1 uCR, 3 SD. Response are durable: 5 CRs have been maintained for CR at 33, 26, 22, 15 and 14 months, respectively.CONCLUSIONS: 90Y-Ibritumomab Tiuxetan seems to be very active in pts with MZL resistant or refractory to conventional systemic treatment. Its mechanism of action mimics conventional RT already known as valid option in MZL with localized disease. If these preliminary results are confirmed in larger number of patients, one single administration of 90Y-Ibritumomab Tiuxetan delivered at conventional activity (0,4 mCi/kg) could be considered a possible alternative option in the treatment of such indolent disease.

Cost of 90Y-Ibritumomab Tiuxetan Radioimmunotherapy Versus Cost of Standard Regimens for the Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma in Switzerland.

Current standard second-line regimens for the treatment of non-Hodgkin's lymphoma (NHL) are administered over a period of 3–6 months, generating substantial treatment costs. In Switzerland, Yttrium-90 (90Y)-ibritumomab tiuxetan was introduced in 2004 as the first-in-class radioimmunotherapy for the treatment of relapsed or refractory indolent NHL. It is delivered in an outpatient setting over a period of 8 days. In Switzerland, just as in the United States, assessment of the biodistribution of the antibody is required one week prior to the actual treatment (this step is not required in the European Union). This analysis compared the costs of 90Y-ibritumomab tiuxetan with 8 cycles of rituximab (R), 6 or 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), and 6 or 8 cycles of R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone), respectively. Direct medical treatment costs and costs of absence from work (indirect costs) were included. For each treatment option, the number of cycles per treatment and the total medical resources used to care for the patient throughout the treatment were assessed for a theoretical standard patient, defined as 60 years old with therapy refractory, grade 1–2, stage III-IV NHL. The resources used were valued with unit costs or prices gained from the Swiss national fee schedule for medical services, lists of administered prices for laboratory tests and pharmaceuticals, and purchasing prices for all other relevant items. Total lost productivity due to absence from work was estimated by multiplying the days absent from work with average income per day. Results are summarized in Table 1. Direct treatment costs for 90Y-ibritumomab tiuxetan were lower than 8 x R, 8 x R-CHOP, and 8 x R-CVP but higher than 6 x R-CHOP or 6 x R-CVP. When indirect costs were taken into account, total 90Y-ibritumomab tiuxetan cost was lower than for all other regimens except 6 x R-CVP. The only sensitivity analysis that changed the ranking of the treatment options was omitting the biodistribution study and thus adopting the EU regimen for 90Y-ibritumomab tiuxetan. This reduced the costs of radioimmunotherapy to CHF 27,766. In conclusion, 90Y-ibritumomab tiuxetan is not more expensive than other established treatments for relapsed or refractory indolent NHL. Table 1. Per-patient costs by treatment in Switzerland.Costs (CHF)Treatment optionDirectIndirectTotal6 x R-CVP34,0453,79437,83990Y-ibritumomab tiuxetan38,6191,26539,8846 x R-CHOP36,7115,69142,4038 x R42,6252,02444,6498 x R-CVP44,8785,05949,9378 x R-CHOP48,2507,58955,839

Health-Related Quality of Life in Patients with Advanced-Stage Follicular Lymphoma Receiving Consolidation with 90Y-Ibritumomab Tiuxetan (Zevalin®) of First Remission: Results from the Randomized Phase 3 First-Line Indolent Trial (FIT).

A previous phase 3 study showed that in patients with relapsed/refractory low-grade, follicular or transformed non-Hodgkin's lymphoma, radioimmunotherapy with 90Y-ibritumomab tiuxetan (Zevalin) significantly improved patient-reported quality of life (QoL) as measured by the validated Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire (Wiseman et al Blood 2000; 96(11):734a, abstract 3173). The study showed significant improvements in FACT-G total score, as well as in subscores for emotional, physical, and functional well-being. In the recent international phase 3 First-line Indolent Trial (FIT), patients with stage III or IV follicular lymphoma in first remission after initial chemotherapy were randomized to receive consolidation with Zevalin (n=208) or no further treatment (control; n=206). The impact of Zevalin on health-related QoL was evaluated as one of the secondary end points of this study. Health-related QoL was assessed using EORTC QLQ-C30 (version 2) and EuroQoL-5D (EQ-5D) questionnaires. The EORTC QLQ-C30 was developed to specifically assess QoL in patients with cancer, and comprises 30 items grouped into the following dimensions: functional (physical, role, cognitive, social, emotional), symptomatic (nausea, pain, fatigue), global QoL, and other (dyspnea, difficulty sleeping, anorexia, constipation, diarrhea, perceived financial difficulties). The EQ-5D was developed as a generic instrument to assess health-related QoL and comprises 2 sections, an assessment based on 5 dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression) and a visual analogue scale (VAS). These questionnaires were administered at the screening visit, week 14, every 6 months thereafter, and at the end of the follow-up period. Descriptive statistics were used to compare scores across treatment groups. The change in scores from baseline was also assessed by gender, age, and first-line treatment. Mixed effects model was used to assess factors associated with final scores of the VAS of EQ-5D. No notable treatment differences were observed in EORTC QLQ-C30 (all domains) scores across timepoints or changes from baseline. This result was true for all subgroups. The mean scores for EQ-5D at the screening and final visits were 0.83 and 0.84, respectively, for the Zevalin arm, and 0.84 and 0.83, respectively, for the control arm. The mean VAS scores at the screening and final visits were 77.52 and 77.64, respectively, for the Zevalin arm, and 76.57 and 78.60, respectively, for the control arm. An analysis of factors associated with final VAS scores showed that only baseline VAS scores affected final VAS scores (P<0.0001) considerably. No differences were observed in health-related QoL parameters between patients receiving consolidation therapy with Zevalin and patients in the control arm as measured by EORTC QLQ C-30 and EQ-5D questionnaires. Thus, in patients with advanced-stage follicular lymphoma responsive to first-line therapy, treatment with Zevalin consolidation does not impact the health-related QoL compared with no further treatment.

Phase I Trial of Combination Therapy with 90Y Ibritumomab Tiuxetan (Zevalin) and Gemicitabine in Patients with Non-Hodgkin's Lymphoma.

Y90-ibritumomab tiuxetan radioimmunotherapy, or Zevalin (Y90-RIT), is an effective therapy against CD20+ lymphoma. While it is approved for use in patients with relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), it is not curative and ways to enhance its efficacy would be useful. Gemcitabine (G) is a potent radiation sensitizer that also is active against NHL. Its radiation sensitizing ability and activity against NHL provide the rationale for our ongoing phase I trial to assess the safety of concomitant administration of Y90-RIT and gemcitabine in patients with NHL. Nine patients in three cohorts have been treated with 250 mg/m2 of gemcitabine IV on days 1 and 8 of the Y90-RIT treatment program of rituximab + In 111-ibritumomab on day 1 and rituximab + Y90 ibritumomab on day 8, with Y90 at 0.2, 0.3 or 0.4 mCi/kg respectively. Subsequent cohorts only accrued after all patients in the prior cohort had resolution of hematologic toxicities to grade 0–2 or after 60 days from the date of the last treated patient in the previous cohort. One patient has been treated with 300mg/m2 of G and 0.4 mCi/kg of Y90-RIT. No DLTs have been observed so far. The dose of G is continuing to be escalated according to a Bayesian based system. Response evaluation is by standard criteria. Eligibility criteria include: any histology of recurrent B cell NHL (not candidates for high dose therapy), platelets ≥ 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to <25% of bone marrow and no prior bone marrow or stem cell transplant. Ten patients have been treated thus far, five with follicular (FL), four with diffuse large B cell (DLBCL) and one with marginal zone NHL. Median age is 70 (range 55–82). The median number of prior treatments is 2 (range 1–6). Patients 1–3 received Y90 at 0.2 mCi/kg, patients 4–6 at 0.3 mCi/kg and patients 7–9 received standard 0.4 mCi/kg of Y90, all with 250 mg/m2 of gemcitabine on days 1 and 8. Patient number 10 has received full dose of Y90 and G at 300 mg/m2. Grade 3 or 4 toxicities have consisted only of: one grade 3 neutropenia, three grade 3 leukopenia and six grade 3 and three grade 4 lymphopenia. One grade 3 infection occurred, unrelated to the protocol or the study drugs. Grade 3 or 4 non-hematologic toxicities have included one case each of increased bilirubin, increased GGT and increased calcium. In follow up, responses have included: 2 stable disease (one patient each with FL and marginal zone NHL, mean duration of response: 7.2 months), 2 CRu and one CR all in patients with FL (mean duration of response: 17.5 months), one PR and 4 progression of disease (DLBCL). One patient with CRu, and one with SD have ongoing responses. Three additional patients have met the protocol defined criteria for progression but have not had a need for initiation of any other treatments. One patient was diagnosed with a new lung cancer after achieving a PR.Conclusion: Our findings demonstrate that Y90-RIT (Zevalin) at the standard dose of 0.4 mCi/kg can be safely combined with gemcitabine at 250 and 300 mg/m2 days 1 and 8 in the treatment of patients with NHL. Accrual to cohorts with 0.4 mCi/kg of Y90-RIT and escalating doses of gemcitabine is continuing.

Registry of RadioImmunoTherapy: Analysis of Outcomes of Recurrent or Refractory Non-Hodgkin Lymphoma Patients Treated with 90Y Ibritumomab Tiuxetan.

Background: 90Y Ibritumomab tiuxetan (90Y-RIT) is approved for the treatment of refractory or recurrent non- Hodgkin follicular lymphoma (NH FL). The aim of this study was to collect data of NH FL patients (p) treated with RIT within the clinical practice setting, to retrospectively analyze treatment effectiveness and tolerability, in order to provide a pragmatic approach to experimental data.Methods: P treated, since commercial availability in Spain and Portugal, with 90Y - RIT, were registered. Effectiveness endpoints retrospectively studied were: objective response rate (ORR), time to progression (TTP) overall survival (OS) and safety. Clinical prognostic factors were collected to asses their possible influence upon treatment effectiveness, by multivariate analyses.Results: 118 p from 44 centres have been registered, treated since commercial availability until March 2007: M/F, 55.9%/44.1%; mean age, 58.6 years (22–83); ECOG 0–1, 83.5%. Eighty five p had FL (72%) and 33 non-FL (28%). Median time since NHL diagnosis was 3.9 years (0.4–23.9). Before 90Y-RIT, most of the cases were refractory to previous treatments (73.5%). FLIPI distribution previous to RIT was: low-risk 50.6%, intermediate-risk 22.4% and high-risk 25.9%. IPI distribution previous to RIT was: low-risk 33.3%, intermediate low-risk 30.3%, intermediate high-risk 18.2% and high-risk 15.2%. Median number of previous treatments was 3 (range 1.0–8.0). ORR was 67.8% (95% CI: 59.4, 76.2). According to FLIPI ORR was: LR: 90.7%; IR: 63.1%; HR: 59.1%. According to IPI ORR was: LR: 54.5%; ILR: 40.0%; IHR: 33.3%; HR: 40.0%. With a median follow-up time of 7 months, median TTP was 9.9 months (95% CI: 6.4, 13.4) and median OS was 20.9 months (95% CI: 14.1–27.7), with an estimated OS at 1 and 2 years of 73.3% and 44.3%, respectively. High FLIPI score was significantly associated with worse response rate: Odds ratio 0.185 (95% CI: 0.047, 0.732). More than 2 previous treatments was also related with worse response rate, for both FL p and non FL p: Odds ratio 4.025 (95% CI: 1.127, 14.373) and 7.0 (95% CI: 1.173–41.759), respectively. Safety analysis was performed for the global sample, for p with or without previous transplant and for p previously treated or not with Fludarabine containing regimens.Safety analysesPrevious TransplantPrevious FludarabineGlobal N=118Yes N=22No N=96Yes N=41No N=77G3-4 haematological (%)Anemia45.522.931.724.727.1Neutropenia54.543.753.641.645.8Leucopenia45.534.443.932.536.4Thrombocitopenia54.547.951.248.149.2Neutropenia febrile27.27.39.811.711.0G3-4 non haematological toxicity (%)Asthenia13.67.39.87.88.5Treatment/interventions required (%)Hospitalization36.418.829.318.222.0G-CSF63.640.648.842.944.9Red blood cell transfusions59.122.939.024.729.7Platelet transfusions50.028.134.131.232.2Conclusions: Despite the limitations of the retrospective design of the Registry, these results obtained with 90Y - RIT for lymphoma patients treated within the clinical practice setting are similar to that obtained in clinical trials. Updated data will be presented at the meeting.

Role of Yttrium-90 Ibritumomab Tiuxetan (Zevalin®) in Inducing and Maintaining Complete Molecular Response in B Non Hodgkin's Lymphoma Patients in Clinical Complete Remission after Chemotherapy Regimen.

Introduction: Radioimmunotherapy (RIT) is a new treatment for B non Hodgkin's lymphoma (NHL) patients. 90Y ibritumomab tiuxetan (Zevalin®) consists of a murine monoclonal antibody to CD20, conjugated to a metal chelator tiuxetan for retention of the beta emitter 90Y. Thus Zevalin® delivers radiation to B-NHL, combining the tumor targeting attributes of a monoclonal antibody and the beta radiation of 90Y. Zevalin® is approved for the treatment of follicular lymphoma (FL) refractory to or relapsed after rituximab, on the bases of clinical trials where it achieved a response rate as high as 83%. Several ongoing registrational trials are evaluating the efficacy of Zevalin® in other NHL, as diffuse large B cell (DLCL) and mantle cell lymphoma (MCL). We are here evaluating the effect of Zevalin® as consolidation therapy in NHL patients that achieved a complete clinical response (CCR) with chemotherapy.Methods: In B cell NHL patients that achieved a CCR after 1st or multiple lines anthracyclines based chemotherapy +/− Rituximab, minimal residual disease was evaluated by PCR on bone marrow samples, for the following rearrangements: JH, Bcl-1, Bcl-2. Patients received Zevalin® 6-9 weeks post chemotherapy. Evaluation of molecular response was assessed after a follow up period at 12 weeks. The aim of the study was the role of Zevalin® in inducing a complete molecular response (CMR).Results: 23 B-NHL patients (13 FL, 6 MCL, 4 DLCL; male:female 13:10, median age 63, range 42–73. See table) in a CCR after chemotherapy (documented by TC scan and/or PET-scan negative for abnormal lesions or glucose captation) have been enrolled. 10 patients had a pathological rearrangement before RIT, while 13 were already in a CMR condition. Zevalin® was completed in all 23 patients and the post infusion evaluation was performed after 12 weeks. In the follow-up period thrombocitopenia was commonly documented, but it was not associated to bleeding or need of platelet transfusion, but in one singular case. After 12 weeks from RIT a new molecular evaluation was performed on bone marrow samples. All the 23 patients have completed the 12 weeks follow-up: 8 of 10 (80%) patients positive before RIT achieved a CMR with Zevalin® administration. The 13 PCR negative patients maintained the CMR. The 21 PCR negative patients are now under follow-up to evaluate the molecular disease free survival after Zevalin® RIT.Conclusion: Zevalin® is an efficient consolidation therapy in B cell NHL patients after chemotherapy. In this series of patients Zevalin® administration allowed to convert 8 of 10 CCR to CMR. In the remaining 13 patients Zevalin® maintained the CMR. Zevalin® addition to medication treatment is feasible and associated with manageable hematological toxicity.Ptsdiseasesexageprevious chemotherapy linesmolecular response before RITmolecular response after RIT1FLM681POSNEG2FLF531NEGNEG3FLM541NEGNEG4FLM514NEGNEG5DLCLF662POSNEG6DLCLF671NEGNEG7FLF421POSPOS8FLM521POSNEG9FLF543NEGNEG10FLM572POSNEG11FLF622POSNEG12FLM582POSNEG13FLF692NEGNEG14MCLM621POSNEG15MCLM661POSPOS16MCLM662NEGNEG17MCLM671POSNEG18FLF672NEGNEG19DLCLF673NEGNEG20MCLM702NEGNEG21FLM614NEGNEG22DLCLM432NEGNEG23MCLF732NEGNEG

Phase II Study of R-CHOP Followed by 90Y-Ibritumomab Tiuxetan in Untreated Mantle Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499.

Background: As MCL has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate,90Y-ibritumomab tiuxetan (90Y-RIT), following 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction.Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr with measurable/evaluable disease and adequate organ function were eligible. At 4–8 weeks after 4 cycles of R-CHOP, responding (CR/PR) and stable pt received 0.4 mCi/kg 90Y-RIT. The primary endpoint was failure-free survival (FFS) and secondary objectives were evaluation of response and toxicity after R-CHOP and after 90Y-RIT. The study design required 52 eligible pt to demonstrate a prolongation of FFS by 50% compared with R-CHOP alone (median FFS 16 mo, Howard et al., JCO 20:1288, 2002).Results: The characteristics of 56 eligible pt are: 73% male, median age 61 (33–83) yrs, 91% stage III/IV, 68% >1 extranodal site, 78% marrow-positive. IPI was 0–2 in 51%, 3–5 in 49%. Fifty-one (91%) pt received all treatment and best response (n=50) was 42% CR/CRu, 32% PR, 12% stable and 4% unevaluable, with an improvement in response in 16 pt after 90Y-RIT. After 90Y-RIT, 55% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 22/23 pt. Median follow-up (all pt) is 24.4 months. Median FFS for all 56 pt is 27 months with an estimated 71% FFS and 93% overall survival at 18 months. Among pt who completed all treatment and have been followed ≥1.5 yr (n=45), 33 remain failure-free and 12 have progressed (4 dead).Conclusions: 90Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. These data suggest prolongation of FFS over that expected with R-CHOP alone. Consolidation of remission in MCL with 90Y-RIT shows potential as a strategy to prolong remission duration and is applicable to most pt with MCL. However, longer follow-up in needed to evaluate the durability of remissions achieved.