Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics

Purpose It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated ¹³¹I-rituximab injections during treatment with unlabelled rituximab in patients with non-Hodgkins lymphoma (NHL).Methods Patients received standard weekly therapy with rituximab (375 mg/m²) for 4 weeks and a fifth injection at 7 or 8 weeks. Each patient had three additional injections of 185 MBq ¹³¹I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post ¹³¹I-rituximab injection prior to the second and third injections, respectively.Results A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T_1/2, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T_1/2 of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05 mSv/MBq (range 0.48–0.59 mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver.Conclusion These results show that the biodistribution and tissue kinetics of ¹³¹I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry study.     

Radioimmunotherapy using 131I-rituximab in patients with advanced stage B-cell non-Hodgkin’s lymphoma: initial experience

Purpose The aim of this study was to evaluate the safety, toxicity and therapeutic response of non-myeloablative radioimmunotherapy using ¹³¹I-rituximab in previously heavily treated patients with B-cell non-Hodgkins lymphoma (B-NHL).Methods Nine patients with relapsed, refractory or transformed B-NHL received ten radioimmunotherapies. Patients had a median of 5 (range 2–7) prior standard therapies. Four patients had received prior high-dose chemotherapy followed by autologous stem cell transplantation, and eight had received prior rituximab therapy. Histopathology consisted of four mantle cell, one follicular and four diffuse large B-cell lymphomas. Rituximab, a monoclonal chimeric anti-CD20 antibody (IDEC-C2B8), was labelled with ¹³¹I using the Iodogen method. The administered activity (2,200±600 MBq) was based on a dosimetrically calculated 45 cGy total-body radiation dose. All patients received an infusion of 2.5 mg/kg of rituximab prior to administration of the radiopharmaceutical.Results No acute adverse effects were observed after the administration of ¹³¹I-rituximab. Radioimmunotherapy was safe in our patient group and achieved one complete response ongoing at 14 months and two partial responses progressing at 12 and 13 months after treatment. One partial responder was re-treated with radioimmunotherapy and achieved an additional progression-free interval of 7 months. Four non-responders with bulky disease died 4.8±2.0 months after therapy. Three patients had an elevated serum lactate dehydrogenase (LDH) level prior to radioimmunotherapy and none of the patients responded. Of two patients who received radioimmunotherapy as an additional treatment after salvage chemotherapy, one continues to be disease-free at 9 months and one relapsed at 5 months follow-up. Reversible grade 3 or 4 haematological toxicity occurred in seven of nine patients. Median nadirs were 35 days for platelets, 44 days for leucocytes and 57 days for erythrocytes.Conclusion Radioimmunotherapy with ¹³¹I-rituximab in previously heavily treated B-NHL patients was safe and well tolerated, and four out of ten therapies induced responses. Radioimmunotherapy was less efficient in patients with bulky disease and elevated LDH. Severe haematological toxicity in seven patients did not cause significant clinical problems. Radioimmunotherapy seems to be an additional therapeutic option in carefully selected therapy-refractory B-NHL patients.     

Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin's lymphoma: combined data from 4 clinical trials.

Ibritumomab tiuxetan is an anti-CD20 murine IgG1 kappa monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates (111)In for imaging or dosimetry and (90)Y for radioimmunotherapy (RIT). Dosimetry and pharmacokinetic data from 4 clinical trials of (90)Y-ibritumomab tiuxetan RIT for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) were combined and assessed for correlations with toxicity data. METHODS: Data from 179 patients were available for analysis. Common eligibility criteria included <25% bone marrow involvement by NHL, no prior myeloablative therapy, and no prior RIT. The baseline platelet count was required to be > or = 100,000 cells/mm(3) for the reduced (90)Y-ibritumomab tiuxetan administered dose (7.4-11 MBq/kg [0.2-0.3 mCi/kg]) or > or = 150,000 cells/mm(3) for the standard (90)Y-ibritumomab tiuxetan administered dose (15 MBq/kg [0.4 mCi/kg]). Patients were given a tracer administered dose of 185 MBq (5 mCi) (111)In-ibritumomab tiuxetan on day 0, evaluated with dosimetry, and then a therapeutic administered dose of 7.4-15 MBq/kg (0.2-0.4 mCi/kg) (90)Y-ibritumomab tiuxetan on day 7. Both ibritumomab tiuxetan administered doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve ibritumomab tiuxetan biodistribution. Residence times for (90)Y in blood and major organs were estimated from (111)In biodistribution, and the MIRDOSE3 computer software program was used, with modifications to account for patient-specific organ masses, to calculate radiation absorbed doses to organs and red marrow. RESULTS: Median radiation absorbed doses for (90)Y were 7.42 Gy to spleen, 4.50 Gy to liver, 2.11 Gy to lung, 0.23 Gy to kidney, 0.62 Gy (blood-derived method) and 0.97 Gy (sacral image-derived method) to red marrow, and 0.57 Gy to total body. The median effective blood half-life was 27 h, and the area under the curve (AUC) was 25 h. No patient failed to meet protocol-defined dosimetry safety criteria and all patients were eligible for treatment. Observed toxicity was primarily hematologic, transient, and reversible. Hematologic toxicity did not correlate with estimates of red marrow radiation absorbed dose, total-body radiation absorbed dose, blood effective half-life, or blood AUC. CONCLUSION: Relapsed or refractory NHL in patients with adequate bone marrow reserve and <25% bone marrow involvement by NHL can be treated safely with (90)Y-ibritumomab tiuxetan RIT on the basis of a fixed, weight-adjusted dosing schedule. Dosimetry and pharmacokinetic results do not correlate with toxicity.     

Radioimmunotherapy of B-cell non-Hodgkin's lymphoma: from clinical trials to clinical practice.

Radioimmunotherapy (RIT) is a new treatment modality for B-cell non-Hodgkin's lymphoma (NHL). Recent clinical trials have clearly established its efficacy in NHL patients refractory to standard chemotherapy or immunotherapy with the widely used unconjugated rituximab monoclonal antibody (mAb). The Food and Drug Administration has approved (90)Y-ibritumomab tiuxetan anti-B-cell NHL mAb as the first commercially available radiolabeled antibody for cancer therapy. This comes only a few years after the introduction of rituximab into clinical practice as the first unconjugated antibody for cancer treatment, underscoring the success of both immunotherapy and RIT in the treatment of NHL. With the approval of (90)Y-ibritumomab tiuxetan, and based on the results of numerous clinical trials with radiolabeled anti-B-cell NHL mAbs, RIT promises to become integral to nuclear medicine practice. In this article, the basic concepts of RIT are reviewed with important milestones in its development for B-cell NHL treatment and particular emphasis on phase II and III clinical trials establishing its efficacy in clearly defined patient populations. Finally, the prospects for the expected widespread clinical use of RIT in the management of B-cell NHL, alone or in combination with other more established therapies, are discussed. This article provides both investigative and clinical nuclear medicine physicians with a better understanding of RIT capabilities and limitations in B-cell NHL and their role as consultants in the care of NHL patients.     

The number of 131I therapy courses needed to achieve complete remission is an indicator of prognosis in patients with differentiated thyroid carcinoma

Purpose

To assess the risk of differentiated thyroid cancer (DTC) recurrence, DTC-related mortality and life expectancy in relation to the number of courses of ¹³¹I therapy (RIT) and cumulative ¹³¹I activities required to achieve complete remission (CR).

Methods

The study was a database review of 1,229 patients with DTC, 333 without and 896 with CR (negative TSH-stimulated thyroglobulin and negative ¹³¹I diagnostic whole-body scintigraphy) after one or more courses of RIT.

Results

The median follow-up was 9.0 years (range 0.1 – 31.8 years) after CR. Recurrence rates at 5 years, 10 years and the end of follow-up were 1.0?±?0.3 %, 4.0?±?0.7 % and 6.2?±?1.1 %, and DTC-related mortality was 0.1?±?0.1 %, 0.5?±?0.3 % and 3.4?±?1.1 %, respectively. Recurrence rates also increased with an increasing number of RIT courses required (p?=?0.001). DTC-related mortality increased from four RIT courses. In patients with CR after one RIT course, there were no differences in recurrence or DTC-related mortality rates between low-risk and high-risk patients. In patients requiring two RIT courses these rates remain elevated in high-risk patients. Recurrence and DTC-related mortality rates were only significantly elevated in those requiring a cumulative activity over 22.2 GBq (600 mCi) from multiple RIT courses for CR. Regardless of the number of RIT courses or activity needed, life expectancy was not significantly lowered.

Conclusion

If more than one RIT course is needed to achieve CR, higher recurrence and DTC-related mortality rates are observed, especially in high-risk patients. Patients requiring >22.2 GBq ¹³¹I for CR should be followed in the same way as patients in whom CR is never reached as long-term mortality rates are similar.     

Radioimmunotherapy with yttrium-90 ibritumomab tiuxetan. Clinical considerations, radiopharmacy, radiation protection, perspectives

90Y-ibritumomab tiuxetan (Zevalin) is currently approved for radioimmunotherapy of patients with relapsed or refractory follicular non-Hodgkin's lymphoma pretreated with rituximab. Future directions are the combined use of 90Y-ibritumomab tiuxetan as part of the initial treatment and as first-line multi-agent therapy of relapsed disease. Current studies investigate patients with other than follicular indolent histologies, e. g. diffuse large cell lymphoma. Labelling of 90Y ibritumomab tiuxetan is a safe procedure, the radiochemical purity is not disturbed by a higher room temperature or by metallic impurity. Quality control is recommended by thin layer chromatography (TLC), strips >15 cm are favourable. TLC cannot distinguish between the correctly radiolabelled antibodies and radiocolloid impurity. If necessary, additional HPLC should be performed. Radiocolloid impurities are absorbed to the solid phase and do not reach the eluate. If the radiochemical purity test is insufficient (<95%), the additional cleaning using EconoPac 10 DG columns (Biorad, Hercules, CA, USA) is a reliable procedure to reduce the percentage of free radionuclide. However, this procedure is not part of the approval.     

Extensive Extranodal Involvement of Rare Sites in Non Hodgkin’s Lymphoma Detected on 18F- FDG PET-CT: A Case Report

We present a case of a 23 year-old male treated for Hodgkin’s lymphoma who developed diffuse large B-cell lymphoma (DLBCL) 8 years after achieving remission. ¹⁸F-fluorodeoxyglucose positron emission tomography computed tomography (¹⁸F-FDG PET-CT) was done, which revealed extensive extranodal involvement of bilateral atria, bilateral kidneys, ileo-caecal junction and left testis along with mesenteric and retroperitoneal lymph nodal involvement. Renal and cardiac lesions were not detected by contrast-enhanced CT. Simultaneous lymphomatous involvement of rare sites such as heart, kidneys and testis in a single patient has not been reported before.     

Absorbed dose and biologically effective dose in patients with high-risk non-Hodgkin’s lymphoma treated with high-activity myeloablative <Superscript>90</Superscript>Y-ibritumomab tiuxetan (Zevalin®)

Purpose

The aim of this study was to carry out two different dose estimation approaches in patients with non-Hodgkin’s lymphoma (NHL) treated with a myeloablative amount of ⁹⁰Y-labelled ibritumomab tiuxetan (Zevalin®) in an open-label dose escalation study.

Methods

Twenty-seven patients with relapsed/refractory or de novo high-risk NHL receiving one myeloablative dose of ⁹⁰Y-ibritumomab tiuxetan followed by tandem stem cell reinfusion were evaluated for dose estimate. The injected activity was 30 MBq/kg in 12 patients and 45 MBq/kg in 15 patients. Dose estimation was performed 1 week prior to ⁹⁰Y-ibritumomab tiuxetan by injection of ¹¹¹In-ibritumomab tiuxetan (median activity: 200 MBq). The absorbed dose (D) and the biologically effective dose (BED) were calculated.

Results

The absorbed doses per unit activity (Gy/GBq) were [median (range)]: heart wall 4.6 (2.5–9.7), kidneys 5.1 (2.8–10.5), liver 6.1 (3.9–10.4), lungs 2.9 (1.5–6.8), red marrow 1.0 (0.5–1.7), spleen 7.0 (1.5–14.4) and testes 4.9 (2.9–16.7). The absorbed dose (Gy) for the 15 patients treated with 45 MBq/kg were: heart wall 17.0 (8.7–25.4), kidneys 17.1 (7.9–22.4), liver 20.8 (15.4–28.3), lungs 8.1 (5.4–11.4), red marrow 3.1 (2.0–4.0), spleen 26.2 (17.0–35.6) and testes 17.3 (9.0–28.4). At the highest activities the acute haematological toxicity was mild or moderate and of very short duration, and it was independent of the red marrow absorbed dose. No secondary malignancy or treatment-related myelodysplastic syndrome was observed. No non-haematological toxicity (liver, kidney, lung) was observed during a follow-up period of 24–48 months.

Conclusion

The use of 45 MBq/kg of ⁹⁰Y-ibritumomab tiuxetan in association with stem cell autografting resulted in patients being free of toxicity in non-haematological organs. These clinical findings were in complete agreement with our dose estimations, considering both organ doses and BED values.

     

放射性核素标记抗CD20单克隆抗体治疗B细胞淋巴瘤的研究进展

放射免疫治疗(radioimmunotherapy,RIT)属于内照射治疗,可以用较少的单克隆抗体耦联放射性核素,在肿瘤局部产生足够的电离辐射生物学效应,达到高效低毒的治疗效果。B细胞淋巴瘤有较高的复发比例,其CD20抗原表达率达90%以上,且不易从细胞膜上脱落,因此131I-利妥昔单抗CD20是B细胞淋巴瘤放免治疗的最佳靶点。目前已有数个放免治疗的药物,如:131I-托西莫单抗(131I-tositumomab)、131I-Rituximab、90Y-替坦异贝莫单抗(90Y-ibritumomabtiuxetan)等,用于B细胞淋巴瘤的临床治疗,它们具有各自的优缺点。使用结果表明:肿瘤部位的高吸收剂量保证了治疗的有效性,其对非靶器官的照射剂量是安全的。最主要的副反应包括:血小板减少症、中性粒细胞减少症、胃肠道反应及甲状腺功能减低症。在取得满意结果的同时,B细胞淋巴瘤放免治疗仍存在许多问题,人们正致力于更进一步的研究解决此类问题,以取得更好的治疗效果。     

Comparison of 90Y-ibritumomab tiuxetan and 131I-tositumomab in clinical practice.

We retrospectively evaluated our single-center clinical experience with (90)Y-ibritumomab tiuxetan and (131)I-tositumomab for therapy of refractory non-Hodgkin's lymphoma (NHL). We evaluated the hypothesis that the patient-specific dosing regimen used with (131)I-tositumomab results in less bone marrow toxicity than does the weight-based dosing regimen used with (90)Y-ibritumomab tiuxetan. METHODS: Thirty-eight patients (25 male and 13 female; median age, 64 y) received radioimmunotherapy for NHL (20 received (90)Y-ibritumomab tiuxetan; 18 received (131)I-tositumomab). Patient and disease characteristics were evaluated to determine whether any were prognostic indicators of short- or long-term clinical response. The 12-wk response rate and clinical and hematologic toxicities attributable to each therapy were assessed. The response rate at 12 wk was correlated with long-term overall survival. RESULTS: Twenty-six patients received full-radiation-dose radioimmunotherapy and 12 received attenuated doses because of hematologic concerns. The 12-wk overall response rate for all patients was 47%, and the complete response rate was 13%. The 12-wk overall response rate did not significantly differ between the (90)Y-ibritumomab tiuxetan and (131)I-tositumomab groups. Responses at 12 wk were more frequent in patients with normal levels of serum lactate dehydrogenase, no bone marrow involvement, and International Prognostic Index scores of no more than 2 (P < or = 0.04). Grade 3 or 4 thrombocytopenia occurred in 57% and 56% of patients treated with (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, respectively. Grade 3 or 4 neutropenia was observed in 57% and 50%, respectively. The time to the absolute neutrophil count nadir was shorter for the (90)Y-ibritumomab tiuxetan group than for the (131)I-tositumomab group (36 +/- 9 vs. 46 +/- 14 d, P = 0.01). The mean percentage decline in platelet count after radioimmunotherapy was greater in the (90)Y-ibritumomab tiuxetan group than in the (131)I-tositumomab group (79% +/- 17% vs. 63% +/- 28%, P = 0.04). Overall survival was longer in responders than in nonresponders 12 wk after therapy (P < or = 0.05). CONCLUSION: Both (90)Y-ibritumomab tiuxetan and (131)I-tositumomab were well tolerated. We observed response rates at the lower range of those reported in the literature, possibly because of referral bias, dose attenuation, and reasonably liberal acceptance criteria for a patient to receive therapy. Initial response assessments 12 wk after radioimmunotherapy predict longer-term response. (131)I-tositumomab caused significantly less severe declines in platelet counts than did (90)Y-ibritumomab tiuxetan and may be a more appropriate choice for patients with limited bone marrow reserve, but large, randomized, prospective trials are needed to better compare the performance of these 2 treatments.     

Feasibility of bremsstrahlung dosimetry for direct dose estimation in patients undergoing treatment with <Superscript>90</Superscript>Y-ibritumomab tiuxetan

Purpose  

Radioimmunotherapy with ⁹⁰Y-ibritumomab tiuxetan has been used successfully used in the treatment of CD20-positive non-Hodgkin’s lymphoma (NHL). Pretherapy imaging with ¹¹¹In-ibritumomab tiuxetan has been used in provisional dosimetry studies. Posttherapy imaging of ⁹⁰Y-ibritumomab tiuxetan for clinical use is appealing as it would simplify the data acquisition process and allow measurements of actual doses absorbed during treatment.     

Comparisons of 131I-rituximab treatment responses in patients with aggressive lymphoma and indolent lymphoma

Annals of Nuclear Medicine - We evaluated the changes in treatment response over time after single 131I-rituximab radioimmunotherapy (RIT) according to non-Hodgkin lymphoma (NHL) types. Fifteen...     

Administration guidelines for radioimmunotherapy of non-Hodgkin's lymphoma with (90)Y-labeled anti-CD20 monoclonal antibody.

90Y-ibritumomab tiuxetan is a novel radioimmunotherapeutic agent recently approved for the treatment of relapsed or refractory low-grade, follicular, or CD20+ transformed non-Hodgkin's lymphoma (NHL). (90)Y-ibritumomab tiuxetan consists of a murine monoclonal antibody covalently attached to a metal chelator, which stably chelates (111)In for imaging and (90)Y for therapy. Both health care workers and patients receiving this therapy need to become familiar with how it differs from conventional chemotherapy and what, if any, safety precautions are necessary. Because (90)Y is a pure beta-emitter, the requisite safety precautions are not overly burdensome for health care workers or for patients and their families. (90)Y-ibritumomab tiuxetan is dosed on the basis of the patient's body weight and baseline platelet count; dosimetry is not required for determining the therapeutic dose in patients meeting eligibility criteria similar to those used in clinical trials, such as <25% lymphomatous involvement of the bone marrow. (111)In- and (90)Y-ibritumomab tiuxetan are labeled at commercial radiopharmacies and delivered for on-site dose preparation and administration. Plastic and acrylic materials are appropriate for shielding during dose preparation and administration; primary lead shielding should be avoided because of the potential exposure risk from bremsstrahlung. Because there are no penetrating gamma-emissions associated with the therapy, (90)Y-ibritumomab tiuxetan is routinely administered on an outpatient basis. Furthermore, the risk of radiation exposure to patients' family members has been shown to be in the range of background radiation, even without restrictions on contact. There is therefore no need to determine activity limits or dose rate limits before patients who have been treated with (90)Y radioimmunotherapy are released, as is necessary with patients who have been treated with radiopharmaceuticals that contain (131)I. Standard universal precautions for handling body fluids are recommended for health care workers and patients and their family members after (90)Y-ibritumomab tiuxetan administration. In summary, (90)Y-ibritumomab tiuxetan introduces (90)Y into clinical practice and expands the role nuclear medicine plays in the care of patients with cancer. Understanding the unique properties of this novel radioimmunoconjugate will facilitate its safe and effective use.     

Radioimmunotherapy for non-Hodgkin lymphoma: historical development and current status

Radioimmunotherapy treatment for lymphoma is a novel targeted therapeutic approach. Several years of development of radioimmunotherapeutic compounds came to fruition in February of 2002 when 90Y-ibritumomab tiuxetan (Zevalin, Y2B8) was approved in the USA and later in Europe, for the treatment of relapsed or refractory, low grade or transformed B-cell lymphoma in the USA. 90Y-ibritumomab tiuxetan utilizes a monoclonal anti-CD20 antibody to deliver beta-emitting yttrium-90 to the malignant B-cells. Clinical trials have demonstrated its efficacy, with observed clinical responses in the 80 % range. This product has become available in Europe, with simplified administration, for the treatment of relapsed follicular lymphoma. A similar anti-CD20 radiotherapeutic compound, 131I-tositumomab, was subsequently approved in the USA. Promising studies exploring expanded applications of radioimmunotherapy as consolidation, as part of transplant, or in other histologic types have been recently completed or are under way. Radioimmunotherapy has been shown to be an effective and clinically relevant complementary therapeutic approach for patients with lymphoma, bringing the Nuclear Medicine into lymphoma therapeutics.     

Biodistribution,radiation dosimetry and scouting of <Superscript>90</Superscript>Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin’s lymphoma using <Superscript>89</Superscript>Zr-ibritumomab tiuxetan and PET

Purpose  

Positron emission tomography (PET) with ⁸⁹Zr-ibritumomab tiuxetan can be used to monitor biodistribution of ⁹⁰Y-ibritumomab tiuxetan as shown in mice. The aim of this study was to assess biodistribution and radiation dosimetry of ⁹⁰Y-ibritumomab tiuxetan in humans on the basis of ⁸⁹Zr-ibritumomab tiuxetan imaging, to evaluate whether co-injection of a therapeutic amount of ⁹⁰Y-ibritumomab tiuxetan influences biodistribution of ⁸⁹Zr-ibritumomab tiuxetan and whether pre-therapy scout scans with ⁸⁹Zr-ibritumomab tiuxetan can be used to predict biodistribution of ⁹⁰Y-ibritumomab tiuxetan and the dose-limiting organ during therapy.     

The effect of short-term treatment with lithium carbonate on the outcome of radioiodine therapy in patients with long-lasting Graves’ hyperthyroidism

Objective

The outcome of radioiodine therapy (RIT) in Graves’ hyperthyroidism (GH) mainly depends on radioiodine (¹³¹I) uptake and the effective half-life of ¹³¹I in the gland. Studies have shown that lithium carbonate (LiCO₃) enhances the ¹³¹I half-life and increases the applied thyroid radiation dose without affecting the thyroid ¹³¹I uptake. We investigated the effect of short-term treatment with LiCO₃ on the outcome of RIT in patients with long-lasting GH, its influence on the thyroid hormones levels 7 days after RIT, and possible side effects.

Methods

Study prospectively included 30 patients treated with LiCO₃ and ¹³¹I (RI-Li group) and 30 patients only with ¹³¹I (RI group). Treatment with LiCO₃ (900 mg/day) started 1 day before RIT and continued 6 days after. Anti-thyroid drugs withdrawal was 7 days before RIT. Patients were followed up for 12 months. We defined a success of RIT as euthyroidism or hypothyroidism, and a failure as persistent hyperthyroidism.

Results

In RI-Li group, a serum level of Li was 0.571?±?0.156 mmol/l before RIT. Serum levels of TT₄ and FT₄ increased while TSH decreased only in RI group 7 days after RIT. No toxic effects were noticed during LiCO₃ treatment. After 12 months, a success of RIT was 73.3% in RI and 90.0% in RI-Li group (P?<?0.01). Hypothyroidism was achieved faster in RI-Li (1st month) than in RI group (3rd month). Euthyroidism slowly decreased in RI-Li group, and not all patients became hypothyroid for 12 months. In contrast, euthyroidism rapidly declined in RI group, and all cured patients became hypothyroid after 6 months.

Conclusion

The short-term treatment with LiCO₃ as an adjunct to ¹³¹I improves efficacy of RIT in patients with long-lasting GH. A success of RIT achieves faster in lithium-treated than in RI group. Treatment with LiCO₃ for 7 days prevents transient worsening of hyperthyroidism after RIT. Short-term use of LiCO₃ shows no toxic side effects.

     

Treatment of non-Hodgkin's lymphoma (NHL) with radiolabeled antibodies (mAbs)

Most patients with non-Hodgkin's lymphoma (NHL) achieve remission but, despite newer drugs, the natural history of this disease has not improved during the last 20 years. Less than one half of patients with aggressive NHL are cured, and few of those with low-grade NHL are curable. Furthermore, NHL becomes progressively more chemoresistant while remaining responsive to external beam radiation therapy. Radioimmunotherapy (RIT) is a logical strategy for the treatment of NHL because this disease is multifocal and radiosensitive. Because of their remarkable effectiveness for RIT, 2 anti-CD20 monoclonal antibodies (mAbs), one labeled with (111)In for imaging or (90)Y for therapy and a second labeled with (131)I for imaging and therapy, have been approved for use in patients with NHL. These drugs have proven remarkably effective and safe. Evidence for the importance of the radionuclide is manifested by the data in the randomized pivotal phase III trial of (90)Y-ibritumomab that revealed response rates were several times greater in the (90)Y-ibritumomab arm than in the rituximab arm. A second drug for RIT, (131)I-tositumomab, was compared in a pivotal trial with the efficacy of the last chemotherapy received by each patient. Once again, response rates were much higher for RIT. Both (90)Y-ibritumomab and (131)I-tositumomab require preinfusion of several hundred milligrams of unlabeled anti-CD20 mAb to obtain "favorable" biodistribution, that is, targeting of NHL. Response rates for other mAbs and radionuclides in NHL also have been high but these drugs have not reached the approval stage. These drugs can be used safely by physicians who have suitable training and judgment. Unlike chemotherapy, RIT is not associated with mucositis, hair loss, or persistent nausea or vomiting. Although hematologic toxicity is dose limiting, hospitalization for febrile neutropenia is uncommon. Randomized trials of RIT in different formulations have not been conducted, but there is evidence to suggest that the mAb, antigen, radionuclide, chelator, linker, and dosing strategy may make a difference in the outcome.     

Applying near-infrared photoimmunotherapy to B-cell lymphoma: comparative evaluation with radioimmunotherapy in tumor xenografts

Objective

Radioimmunotherapy (RIT) has proven effective for patients with relapsed and refractory lymphoma. However, new types of therapy are strongly desired as B-cell lymphoma remains incurable for many patients. Photoimmunotherapy (PIT) is an emerging targeted cancer therapy that uses photosensitizer (IR700)-conjugated monoclonal antibodies (mAbs) to specifically kill cancer cells. To evaluate the usefulness and potential role of PIT for treating B-cell lymphoma in a comparison with RIT, we performed in vivo PIT and RIT studies with an IR700 or ⁹⁰Y-conjugated anti-CD20 mAb, NuB2.

Methods

IR700 or ⁹⁰Y were conjugated to NuB2. Since cell aggressiveness greatly affects the therapeutic effect, we selected both an indolent (RPMI 1788) and an aggressive (Ramos) type of B-cell lymphoma cell line. The in vitro therapeutic effect of PIT and the biodistribution profiles of IR700–NuB2 were evaluated. In vivo PIT and RIT studies were performed with 100 or 500 μg of IR700–NuB2 and 150 μCi/20 μg of ⁹⁰Y-NuB2, respectively, in two types of B-cell lymphoma-bearing mice.

Results

The in vitro studies revealed that Ramos was more sensitive than RPMI 1788 to PIT. The therapeutic effect of PIT with 500 µg IR700–NuB2 was superior to any other therapies against aggressive Ramos tumors, whereas RIT showed the highest therapeutic effect in indolent RPMI 1788 tumors. Since the uptake levels and intratumoral distribution of IR700–NuB2 were comparable in both tumors, a possible cause of this difference is the tumor growth rate. The PIT with 500 µg (IR700–NuB2) group showed a significantly greater therapeutic effect than the PIT with 100 µg group due to the higher and more homogeneous tumor distribution of IR700–NuB2.

Conclusions

PIT was effective for both indolent and aggressive B-cell lymphoma, and the higher dose provided a better therapeutic effect. In aggressive tumors, PIT was more effective than RIT. Thus, PIT would be a promising strategy for the locoregional treatment or control of B-cell lymphoma. Since PIT and RIT have distinctive advantages over each other, they could play complementary rather than competitive roles in B-cell lymphoma treatment.

     

Does tumoral 111In-ibritumomab accumulation correlate with therapeutic effect and outcome in relapsed or refractory low-grade B-cell lymphoma patients undergoing 90Y-ibritumomab radioimmunotherapy?

Objectives

The aim of this study was to determine whether tumoral ¹¹¹In-ibritumomab accumulation on pre-treatment imaging correlates with therapeutic responses and progression-free survival (PFS) in patients with non-Hodgkin’s lymphoma (NHL) undergoing ⁹⁰Y-ibritumomab radioimmunotherapy (RIT).

Methods

This was a retrospective study of 39 patients with low-grade B-cell NHL treated with RIT. We classified the patients into positive and negative groups according to the presence or absence of tumoral ¹¹¹In-ibritumomab accumulation on pre-treatment ¹¹¹In-ibritumomab examinations. We then determined the correlation between the ¹¹¹In-ibritumomab imaging findings and the patients’ therapeutic responses and PFS.

Results

Tumoral ¹¹¹In-ibritumomab accumulation was positive in 64.1 % and negative in 35.9 % of the patients. The ¹¹¹In-positive patients had a significantly higher overall response rate (ORR) compared to the ¹¹¹In-negative patients (100.0 % vs. 78.6 %, p?=?0.02). The ¹¹¹In-negative patients with advanced disease (stages III/IV) had a significantly lower ORR (40 %) and a significantly higher rate of progressive disease (40.0 %) compared to those of the ¹¹¹In-negative patients with limited disease (stages I/II) (100 % and 0 %, p?=?0.009 each). However, these two groups had similar 2-year PFS rates (65.0 % vs. 50.0 %, p?=?0.80).

Conclusions

¹¹¹In-ibritumomab imaging findings seem to correlate with ORR and the progressive disease rate after RIT, but not with PFS.

Key Points

? All 39 NHL patients had tumoral accumulation on pretreatment FDG-PET/CT ? 64.1 % of NHL patients had tumoral accumulation on a pretreatment ¹¹¹ In-ibritumomab examination ? ⁹⁰ Y-ibritumomab RIT resulted in high overall response and complete remission rates ? ¹¹¹ In-ibritumomab avidity of lymphoma lesions could predict a strong therapeutic effect ? ¹¹¹ In-ibritumomab imaging findings did not correlate with progression-free survival     

In vitro characterization of <Superscript>177</Superscript>Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study

Purpose   ¹³¹I- and ⁹⁰Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin’s lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was prepared as a kit formulation and can be labelled in a short time (<20 min) with either ¹⁷⁷Lu or ⁹⁰Y. Materials and methods  Immunoconjugates with different numbers of DOTA molecules per rituximab were prepared using p-SCN-Bz-DOTA. In vitro immunoreactivity and stability were tested and preliminary dosimetric results were acquired in two patients. Results  The immunological binding properties of DOTA-rituximab to the CD20 antigen were found to be retained after conjugation with up to four chelators. The labelled product was stable against a 10⁵ times excess of diethylenetriaminepentaacetic acid (DTPA, 37°C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m² body surface ¹⁷⁷Lu-DOTA-rituximab. Scintigraphic images showed specific uptake at tumour sites and acceptable dosimetric results. The mean whole-body dose was found to be 314 mGy. The administration of ¹⁷⁷Lu-DOTA-rituximab was tolerated well. Conclusion  Our results show that DOTA-rituximab (4:1) can be labelled with ¹⁷⁷Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. ¹⁷⁷Lu-DOTA-rituximab is an interesting, well-tolerated radiolabelled antibody with clinical activity in a low dose range, and provides an approach to the efficient treatment with few side effects for patients with relapsed NHL. Flavio Forrer and Jianhua Chen contributed equally to this work.