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Clinical and Experimental Medicine Mar 2006CD20 has proven to be an excellent target for the treatment of B-cell lymphoma, first for the chimeric monoclonal antibody rituximab (Rituxan), and more recently for the... (Review)
Review
CD20 has proven to be an excellent target for the treatment of B-cell lymphoma, first for the chimeric monoclonal antibody rituximab (Rituxan), and more recently for the radiolabelled antibodies Y-90 ibritumomab tiuxetan (Zevalin) and I-131 tositumomab (Bexxar). Radiation therapy effects are due to beta emissions with path lengths of 1-5 mm; gamma radiation emitted by I-131 is the only radiation safety issue for either product. Dose-limiting toxicity for both radiolabelled antibodies is reversible bone marrow suppression. They produce response rates of 70%-90% in low-grade and follicular lymphoma and 40%-50% in transformed low-grade or intermediate-grade lymphomas. Both products produce higher response rates than related unlabelled antibodies, and both are highly active in patients who are relatively resistant to rituximab-based therapy. Median duration of response to a single course of treatment is about 1 year with complete remission rates that last 2 years or longer in about 25% of patients. Clinical trials suggest that anti- CD20 radioimmunotherapy is superior to total body irradiation in patients undergoing stem cell supported therapy for B-cell lymphoma, and that it is a safe and efficacious modality when used as consolidation therapy following chemotherapy. Among cytotoxic treatment options, current evidence suggests that one course of anti-CD20 radioimmunotherapy is as efficacious as six to eight cycles of combination chemotherapy. A major question that persists is how effective these agents are in the setting of rituximab- refractory lymphoma. These products have been underutilised because of the complexity of treatment coordination and concerns regarding reimbursement.
Topics: Antibodies, Monoclonal; Antigens, CD20; Clinical Trials as Topic; Humans; Lymphoma, B-Cell; Radioimmunotherapy
PubMed: 16550338
DOI: 10.1007/s10238-006-0087-6 -
OncoTargets and Therapy Feb 2009Targeted radioimmunotherapy in non-Hodgkin's B-cell lymphoma (NHL) offers an efficacious therapy and minimal toxicity compared to conventional chemotherapy. Iodine 131...
Targeted radioimmunotherapy in non-Hodgkin's B-cell lymphoma (NHL) offers an efficacious therapy and minimal toxicity compared to conventional chemotherapy. Iodine 131 tositumomab ((131)I-TST) is a murine monoclonal antibody against the CD20 cell surface protein and is directly covalently conjugated to (131)I, a radioactive beta and gamma emitter. While initially approved for use in relapsed, refractory, or transformed low grade B-cell NHL, investigational uses with promising results include autologous stem cell transplant, intermediate grade NHL, and the frontline management of indolent NHL. This review summarizes the (131)I-TST literature on mechanism of action, treatment indications, treatment delivery, efficacy, investigational uses, and future prospects.
PubMed: 20616910
DOI: 10.2147/ott.s4456 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2020Mantle-cell lymphoma (MCL) is sensitive to radiotherapy, and the CD20 antigen is relatively highly expressed in MCL. Therefore, radioimmunotherapy using radiolabeled...
BACKGROUND
Mantle-cell lymphoma (MCL) is sensitive to radiotherapy, and the CD20 antigen is relatively highly expressed in MCL. Therefore, radioimmunotherapy using radiolabeled anti-CD20 monoclonal antibodies has the potential to treat MCL. The objective of this study was to investigate the efficacy, pharmacokinetics, and safety of tositumomab (TST) and iodine-131 tositumomab (I-131 TST) followed by 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with previously untreated MCL (ClinicalTrials.govNCT00022945).
PATIENTS AND METHODS
In this phase 2 open-label study, patients received dosimetric (day 0: 450 mg TST, then 35 mg I-131 TST [5 mCi]) and therapeutic (between days 7 and 14: 450 mg TST, then an individualized dose of I-131 TST [65-75 cGy]) TST/I-131 TST, with CHOP treatment commencing approximately 13 weeks after the therapeutic dose. The primary end point was the MCL response rate to treatment; secondary end points included confirmed complete response rate and total body residence time.
RESULTS
Twenty-six patients were enrolled, and 25 were included in the intent-to-treat population. The overall unconfirmed response rate was 84%, and the confirmed complete response rate was 44%. The median progression free-survival was 27.6 months. The median total body residence time was 94.5 hours. No new or unexpected safety signals were identified.
CONCLUSION
Patients with previously untreated MCL who received radioimmunotherapy with TST/I-131 TST followed by CHOP had a high response rate and a long duration of response, indicating that radioimmunotherapy is a therapeutic option in this patient population.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Progression-Free Survival
PubMed: 32800518
DOI: 10.1016/j.clml.2019.04.010 -
The Oncologist 2009Non-Hodgkin's lymphoma (NHL) comprises both indolent forms, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), and aggressive forms, including diffuse... (Review)
Review
Non-Hodgkin's lymphoma (NHL) comprises both indolent forms, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), and aggressive forms, including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). FL and DLBCL are the most common subtypes of indolent and aggressive NHL, respectively. Although these lymphomas exhibit different clinical behaviors and outcomes, the prognosis is negatively affected in both DLBCL and FL by the lack of a complete response (CR) with standard treatment options. The aim of therapy should therefore be achievement of a CR, which is not only associated with longer progression-free survival (PFS) and overall survival times, but is also a prerequisite for a cure, particularly in DLBCL. Consolidation treatment with radioimmunotherapy (RIT) is an innovative treatment approach to increase CR rates. Phase II studies have indicated promising results with yttrium-90 ((90)Y)-ibritumomab tiuxetan and iodine-131 ((131)I)-tositumomab as consolidation following induction therapy for previously untreated patients with advanced FL. More recently, investigators reported a marked increase in CR rates and significant improvements in PFS using standard chemotherapy regimens followed by (90)Y-ibritumomab tiuxetan in a phase III randomized trial in patients with previously untreated FL. Data also suggest that RIT may play a role in the treatment of high-risk DLBCL, with encouraging PFS results from a phase II trial of (90)Y-ibritumomab tiuxetan consolidation following induction with rituximab plus chemotherapy in elderly patients with previously untreated DLBCL. With the higher CR rates and longer PFS times observed in patients with FL and DLBCL, as well as encouraging early data from MZL and MCL consolidation trials, RIT appears to have an important role in the treatment of patients with NHL.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease-Free Survival; Humans; Immunotoxins; Lymphoma, Non-Hodgkin; Radioimmunotherapy; Yttrium Radioisotopes
PubMed: 19819921
DOI: 10.1634/theoncologist.2009-S2-17 -
American Journal of Hematology Jul 2020Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers...
A phase II trial evaluating the efficacy of high-dose Radioiodinated Tositumomab (Anti-CD20) antibody, etoposide and cyclophosphamide followed by autologous transplantation, for high-risk relapsed or refractory non-hodgkin lymphoma.
Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. A group of 107 patients were treated including aggressive lymphoma (N = 29), indolent lymphoma (N = 45), and MCL (N = 33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% of patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43%-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared.
Topics: Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Autografts; Cyclophosphamide; Disease-Free Survival; Etoposide; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Stem Cell Transplantation; Survival Rate
PubMed: 32243637
DOI: 10.1002/ajh.25818 -
The New England Journal of Medicine Feb 2005Advanced-stage follicular B-cell lymphoma is considered incurable. Anti-CD20 radioimmunotherapy is effective in patients who have had a relapse after chemotherapy or who... (Clinical Trial)
Clinical Trial
BACKGROUND
Advanced-stage follicular B-cell lymphoma is considered incurable. Anti-CD20 radioimmunotherapy is effective in patients who have had a relapse after chemotherapy or who have refractory follicular lymphoma, but it has not been tested in previously untreated patients.
METHODS
Seventy-six patients with stage III or IV follicular lymphoma received as initial therapy a single course of treatment with 131I-tositumomab therapy (registered as Tositumomab and Iodine I 131 Tositumomab [the Bexxar therapeutic regimen]). This consisted of a dosimetric dose of tositumomab and 131I-labeled tositumomab followed one week later by a therapeutic dose, delivering 75 cGy of radiation to the total body.
RESULTS
Ninety-five percent of the patients had any response, and 75 percent had a complete response. The use of polymerase chain reaction (PCR) to detect rearrangement of the BCL2 gene showed molecular responses in 80 percent of assessable patients who had a clinical complete response. After a median follow-up of 5.1 years, the actuarial 5-year progression-free survival for all patients was 59 percent, with a median progression-free survival of 6.1 years. The annualized rate of relapse progressively decreased over time: 25 percent, 13 percent, and 12 percent during the first, second, and third years, respectively, and 4.4 percent per year after three years. Of 57 patients who had a complete response, 40 remained in remission for 4.3 to 7.7 years. Hematologic toxicity was moderate, with no patient requiring transfusions or hematopoietic growth factors. No cases of myelodysplastic syndrome have been observed.
CONCLUSIONS
A single one-week course of 131I-tositumomab therapy as initial treatment can induce prolonged clinical and molecular remissions in patients with advanced follicular lymphoma.
Topics: Adult; Aged; Antibodies, Monoclonal; Antigens, CD20; B-Lymphocytes; Bone Marrow Examination; Disease-Free Survival; Female; Gene Rearrangement; Genes, bcl-2; Humans; Leukocyte Count; Lymphoma, Follicular; Male; Middle Aged; Radioimmunotherapy; Radiometry; Remission Induction; Survival Analysis; Thyrotropin
PubMed: 15689582
DOI: 10.1056/NEJMoa041511 -
World Journal of Gastroenterology Nov 2010In recent years, therapies for follicular lymphoma (FL) have steadily improved. A series of phase III trials comparing the effect of rituximab with chemotherapy vs... (Review)
Review
In recent years, therapies for follicular lymphoma (FL) have steadily improved. A series of phase III trials comparing the effect of rituximab with chemotherapy vs chemotherapy alone in treating FL have indicated significant improvements in progression-free survival (PFS) and overall survival. Recent studies have found that prolonged response durations and PFS were obtained with maintenance therapy using rituximab or interferon after completion of first line therapy. For patients with relapsed or refractory FL, phase II studies have assessed the effectiveness of combination therapies using a Toll-like receptor-9 agonist (1018ISS), oblimersen sodium (a Bcl-2 antisense oligonucleotide), bendamustine, and rituximab, as well as veltuzumab, a new humanized anti-CD20 antibody, and epratuzumab. In addition, the effectiveness of yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab as radioimmunotherapies has been reported. Furthermore, three phase III studies on an idiotype vaccine are near completion. Unfortunately, these vaccines, which appeared highly effective in phase I and II trials, do not appear to result in prolonged PFS. This report will summarize the current knowledge on therapies for treatment of FL, and will conclude with a brief discussion of feasible future options for effective treatments. Lastly, we added descriptions of the management of gastrointestinal FL, which is considered to be controversial because it is rare.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Disease-Free Survival; Gastrointestinal Neoplasms; Humans; Immunotherapy; Lymphoma, Follicular; Neoplasm Staging; Radioimmunotherapy; Time Factors; Treatment Outcome
PubMed: 21105187
DOI: 10.3748/wjg.v16.i44.5543 -
Nuclear Medicine Communications Dec 2012To investigate radiation doses to the testes delivered by a radiolabeled anti-CD20 antibody and its effects on male sex hormone levels.
PURPOSE
To investigate radiation doses to the testes delivered by a radiolabeled anti-CD20 antibody and its effects on male sex hormone levels.
MATERIALS AND METHODS
Testicular uptake and retention of (131)I-tositumomab were measured, and testicular absorbed doses were calculated for 67 male patients (54 ± 11 years of age) with non-Hodgkin's lymphoma who had undergone myeloablative radioimmunotherapy (RIT) using (131)I-tositumomab. Time-activity curves for the major organs, testes, and whole body were generated from planar imaging studies. In a subset of patients, male sex hormones were measured before and 1 year after the therapy.
RESULTS
The absorbed dose to the testes showed considerable variability (range = 4.4-70.2 Gy). Pretherapy levels of total testosterone were below the lower limit of the reference range, and post-therapy evaluation demonstrated further reduction [4.6 ± 1.8 nmol/l (pre-RIT) vs. 3.8 ± 2.9 nmol/l (post-RIT), P<0.05]. Patients receiving higher radiation doses to the testes (≥ 25 Gy) showed a greater reduction [4.7 ± 1.6 nmol/l (pre-RIT) vs. 3.3 ± 2.7 nmol/l (post-RIT), P<0.05] compared with patients receiving lower doses (<25 Gy), who showed no significant change in total testosterone levels.
CONCLUSION
The testicular radiation absorbed dose varied highly among individual patients. Patients receiving higher doses to the testes were more likely to show post-RIT suppression of testosterone levels.
Topics: Ablation Techniques; Adult; Aged; Antibodies, Monoclonal; Bone Marrow; Gonadal Steroid Hormones; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Organs at Risk; Radiation Dosage; Radioimmunotherapy; Radiotherapy Dosage; Retrospective Studies; Testis
PubMed: 22955187
DOI: 10.1097/MNM.0b013e328358d34b -
Frontiers in Oncology 2013This manuscript reviews current advances in the use of radioimmunotherapy (RIT) for the treatment of B-cell non-Hodgkin's lymphoma (NHL). RIT has been in use for more...
This manuscript reviews current advances in the use of radioimmunotherapy (RIT) for the treatment of B-cell non-Hodgkin's lymphoma (NHL). RIT has been in use for more than 20 years and has progressed significantly with the discovery of new molecular targets, the development of new stable chelates, the humanization of monoclonal antibodies (MAbs), and the use of pretargeting techniques. Today, two products targeting the CD20 antigen are approved: (131)I-tositumomab (Bexxar(®)), and (90)Y-ibritumomab tiuxetan (Zevalin(®)). (131)I-tositumomab is available in the United States, and (90)Y-ibritumumab tiuxetan in Europe, the United States, Asia, and Africa. RIT can be integrated in clinical practice using non-ablative activities for treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy in front-line treatment in FL patients. Despite the lack of phase III studies to clearly define the efficacy of RIT in the management of B lymphoma in the era of rituximab-based therapy, RIT efficacy in NHL has been demonstrated. In relapsing refractory FL and transformed NHL, RIT as a monotherapy induces around 30% complete response with a possibility of durable remissions. RIT consolidation after induction therapy significantly improves the quality of the response. Dose-limiting toxicity of RIT is hematological, depending on bone marrow involvement and prior treatment. Non-hematological toxicity is generally low. Different studies have been published assessing innovative protocols of RIT or new indications, in particular treatment in patients with aggressive lymphomas. High-dose treatment, RIT as consolidation after different therapeutic induction modalities, RIT in first-line treatment or fractionated RIT showed promising results. New MAbs, in particular humanized MAbs, or combinations of naked and radiolabeled MAbs, also appear promising. Personalized dosimetry protocols should be developed to determine injected activity.
PubMed: 23875170
DOI: 10.3389/fonc.2013.00177 -
Seminars in Hematology Apr 2008Radioimmunotherapy (RIT) combines the mechanism of action and targeting capability of monoclonal antibodies with the tumoricidal effect of radiation and has shown... (Review)
Review
Radioimmunotherapy (RIT) combines the mechanism of action and targeting capability of monoclonal antibodies with the tumoricidal effect of radiation and has shown promising results in the treatment of various hematologic malignancies. Based on RIT's efficacy and safety profile, many investigators have evaluated its use in transplant conditioning regimens with the goal of improving long-term disease control with limited toxicity. In lymphoma, two basic transplant approaches targeting CD20 have emerged: (1) myeloablative doses of RIT with or without chemotherapy, and (2) standard nonmyeloablative doses of RIT combined with high-dose chemotherapy. Myeloablative RIT has been shown to be feasible and efficacious using escalated doses of iodine 131-tositumomab, yttrium 90-ibritumomab tiuxetan, and (131)I-rituximab with or without chemotherapy followed by autologous stem cell transplant (ASCT). The second approach predominantly has used standard doses of (90)Y-ibritumomab tiuxetan or (131)I-tositumomab plus BEAM chemotherapy (carmustine [BCNU], etoposide, cytarabine, melphalan) followed by ASCT. RIT targeting CD45, CD33, and CD66 prior to allogeneic transplantation also has been evaluated for the treatment of acute leukemia. Overall RIT-based transplant conditioning for lymphoma and leukemia has been shown to be safe, effective, and feasible with ongoing randomized trials currently underway to definitively establish its place in the treatment of hematologic malignancies.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD; Antigens, CD20; Antigens, Differentiation, Myelomonocytic; Antineoplastic Combined Chemotherapy Protocols; Cell Adhesion Molecules; Clinical Trials as Topic; Combined Modality Therapy; Forecasting; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukocyte Common Antigens; Myeloablative Agonists; Radioimmunotherapy; Rituximab; Sialic Acid Binding Ig-like Lectin 3; Survival Analysis; Transplantation Conditioning; Yttrium Radioisotopes
PubMed: 18381107
DOI: 10.1053/j.seminhematol.2008.02.002