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CA: a Cancer Journal For Clinicians 2004The lymphomas are a diverse group of malignant disorders that vary with respect to their molecular features, genetics, clinical presentation, treatment approaches, and... (Review)
Review
The lymphomas are a diverse group of malignant disorders that vary with respect to their molecular features, genetics, clinical presentation, treatment approaches, and outcome. Over the past few years, there have been major advances in our understanding of the biology of these diseases, leading to a universally adopted World Health Organization classification system. New therapies are now available with the potential to improve patient outcome, and the International Prognostic Index and standardized response criteria help make clinical trials interpretable. Most notably, the chimeric antiCD20 monoclonal antibody rituximab has altered our therapeutic paradigms for B-cell disorders. Combinations of this antibody with chemotherapy and other biologic agents have shown promise in treating lymphoma. Other antibodies, radioimmunoconjugates (such as Y-90 ibritumomab tiuxetan and I-131 tositumomab), and oblimerson sodium (a BCL-2 antisense oligonucleotide) have all shown promise. New chemotherapy regimens such as bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), agents such as gemcitabine, and monoclonal antibodies directed against CD30 are also being studied in Hodgkin Lymphoma. The challenge of clinical research is to optimize the use of these agents, select patients most likely to respond, and develop multitargeted strategies based on sound scientific rational, with the potential to increase the cure rate of patients with lymphomas.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Cancer Vaccines; Histone Deacetylase Inhibitors; Humans; Ki-1 Antigen; Lymphoma; Oligonucleotides, Antisense; Prognosis; Radioimmunotherapy
PubMed: 15371284
DOI: 10.3322/canjclin.54.5.260 -
Blood Jun 2005The incidence of treatment-related myelodysplastic syndromes and acute myeloid leukemia (tMDSs/tAML) after tositumomab and iodine I(131) tositumomab administration to...
Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine I131 tositumomab.
The incidence of treatment-related myelodysplastic syndromes and acute myeloid leukemia (tMDSs/tAML) after tositumomab and iodine I(131) tositumomab administration to previously treated and untreated patients with non-Hodgkin lymphoma (NHL) was evaluated. A total of 1071 patients were enrolled in 7 studies: 995 with relapsed/refractory low-grade NHL, +/- transformation (median, 3 prior regimens [range, 1-13 regimens]) and 76 patients with previously untreated low-grade follicular NHL. A single dose of iodine tositumomab and I(131) tositumomab was administered. For tMDS/tAML patients, baseline and posttherapy peripheral blood and marrow specimens were reviewed in a blinded fashion. Median follow-up was 6 years from diagnosis and 2 years from radioimmunotherapy (RIT) for previously treated patients, and 4.6 years from radioimmunotherapy for previously untreated patients. tMDS/tAML was reported in 35 (3.5%) of 995 patients (annualized incidence, 1.6%/y [95% confidence interval, 1.0%-2.0%/y]), and 52% of the tMDS/tAML diagnoses of tMDS/tAML were confirmed in a blinded review (annualized incidence of 1.1%/y [95% confidence interval, 0.7%-1.6%/y]). Of the 25 cases, 10 patients (40%) were diagnosed with tMDS/tAML prior to receiving radioimmunotherapy; 2 (8%) had no pathologic or clinical evidence to support such a diagnosis; and 13 (52%) were confirmed to have developed tMDS/tAML following RIT. This incidence is consistent with that expected on the basis of patients' prior chemotherapy for NHL. With a median follow-up approaching 5 years, no case of tMDS/tAML has been reported in any of the 76 patients receiving iodine I(131) tositumomab as their initial therapy (P = .011 compared with previously treated patients).
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Female; Follow-Up Studies; Humans; Incidence; Iodine Radioisotopes; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Middle Aged; Models, Statistical; Myelodysplastic Syndromes; Radioimmunotherapy; Radiometry; Remission Induction; Time Factors; Whole-Body Irradiation
PubMed: 15731177
DOI: 10.1182/blood-2004-12-4690 -
Blood Jan 2003Enthusiasm for the use of monoclonal antibodies, such as rituximab, has markedly changed the approach to patients with non-Hodgkin lymphomas (NHLs). Nevertheless, more... (Review)
Review
Enthusiasm for the use of monoclonal antibodies, such as rituximab, has markedly changed the approach to patients with non-Hodgkin lymphomas (NHLs). Nevertheless, more effective therapies are needed. Radioimmunotherapy as a form of targeted radiation therapy may add significantly to our therapeutic options. Yttrium Y 90 ibritumomab tiuxetan, recently approved by the Food and Drug Administration, and iodine I 131 tositumomab have demonstrated a high level of activity in patients whose NHL has failed to respond to chemotherapy and rituximab. Toxicities have primarily included prolonged myelosuppression, with a potential risk of treatment-associated myelodysplastic syndrome and acute myelogenous leukemia. Ongoing clinical trials are attempting to better characterize the role of these promising agents.
Topics: Antibodies, Monoclonal; Clinical Trials as Topic; Humans; Lymphoma, Non-Hodgkin; Radioimmunotherapy; Salvage Therapy
PubMed: 12393555
DOI: 10.1182/blood-2002-06-1793 -
Cancer Feb 2006Iodine I-131 tositumomab is a well tolerated and effective therapy for recurrent low-grade and transformed low-grade non-Hodgkin lymphoma (NHL). Hematologic reserve...
BACKGROUND
Iodine I-131 tositumomab is a well tolerated and effective therapy for recurrent low-grade and transformed low-grade non-Hodgkin lymphoma (NHL). Hematologic reserve after radioimmunotherapy (RIT) is an important consideration when subsequent therapy is required.
METHODS
One hundred fifty-five patients who received treatment with I-131 tositumomab were assessed, and 68 patients had progressive disease after RIT. The median age (n=68 patients) was 59 years (range,18-82 yrs), and patients received a median of 2 pre-RIT regimens (range,1-8 regimens), including 66% who received anthracycline, 19% who received platinum, and 50% who received fludarabine.
RESULTS
The median time to disease progression (among progressors) was 168 days (range, 19-771 days). At the time they developed recurrent disease, patients had median white blood cell count (WBC) of 4.9 K cells/microL (range, 1.1-21.4 K cells/microL), a median absolute neutrophil count (ANC) of 3.25 K cells/microL (range, 0.59-8.20 K cells/microL), a median platelet count of 130 K cells/microL (range, 9-440 K cells/microL), and there was no significant difference between pre-RIT and recurrence values except for the platelet count (P<0.05). No patient demonstrated a WBC<1.0 K cells/microL or an ANC<0.5 K cells/microL, although 1 patient had a platelet count<10 K cells/microL. Twenty-four patients subsequently received no further chemotherapy; and, in 21 patients (88%), hematologic parameters appeared to allow subsequent chemotherapy if necessary (blood counts: National Cancer Institute Grade 0-2). Among 44 patients (65%) who received further chemotherapy (median, 2 regimens; range, 1-4 regimens), 19 patients (43%) were treated with anthracyclines, 17 patients (39%) were treated with platinum, 10 patients (23%) were treated with fludarabine, and 13 patients (30%) underwent stem cell transplantation. Disease improvement occurred in most patients, although 18 patients died (40%) after further chemotherapy, predominantly from refractory lymphoma.
CONCLUSIONS
Most patients with progressive disease after treatment with iodine I-131 tositumomab were able to receive subsequent therapy, including cytotoxic chemotherapy and stem cell transplantation.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease Progression; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neutropenia; Retrospective Studies; Stem Cell Transplantation; Thrombocytopenia; Treatment Outcome
PubMed: 16362977
DOI: 10.1002/cncr.21606 -
The Yale Journal of Biology and Medicine Dec 2011Radioimmunotherapy (RIT) of lymphoma with Zevalin and Bexxar was approved by FDA in 2002 and 2003, respectively, for the treatment of relapsed or refractory CD20+... (Review)
Review
Radioimmunotherapy (RIT) of lymphoma with Zevalin and Bexxar was approved by FDA in 2002 and 2003, respectively, for the treatment of relapsed or refractory CD20+ follicular B-cell non-Hodgkin´s lymphoma. In 2009, Zevalin was also approved for consolidation therapy in patients with follicular non-Hodgkin's lymphoma that achieve a partial or complete response to first-line chemotherapy. For follicular lymphoma patients, the overall response and progression-free survival rates have significantly improved since the implementation of RIT. The predominant complication of RIT is hematological toxicity that is usually manageable. There are ongoing trials to further define the expanding role of RIT as first line or concomitant therapy in the treatment of lymphoma as well as for certain antibiotic resistant infections and aggressive malignancies. There is also growing interest in the development of newer protocols for increased and more uniform dose delivery resulting in better outcomes and improved patient survival. This review will primarily focus on the role of RIT in treatment of non-Hodgkin's lymphoma, which is of established clinical utility and FDA approved. The mechanism of RIT, available radionuclides and pharmacokinetics, therapy administration, clinical utility and toxicities, and future directions would be discussed.
Topics: Antibodies, Monoclonal; Humans; Lymphoma, Non-Hodgkin; Radioimmunotherapy
PubMed: 22180677
DOI: No ID Found -
Journal of Nuclear Medicine : Official... Aug 2018Radioimmunotherapies with monoclonal antibodies to the B-lymphocyte antigen 20 (CD20) are effective treatments for B-cell lymphomas, but U.S. Food and Drug...
Radioimmunotherapies with monoclonal antibodies to the B-lymphocyte antigen 20 (CD20) are effective treatments for B-cell lymphomas, but U.S. Food and Drug Administration-approved radioimmunotherapies exclusively use radiolabeled murine antibodies, potentially limiting redosing. The Food and Drug Administration recently approved 2 unlabeled anti-CD20 monoclonal antibodies, obinutuzumab and ofatumumab, termed next generation as they are humanized (obinutuzumab) or fully human (ofatumumab), thus potentially allowing a greater potential for redosing than with previous-generation anti-CD20 antibodies, including rituximab (chimeric) and tositumomab (murine), which contain more murine peptide sequences. We prepared Zr-ofatumumab and Zr-obinituzumab and assessed their tumor targeting by PET/CT imaging and their biodistribution in a preclinical mouse model with CD20 xenografts to determine whether these antibodies have potential as theranostics or for radioimmunotherapy. Obinutuzumab, ofatumumab, rituximab, tositumomab, and human IgG (as control) were radiolabeled with Zr. Raji Burkitt lymphoma xenografts were established in severe combined immunodeficient mice. Mice with palpable tumors ( = 4-9) were injected with Zr-obinutuzumab, Zr-ofatumumab, Zr-rituximab, Zr-tositumomab, or Zr-IgG, with small-animal PET/CT images acquired at 1, 3, and 7 d after injection, and then sacrificed for biodistribution analyses. At 1, 3, and 7 d after injection, all anti-CD20 antibodies showed clear tumor uptake on PET/CT, with minimal tumor uptake of IgG. Biodistribution data showed significantly ( < 0.005) higher tumor uptake for obinutuzumab (41.4 ± 7.6 percentage injected dose [%ID]/g), ofatumumab (32.6 ± 17.5 %ID/g), rituximab (28.6 ± 7.6 %ID/g), and tositumomab (28.0 ± 6.5 %ID/g) than IgG (7.2 ± 1.2 %ID/g). Tositumomab had much higher splenic uptake (186.4 ± 49.7 %ID/g, < 0.001) than the other antibodies. Zr-labeled obinutuzumab and ofatumumab localized to tumor as well as or better than labeled rituximab and tositumomab, 2 monoclonal antibodies that have been used previously in B-cell lymphoma radioimmunotherapy, and both obinutuzumab and ofatumumab have the potential for repeated dosing.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Cell Line, Tumor; Cell Transformation, Neoplastic; Female; Humans; Isotope Labeling; Lymphoma; Mice; Positron Emission Tomography Computed Tomography; Radiochemistry; Radioimmunotherapy; Radioisotopes; Tissue Distribution; Zirconium
PubMed: 29348316
DOI: 10.2967/jnumed.117.203299 -
Blood Advances Sep 2023Although TP53 is commonly mutated in transformed follicular lymphoma, mutations are reported in <5% of pretreatment follicular lymphoma (FL) specimens. We assayed... (Randomized Controlled Trial)
Randomized Controlled Trial
Although TP53 is commonly mutated in transformed follicular lymphoma, mutations are reported in <5% of pretreatment follicular lymphoma (FL) specimens. We assayed archival follicular B-cell non-Hodgkin lymphoma specimens from a completed clinical trial, Southwest Oncology Group S0016, a phase 3 randomized intergroup trial of CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone) chemotherapy plus R-CHOP (rituximab-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radioimmunotherapy [RIT]-CHOP). Subclonal TP53 mutations (median allele frequency 0.02) were found in 25% of diagnostic FL specimens and in 27% of a separate validation cohort. In the R-CHOP arm, pathogenic TP53 mutations were not associated with progression-free survival (PFS) (10-year PFS 43% vs 44%). In contrast, among patients with no detectable pathogenic TP53 mutation, RIT-CHOP was associated with a longer PFS than with R-CHOP (10-year PFS 67% vs 44%; hazard ratio = 0.49; P = .008). No relationship was detected between PFS and the extent of activation-induced cytidine deaminase (AICDA)-mediated heterogeneity. In summary, subclonal TP53 mutations are common in FL and are a distinct phenomenon from AICDA-mediated genetic heterogeneity. The absence of a detectable subclonal mutation in TP53 defined a population that particularly benefited from RIT.
Topics: Humans; Lymphoma, Follicular; Radioimmunotherapy; Neoplasm Recurrence, Local; Rituximab; Lymphoma, Non-Hodgkin; Vincristine; Cyclophosphamide; Prednisone; Doxorubicin; Mutation; Tumor Suppressor Protein p53
PubMed: 37379264
DOI: 10.1182/bloodadvances.2022009467 -
Biologics : Targets & Therapy Jun 2007With the success of targeted monoclonal antibody therapy in non-Hodgkin's lymphoma, attempts were made to further improve efficacy through the addition of a...
With the success of targeted monoclonal antibody therapy in non-Hodgkin's lymphoma, attempts were made to further improve efficacy through the addition of a radioisotope. A goal of radioimmunotherapy is to utilize the monoclonal antibody to deliver radiation to a tumor bed with relatively limited toxicity to the surrounding normal tissues. I-131 Tositumomab is an iodine-131 labeled anti-CD20 murine IgG2a monoclonal antibody and is one of two FDA-approved radioimmunotherapeutic drugs for patients with non-Hodgkin's lymphoma (NHL). For more than a decade now, radiolabeled tositumomab has principally been evaluated in low-grade and transformed low-grade NHL patients with proven efficacy in both the up-front and salvage settings. Studies have included its use as a single agent, in combination with chemotherapy and as part of a conditioning regimen for autologous stem cell transplantation. These data suggest that this agent has an important role in the treatment of patients with B cell lymphoma.
PubMed: 19707321
DOI: No ID Found -
Current Drug Delivery Jan 2011Radioimmunotherapy of solid tumors remains a challenge despite the tremendous success of ⁹⁰Y ibritumomab tiuxetan (Zevalin) and ¹³¹I Tositumomab (Bexxar) in... (Review)
Review
Radioimmunotherapy of solid tumors remains a challenge despite the tremendous success of ⁹⁰Y ibritumomab tiuxetan (Zevalin) and ¹³¹I Tositumomab (Bexxar) in treating non-Hodgkin's lymphoma. For a variety of reasons, clinical trials of radiolabeled antibodies against solid tumors have not led to responses equivalent to those seen against lymphoma. In contrast, promising responses have been observed with unlabeled antibodies that target solid tumor receptors associated with cellular signaling pathways. These observations suggest that anti-tumor efficacy of the carrier antibody might be critical to achieving clinical responses. Here, we review and compare tumor antigens targeted by radiolabeled antibodies and unlabeled antibodies used in immunotherapy. The review shows that the trend for radiolabeled antibodies under pre-clinical development is to also target antigens associated with signaling pathways that are essential for the growth and survival of the tumor.
Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Clinical Trials as Topic; Humans; Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Signal Transduction
PubMed: 21034423
DOI: 10.2174/156720111793663651