Combining Yttrium 90–Labeled Ibritumomab Tiuxetan with High-Dose Chemotherapy and Stem Cell Support in Patients with Relapsed Non-Hodgkin's Lymphoma

doi:10.3816/CLM.2004.s.005

Clinical Lymphoma

Volume 5, Supplement 1, October 2004, Pages S22-S26

https://doi.org/10.3816/CLM.2004.s.005 Get rights and content

Abstract

Targeted radioimmunotherapy, including yttrium 90–labeled ibritumomab tiuxetan (Zevalin®) and iodine I 131 tositumomab (Bexxar®), has the potential to increase the cure rate for patients with CD20⁺ B-cell malignancies who are undergoing autologous hematopoietic stem cell transplantation. The results of phase I and II trials suggest that radioimmunoconjugates can be safely combined with high-dose chemotherapy, although the optimal approach remains to be established. This review focuses on the use of⁹⁰Y ibritumomab tiuxetan combined with high-dose chemotherapy in the setting of autologous hematopoietic stem cell transplantation.

References (27)

K van Besien et al.
Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma
Blood
(2003)
M Hunault-Berger et al.
Intensive therapies in follicular non-Hodgkin lymphomas
Blood
(2002)
J Winter et al.
Zevalin-dose escalation followed by high-dose BEAM and autotransplant in CD20+ relapsed or refractory non- Hodgkin lymphoma (NHL)
Biol Blood Marrow Transplant
(2004)
A Nademanee et al.
The City of Hope experience with novel transplant regimens that incorporate standard and escalated dose 90- yttrium ibritumomab tiuxetan (90Y-Zevalin) radioimmunotherapy (RIT) for autologous stem cell transplantation (ASCT) in patients with B-cell non-Hodgkin's lymphoma (NHL): targeted intensification without increased toxicity and elimination of total body irradiation (TBI)
Biol Blood Marrow Transpl
(2004)
M Kaminski et al.
Radioimmunotherapy with iodine I 131 tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience
Blood
(2000)
O Press et al.
A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas
Blood
(2000)
A Gopal et al.
High-dose chemo-radioimmune therapy with autologous stem cell support for relapsed mantle cell lymphoma
Blood
(2002)
T Philip et al.
Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma
N Engl J Med
(1995)
H Schouten et al.
High-dose therapy improves progression- free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial
J Clin Oncol
(2003)
W Mills et al.
BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma
J Clin Oncol
(1995)

J Winter et al.

Zevalin dose-escalation followed by high-dose BEAM and autologous peripheral blood progenitor cell (PBPC) transplant in non-Hodgkin's lymphoma: early outcome results

Blood

(2002)

Johnston P, Ansell S, Micallef I, et al. Changes in pulmonary function following high dose therapy with BEAM...

A Nademanee et al.

A phase I/II trial of high-dose radioimmunotherapy (RIT) with Zevalin in combination with high-dose etoposide (VP-16) and cyclophosphamide (CY) followed by autologous stem cell transplant (ASCT) in patients with poor-risk or relapsed B-cell non- Hodgkin's lymphoma (NHL)

Blood

(2002)

Cited by (26)

Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates
2009, Blood
Citation Excerpt :
Although successful in achieving improved response rates, in most patients the duration of remission is short, with an average progression-free survival of less than 12 months. Incorporating conventional RIT into hematopoietic cell transplantation conditioning regimens has improved outcomes, but at least 50% of these patients still relapse.2,4,5 The efficacy of RIT targeting CD45 is well established.
Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in 19 nonhuman primates (Macaca fascicularis), the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation compared with directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)₄SA] produced markedly lower concentrations of radiation in nontarget tissues compared with conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung, and liver (10.3:1, 18.9:1, and 9.9:1, respectively) compared with the conventional RIT controls (2.6:1, 6.4:1, and 2.9:1, respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.
Perspectives concerning Zevalin<sup>®</sup> lymphomas treatment according to Nice's experience
2008, Medecine Nucleaire
Le Zevalin^® (yttrium-90 ibritumomab-tiuxetan) est la première radio-immunothérapie autorisée en France dans le traitement des lymphomes malins non hodgkiniens (LMNH). Il est indiqué, en routine clinique, chez l’adulte, dans le traitement des LMNH folliculaires en rechute ou réfractaires incluant les LMNH réfractaires au rituximab, avec des taux de réponse de l’ordre de 70 à 80 %. Depuis trois ans, 13 patients ont étés traités par Zevalin^® à Nice. À partir de leur étude rétrospective, nous avons discuté les différentes perspectives de ce traitement. La majorité de nos patients ont été évalués par tomographie d’émission de positons au 18-fluorodésoxyglucose (TEP–FDG), parallèlement, nous avons donc rapporté nos résultats sur cet aspect. Bien que nous manquions de recul, notre expérience confirme l’efficacité et la tolérance du Zevalin^® dans le traitement des LMNH multirécidivants, en particulier folliculaires, y compris réfractaires au rituximab. Il apparaîtrait également intéressant chez les personnes âgées et en cas d’antécédent d’autogreffe de cellules souches. L’indication proposée dans le cadre de l’Autorisation de mise sur le marché (AMM) n’est probablement pas la plus favorable puisque l’efficacité du Zevalin^® semble être meilleure en cas de volume tumoral réduit et quand il est utilisé plus précocement dans la séquence thérapeutique. Les bénéfices seront donc vraisemblablement plus significatifs en première ligne thérapeutique et en consolidation après un traitement par chimio-immunothérapie ainsi qu’en conditionnement d’autogreffe. Nous avons souligné l’intérêt d’une évaluation TEP–FDG post-thérapeutique précoce, un à deux mois après traitement par Zevalin^® dans un but pronostique. Cette indication reste encore à être évaluée dans des études menées à plus large échelle.
Zevalin^® (yttrium-90 ibritumomab-tiuxetan) is the first radioimmunotherapy authorized in France for non-Hodgkin's lymphoma (NHL) treatment. It is indicated for clinical use in adults for recurrent or refractory follicular NHL including those refractory to rituximab. Treatment responses are between 70 and 80%. Since three years, 13 patients were treated in Nice by Zevalin^®. From this retrospective study, we discuss the various perspectives of this treatment. The majority of our patients in this study were evaluated by 18-FDG–PET and we also evaluated our results in this regard. Even if our follow-up is short, our experience confirms the efficacy and tolerance of Zevalin^® treatment in multirecurrent follicular NHL including those refractory to rituximab. The treatment is of interest in elderly patients and in case of autologous stem cell transplant. The proposed « Autorisation de Mise sur le Marché » (AMM) indication is probably not the best one since efficacy seems better in smaller tumour volumes and when used earlier in the therapeutic course. Zevalin^® will probably be more beneficial in first line treatment, for immunochemotherapy consolidation and for autologous stem cell transplant conditioning. We pointed out the prognostic value of FDG–PET for early post-treatment evaluation, one to two months after Zevalin^® administration. However, larger scale studies are necessary to confirm these findings.
Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma
2007, Experimental Hematology
Citation Excerpt :
Results were promising; with a median follow-up of 22 months, OS and PFS were 92% and 78%, respectively. Winter et al. used the same approach combining ibritumomab tiuxetan with high-dose BEAM chemotherapy [20]. Ibritumomab tiuxetan was adjusted to 300 to 700 cGy to critical tissues.
To determine the safety and outcome following standard-dose ibritumomab tiuxetan followed by BEAM high-dose chemotherapy and autologous stem cell transplantation (ASCT) in patients with chemo-refractory aggressive non-Hodgkin's lymphoma.
The study included 23 patients, median age 55 years (range, 35–66) with chemo-refractory lymphoma, either primary refractory (n = 11) or in refractory relapse (n = 12). Rituximab 250 mg/m² followed by ibritumomab tiuxetan 0.4 mCi/kg were given on day −14 and high-dose BEAM chemotherapy started on day −6.
All patients engrafted. Twenty-one patients are evaluable for response; 11 achieved CR, 9 achieved PR, 5 of whom converted to CR with additional radiation therapy (overall CR rate 76%). With a median follow-up of 17 months (range, 4–27) 16 patients are alive and 12 are progression-free. The estimated 2-year overall and progression-free survival are 67% (95% CI, 46–87%) and 52% (95% CI, 31–72%), respectively. The day-100 rate of treatment-related mortality was 9% (95% CI, 2–33%) and the 2-year cumulative incidence of relapse was 31% (95% CI, 17–57%). Extensive prior therapy (>3 lines), high LDH and IPI score at ASCT, bulky disease, and progression during last chemotherapy were risk factors for reduced survival.
Ibritumomab tiuxetan–BEAM and ASCT is relatively safe and may improve outcome in patients with refractory lymphoma. Although excess nonrelapse mortality can not be ruled out, relapse rate was relatively low, resulting in improved outcome. Standard-risk patients with chemo-sensitive disease may also benefit from ibritumomab tiuxetan–BEAM and ASCT. This hypothesis merits further study in larger-scale prospective randomized studies.
Radioimmunotherapy for B-cell non-Hodgkin lymphoma
2006, Best Practice and Research: Clinical Haematology
Citation Excerpt :
Another trial – combining 90Y-ibritumomab tiuxetan with BEAM conditioning chemotherapy and stem cells – is dose-escalating the 90Y-ibritumomab tiuxetan in a typical phase I protocol. That trial has been published in abstract form57,58 and continues to accrue patients. The current dose is 1700 cGy to the liver (Jane Winter, MD, personal communication March 2006).
Radioimmunotherapy (RIT) combines the targeting advantage of a monoclonal antibody with the radiosensitivity of non-Hodgkin lymphoma (NHL) cells. There are now two radioimmunoconjugates (RICs) – ibritumomab tiuxetan (Zevalin™) and tositumomab (Bexxar™) – that are approved by the FDA in the US for relapsed low-grade or follicular B-cell NHL. Both agents target the CD20 antigen on B-cell lymphoma cells. In relapsed disease, single doses of RIT produce an 80% overall response rate, with approximately 20% of patients achieving durable responses. RIT is very well tolerated and is delivered on an outpatient basis over 1 week. The only significant toxicity is reversible myelosuppression. Both RIT agents have demonstrated high anti-tumor activity in patients who are refractory to rituximab. Current trials are testing RIT as initial therapy with rituximab maintenance, as adjuvant therapy after chemotherapy, or in high-dose protocols with stem-cell support.
Improving the Efficacy of Reduced Intensity Allogeneic Transplantation for Lymphoma using Radioimmunotherapy
2006, Biology of Blood and Marrow Transplantation
Nonmyeloablative allogeneic transplantation provides a valuable therapeutic option for patients with relapsed non-Hodgkin lymphomas, particularly those that have recurred after autologous transplantation. However, the absence of an intensive conditioning regimen renders this approach less effective for patients with aggressive or bulky lymphoma because rapid tumor growth may outpace the evolution of the graft-versus-lymphoma effect. Radioimmunotherapy provides an attractive, minimally toxic modality to safely prevent early progression of B-cell lymphomas and induce remissions without incurring the risks of traditional intensive therapy. This approach provides a time window during which a robust graft-versus-lymphoma effect may be established before tumor progression, thereby providing more effective long-term disease control. The rationale for incorporation of radioimmunotherapy into reduced intensity allogeneic transplantation regimens for non-Hodgkin lymphoma is discussed, as are current study designs, preliminary results, and future directions.
Radioimmunotherapy in non-Hodgkin lymphomas: Historic development and present status
2006, Revista Espanola de Medicina Nuclear
La radioinmunoterapia (RIT) es un nuevo enfoque terapéutico en el tratamiento de los linfomas. En febrero de 2002, tras varios años de desarrollo de diversos compuestos radioinmunoterápicos se aprobó, primero en Estados Unidos y posteriormente en Europa, el ⁹⁰Y-ibritumomab tiuxetan (Zevalin^®, Y2B8) para el tratamiento de los linfomas de bajo grado o linfomas B transformados, en recaída o refractarios. El ⁹⁰Y-ibritumomab tiuxetan utiliza el anticuerpo monoclonal antiCD20 y la emisión β del ⁹⁰Y frente a las células B malignas. Los ensayos clínicos han demostrado su eficacia, observándose respuesta clínica en un rango del 80 %. Este producto se encuentra disponible en Europa, con una administración simplificada, para el tratamiento de la recaída en el linfoma folicular. En EE.UU. se ha aprobado posteriormente un antiCD20 similar con efecto radioterápico, el ¹³¹I tositumomab. Se están realizando estudios prometedores para ampliar las indicaciones de la RIT, como son en la consolidación, como parte del trasplante o en otros tipos histológicos, encontrándose algunos ya finalizados y otros en curso. La RIT se ha mostrado como una terapia complementaria efectiva y clínicamente relevante en los pacientes con linfoma, introduciendo a la Medicina Nuclear en el tratamiento de los linfomas.
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 β-emitting yittrium-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.

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Combining Yttrium 90–Labeled Ibritumomab Tiuxetan with High-Dose Chemotherapy and Stem Cell Support in Patients with Relapsed Non-Hodgkin's Lymphoma

Abstract

Blood

Blood

Biol Blood Marrow Transplant

Biol Blood Marrow Transpl

Blood

Blood

Blood

Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma

N Engl J Med

High-dose therapy improves progression- free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial

J Clin Oncol

BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma

J Clin Oncol

Zevalin dose-escalation followed by high-dose BEAM and autologous peripheral blood progenitor cell (PBPC) transplant in non-Hodgkin's lymphoma: early outcome results

Blood

A phase I/II trial of high-dose radioimmunotherapy (RIT) with Zevalin in combination with high-dose etoposide (VP-16) and cyclophosphamide (CY) followed by autologous stem cell transplant (ASCT) in patients with poor-risk or relapsed B-cell non- Hodgkin's lymphoma (NHL)

Blood