Bexxar (iodine I 131 tositumomab) / GSK - LARVOL DELTA

The Rebirth of Radioimmunotherapy of Non-Hodgkin Lymphoma: The Phoenix of Nuclear Medicine? (PubMed, Semin Nucl Med) - "However, despite their therapeutic efficacy, Bexxar® was withdrawn from the market by the manufacturer in 2014 due to limited commercial demand and Zevalin® has had very limited to no availability of late. I-131 rituximab is used to a limited extent in Australia, India and other countries, as well. But has RIT of NHL been (perhaps prematurely) left for dead by many? Given the current great clinical and commercial interest in radiopharmaceutical therapies of cancer, notably PSMA and SSTR targeting agents in prostate and neuroendocrine cancers, can radioimmunotherapy of NHL-like the mythical Phoenix-now rise from its ashes in an even better form to fly higher, faster, farther and longer than before?"

Journal • Review • Endocrine Cancer • Hematological Malignancies • Lymphoma • Neuroendocrine Tumor • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • SSTR

Radioligand Therapy in Lymphoma: Past, Present, and Future. (PubMed, PET Clin) - "In the 1990s, preclinical trials evaluated radiolabeled immunotherapy with monoclonal antibodies (MoAbs) such as anti-CD20 agents labeled with Iodine-131 (Bexxar) or Yttrium-90 (Zevalin). This review will discuss the historical timeline of radioimmunotherapy, debate on advantages and difficulties, and explore trials. We will examine future directions of radioligand therapy in hemato-oncology, considering emerging molecules that may become the next theragnostic trend."

Journal • Review • Hematological Malignancies • Lymphoma • Oncology

SWOG S0016: S0016 Combination Chemotherapy With Monoclonal Antibody Therapy in Newly Diagnosed Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P3 | N=571 | Active, not recruiting | Sponsor: SWOG Cancer Research Network | Trial completion date: Mar 2024 ➔ Mar 2025

Trial completion date • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

UNDETECTABLE MEASURABLE RESIDUAL DISEASE (MRD) IS ASSOCIATED WITH IMPROVED LONG-TERM OUTCOME IN PATIENTS WITH FOLLICULAR LYMPHOMA (FL) TREATED WITH CHEMO-IMMUNOTHERAPY: RESULTS FROM SWOG S0016 (EHA 2024) - " SWOG S0016 was a phase III study that randomized 531 patients with advanced-stage FL to either 6 cycles ofR-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-RIT (CHOP + I133-tositumomab). Undetectable MRD status, as assessed by Clonoseq, predicts improved 5- and 10-yearPFS in patients with FL treated with chemoimmunotherapy. MRD assessment by NGS is a promising prognostictool in FL. Figure."

Clinical • Residual disease • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology

Recent preclinical and clinical advances in radioimmunotherapy for non-Hodgkin's lymphoma. (PubMed, Explor Target Antitumor Ther) - "Two radioimmunoconjugates targeting CD20, yttrium-90 (90Y)-ibritumomab-tiuxetan (Zevalin) and iodine-131 (131I)-tositumomab (Bexxar), have been approved in the USA Food and Drug Administration (FDA) for treating relapsed/refractory indolent or transformed NHL in 2002 and 2003, respectively. Immuno-PET strategies targeting CD20 and other antigens are currently being developed. The theragnostic approach by immuno-PET will be useful in monitoring the treatment response."

Journal • Preclinical • Review • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Clinical Trial of Consolidation Treatment With Iodine I 131 Tositumomab for Multiple Myeloma (clinicaltrials.gov) - P2 | N=16 | Active, not recruiting | Sponsor: University of Michigan Rogel Cancer Center | Trial completion date: Mar 2023 ➔ Sep 2024

Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Systematic Review of Clinical Applications of Anti-CD20 Radioimmunotherapy for Lymphoma. (PubMed, Oncologist) - "In the 2 decades since its approval, anti-CD20 RIT continues to demonstrate efficacy, particularly with a proportion of patients maintaining long-term remissions. The combination of prolonged efficacy, tolerability, and treatment convenience makes RIT a reasonable alternative to other systemic therapies. It is recommended that further research on RIT should focus on biomarkers of long-term response, pretargeting, and sequencing of RIT in the treatment course."

IO biomarker • Journal • Review • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Minimal Residual Disease (MRD) Status Predicts Outcomes in Patients with Follicular Lymphoma (FL) Treated with Chemo-Immunotherapy on SWOG S0016 (ASH 2023) - "SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with CHOP-RIT (CHOP + I133-tositumomab) in patients with FL. Despite a relatively high failure rate to detect trackable sequences using current technology (~29%), MRD assessment by NGS is a promising prognostic tool in FL. *co-senior authors"

Biomarker • Clinical • IO biomarker • Minimal residual disease • Residual disease • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology

S0016 Combination Chemotherapy With Monoclonal Antibody Therapy in Newly Diagnosed Non-Hodgkin's Lymphoma (clinicaltrials.gov) - P3 | N=571 | Active, not recruiting | Sponsor: SWOG Cancer Research Network | Trial completion date: Jun 2023 ➔ Mar 2024

Trial completion date • Follicular Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

Sequential Chemo-Radioimmunotherapy Followed by Autologous Transplantation for Patients With Untreated Advanced Stage Mantle Cell Lymphoma (clinicaltrials.gov) - P1/2 | N=96 | Completed | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Completed

Metastases • Trial completion • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Transplantation • CCND1

Subclonal TP53 mutation are frequent and predict resistance to radio-immunotherapy in follicular lymphoma. (PubMed, Blood Adv) - "We assayed archival follicular B-cell non-Hodgkin lymphoma specimens from a completed clinical trial, SWOG S0016, a phase III randomized intergroup trial of CHOP chemotherapy plus rituximab (R-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radio-immunotherapy (RIT)-CHOP). 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."

IO biomarker • Journal • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • TP53

A “FUNCTIONAL CURE” MAY BE ACHIEVABLE IN A SUBSET OF PATIENTS WITH FOLLICULAR LYMPHOMA TREATED WITH CHEMOIMMUNOTHERAPY: 15-YEAR FOLLOW-UP OF PHASE III SWOG-S0016 (ICML 2023) - "S0016 enrolled patients with untreated advanced FL (bulky stage II or III–IV) between 2001 and 2008 and randomized them to CHOP × 6 followed by (131) I-tositumomab radioimmunotherapy (CHOP-RIT) or CHOP-R × 6; no maintenance was included... With more than 15 years of follow-up, 40% of patients remain alive and progression-free after 6 cycles of CHOP-RIT or CHOP-R without maintenance therapy. The average rate of progression decreased overtime indicating a possibility of achieving a functional cure in a subset of patients. These results provide a benchmark for first-line studies utilizing novel agents."

Clinical • P3 data • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology

Theranostics in Hematooncology. (PubMed, J Nucl Med) - "For instance, the theranostic armamentarium for the referring hematooncologist now includes Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia...As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications."

Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CXCR4

Commercial and business aspects of alpha radioligand therapeutics. (PubMed, Front Med (Lausanne)) - "Beta-emitting RLTs have a long history of clinical success dating back to the approval of Zevalin and Bexxar in the early 2000s, later followed by Lutathera and Pluvicto. Understanding of the history of radiation medicine is critical to inform what may be important to the success of ART-most past projections were inaccurate and it is important to analyze the reasons for this. Practical considerations in how radiation medicine is delivered and administered are important to understand in order to inform future approaches."

Journal • Review • Oncology

Radioimmunotherapy of Non-Hodgkin B-cell Lymphoma: An update. (PubMed, Semin Nucl Med) - "However, 20 years following the approval of the first CD20-targeting radioimmunoconjugates Y-Ibritumomab-tiuxetan (Zevalin) and I-tositumomab (Bexxar), the number of patients referred for RIT in western countries has dramatically decreased. Therapeutic targets other than CD20 have been identified, new vector molecules have been produced allowing for faster delivery of RIT to the target, and innovative radionuclides with favorable physical characteristics such as alpha emitters have been more widely available. In this article, we reviewed the current status of RIT in NHL, with particular focus on recent clinical and preclinical developments."

Journal • Review • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Quantitative evaluation of therapy options for relapsed/refractory diffuse large B-cell lymphoma: A model-based meta-analysis. (PubMed, Pharmacol Res) - "With respect to specific treatment regimens, we found that the following had better efficacy: rituximab in association with inotuzumab ozogamicin; rituximab in association with carmustine, etoposide, cytarabine, and melphalan sequential ASCT (R-BEAM+ASCT); lenalidomide in association with rituximab, etoposide, cisplatin, cytarabine, and methylprednisolone; iodine-131 tositumomab in association with BEAM sequential ASCT; and chemotherapy sequential chimeric antigen receptor T-cell immunotherapy, with median OS of 48.2, 34.2, 27.8, 25.8, and 25 months, respectively. Moreover, with respect to association therapy, there was a strong correlation between the 6-month PFS and 2-year OS. The findings of this study provide the necessary quantitative information for clinical practice and clinical trial design for the treatment of r/rDLBCL."

Journal • Retrospective data • Review • Bone Marrow Transplantation • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation

Sequential Chemo-Radioimmunotherapy Followed by Autologous Transplantation for Patients With Untreated Advanced Stage Mantle Cell Lymphoma (clinicaltrials.gov) - P1/2 | N=96 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2022 ➔ Nov 2023 | Trial primary completion date: Nov 2022 ➔ Nov 2023

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Transplantation • CCND1

Clinical Trial of Consolidation Treatment With Iodine I 131 Tositumomab for Multiple Myeloma (clinicaltrials.gov) - P2 | N=16 | Active, not recruiting | Sponsor: University of Michigan Rogel Cancer Center | Trial completion date: Jul 2022 ➔ Mar 2023

Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology

"Nice try. You can't get Bexxar because no one makes it anymore... ;)" (@freddyeescorcia)

Cure of Micrometastatic B-cell Lymphoma in a scid Mouse Model using Bi Anti-CD20 Monoclonal Antibody. (PubMed, J Nucl Med) - " Cure of micrometastatic NHL is achieved in the majority of animals treated at 4 days post-i.v tumor inoculation using either Bi rituximab or I tositumomab in contrast to the lack of cures with unlabeled rituximab, Y rituximab or if there was high tumor burden before RIT. Alpha emitter labeled anti CD-20 antibodies are promising therapeutics for NHL although a longer lived alpha emitter may be of greater efficacy."

Journal • Preclinical • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Immunotherapy in indolent Non-Hodgkin's Lymphoma. (PubMed, Leuk Res Rep) - "Other than that, a resistance mechanism to rituximab emerged by inducing a failure in the apoptosis mechanism...Here came the development of 90Y-ibritumomab tiuxetan and 131I-tositumomab. After it, humanized anti-CD20 emerged ofatumumab, IMMU106 (veltuzumab) in 2005, and ocrelizumab which are considered as second generation anti-CD20 and 3 generation anti-CD20 include AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutuzumab). Also multiple other agents emerged targeting different surface cell antigens like CD52 (alemtuzumab), CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab], Brentuximab vedotin), CD40 (SGN-40), and CD79b (Polatuzumab). Other agents include MAB targeting T-Cells like mogamulizumab, Denileukin Diftitox and BiTEs or bispecific T cell engagers like Mosunetuzumab, Glofitamab, and Epcoritamab...Another important aspect in..."

Journal • Allergy • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Immune Modulation • Indolent Lymphoma • Inflammation • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • CD22 • CD40 • CD52 • CD79B • TNFRSF8

Construction of miRNA-regulated drug-pathway network to screen drug repurposing candidates for multiple sclerosis. (PubMed, Medicine (Baltimore)) - "We analyzed the properties of the miRNA-regulated drug-pathway network through genes and uncovered a number of novel MS agents by assessing their respective Z-values.A total of 20 likely drug candidates were identified, including human immunoglobulin, aspirin, alemtuzumab, minocycline, abciximab, alefacept, palivizumab, bevacizumab, efalizumab, tositumomab, minocycline, etanercept, catumaxomab, and sarilumab. Each of these agents were then explored with regards to their likely mechanism of action in treating MS.The current investigation provides a fresh perspective on MS biological mechanisms as well as likely treatment strategies."

Journal • CNS Disorders • Multiple Sclerosis

Clinical Trial of Consolidation Treatment With Iodine I 131 Tositumomab for Multiple Myeloma (clinicaltrials.gov) - P2 | N=16 | Active, not recruiting | Sponsor: University of Michigan Rogel Cancer Center | Trial completion date: Dec 2021 ➔ Jul 2022

Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas. (PubMed, Cancers (Basel)) - "The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) I-tositumomab and Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody-drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine...Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies."

Journal • Review • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology

Dosimetric Approaches for Radioimmunotherapy of Non-Hodgkin Lymphoma in Myeloablative Setting. (PubMed, Semin Nucl Med) - "In particular, two monoclonal antibodies raised against CD20, that is Zevalin (Y-ibritumomab-tiuxetan) and Bexxar (I-tositumomab) received FDA approval for the treatment of relapsing/refractory indolent or transformed NHLs...However, its use in the clinical setting is still debated and, in case of relapse after optimized rituximab-containing regimens, the efficacy of RIT at standard dosage is suboptimal...In contrast, dose-escalation clinical protocols require the assessment of radiopharmaceutical biodistribution and dosimetry before the therapeutic injection, as dose constrains for critical organs may be exceeded when RIT is administered at high activities. The aim of the present study was to review and discuss the internal dosimetry protocols that were adopted for non-standard RIT administration in the myeloablative setting before hematopoietic stem cell transplantation in patients with NHLs."

Journal • Review • Bone Marrow Transplantation • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CD20