Management of newly diagnosed high‐risk and intermediate‐risk follicular lymphoma with 90Y ibritumomab tiuxetan in a phase II study

Five‐year overall survival for high‐risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high‐risk follicular lymphoma. Front‐line treatment with chemo‐immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio‐ immunotherapy with 90‐Yttrium ibritumomab tiuxetan consolidation, and 2 years of rituximab maintenance. The 5‐year overall survival for intermediate and high‐risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio‐immunotherapy. Three months post radio‐immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo‐immunotherapy and converted to complete response after radio‐immunotherapy. The 5‐year progression‐free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow‐up of 48 months (range 3‐84 months). Post radio‐immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%‐36% and 10%‐24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4 years post treatment. Whereas many patients had prolonged B‐cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov : NCT01446562.     

Myeloablative doses of yttrium-90-ibritumomab tiuxetan and the risk of secondary myelodysplasia/acute myelogenous leukemia

BACKGROUND:

Because the long‐term toxicity of myeloablative radioimmunotherapy remains a matter of concern, the authors evaluated the hematopoietic damage and incidence of secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) in patients who received myeloablative doses of the radiolabeled antibody yttrium‐90 (⁹⁰Y)‐ibritumomab tiuxetan.

METHODS:

The occurrence of sMDS/AML was investigated prospectively in 53 elderly patients with non‐Hodgkin lymphoma (NHL) who underwent an autograft after high‐dose radioimmunotherapy (HD‐RIT) myeloablative conditioning with ⁹⁰Y‐ibritumomab tiuxetan. Bone marrow (BM) hematopoietic progenitors and telomere length (TL) also were investigated.

RESULTS:

At a median follow‐up of 49 months, 4 patients developed sMDS/AML at 6 months, 12 months, 27 months, and 36 months after HD‐RIT, and the 5‐year cumulative incidence of sMDS/AML was 8.29%. A significant but transient decrease in BM granulocyte‐macrophage progenitors was observed; whereas multilineage, erythroid, and fibroblast progenitors were unaffected. A significant and persistent shortening of BM TL also was detected. A matched‐pair analysis comparing the study patients with 55 NHL patients who underwent autografts after chemotherapy‐based myeloablative conditioning demonstrated a 8.05% 5‐year cumulative incidence of sMDS/AML.

CONCLUSIONS:

HD‐RIT for patients with NHL was associated with 1) limited toxicity on hematopoietic progenitors, 2) accelerated TL shortening, and 3) non‐negligible incidence of sMDS/AML, which nevertheless was comparable to the incidence observed in a matched group of patients who received chemotherapy‐based conditioning. Thus, in the current series of elderly patients with NHL, the development of sMDS/AML was not influenced substantially by HD‐RIT. Cancer 2011;. © 2011 American Cancer Society.     

A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma

BACKGROUND:

High‐dose chemotherapy combined with autologous stem‐cell transplantation (ASCT) is the standard therapy for refractory/relapsed aggressive lymphoma. In the era of rituximab‐containing frontline regimens, it is becoming more challenging to salvage patients in this setting, and novel approaches are required. This is a randomized study evaluating the safety and efficacy of standard‐dose ibritumomab tiuxetan (Zevalin) combined with high‐dose BEAM chemotherapy (Z‐BEAM) and ASCT in refractory/relapsed aggressive lymphoma.

METHODS:

Forty‐three patients with CD20⁺‐aggressive lymphoma were randomized to a treatment arm (Z‐BEAM, n = 22) or control arm (BEAM alone, n = 21). Ibritumomab tiuxetan was given at 0.4 mCi/kg on day ?14 before ASCT.

RESULTS:

Patient characteristics, engraftment kinetics, and toxicity profile were similar between the 2 groups. Two‐year progression‐free survival (PFS) for all patients was 48% (95% confidence interval, 32%‐64%): 59% and 37% after Z‐BEAM and BEAM alone, respectively (P = .2). Multivariate analysis identified advanced age (hazard ratio [HR], 8.3; P = .001), high‐risk disease (relapse within 12 months of diagnosis and/or secondary International Prognostic Index >2; HR, 2.8; P = .04), positive positron emission tomography‐computed tomography pretransplant (HR, 2.4; P = .07), and BEAM alone (HR, 2.8; P = .03) as poor prognostic factors. Intermediate‐risk patients with 1 or 2 risk factors had better PFS with Z‐BEAM compared with BEAM: 69% and 29%, respectively (P = .07). Two‐year overall survival was 91% and 62% after Z‐BEAM and BEAM, respectively (P = .05). Similar prognostic factors determined survival. The HR for BEAM alone in the multivariate analysis was 8.1 (P = .01).

CONCLUSIONS:

Standard‐dose ibritumomab tiuxetan combined with BEAM high‐dose chemotherapy is safe and possibly more effective than BEAM alone as a conditioning regimen for ASCT in the era of rituximab‐containing chemotherapy regimens. Cancer 2012. © 2012 American Cancer Society.     

A phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diffuse large B-cell lymphoma patients

Background: A prospective, single-arm, open-label, nonrandomizedphase II combination chemotherapy with cyclophosphamide, doxorubicin,vincristine, and prednisone (CHOP) plus radioimmunotherapy trialwas conducted to evaluate the efficacy and safety in untreatedelderly diffuse large B-cell lymphoma (DLBCL) patients. Patients and methods: From February 2005 to April 2006, in ourinstitute we treated 20 eligible elderly (age 60 years) patientswith previously untreated DLBCL using a novel regimen consistingof six cycles of CHOP chemotherapy followed 6–10 weekslater by ⁹⁰Y ibritumomab tiuxetan. Results: The overall response rate to the entire treatment regimenwas 100%, including 95% complete remission (CR) and 5% partialremission. Four (80%) of the five patients who achieved lessthan a CR with CHOP improved their remission status after radioimmunotherapy.With a median follow-up of 15 months, the 2-year progression-freesurvival was estimated to be 75%, with a 2-year overall survivalof 95%. The ⁹⁰Y ibritumomab tiuxetan toxicity included grade3 hematologic toxicity in 12 of 20 patients; the most commongrade 3 toxic effects were neutropenia (12 patients) and thrombocytopenia(7 patients). Transfusions of red blood cells and/or plateletswere given to one patient. Conclusion: This study has established the feasibility, tolerability,and efficacy of this regimen for elderly patients with DLBCL. Key words: Chemotherapy, DLBCL, elderly patients, yttrium 90 ibritumomab tiuxetan Received for publication April 30, 2007. Revision received July 25, 2007. Revision received September 13, 2007. Accepted for publication November 12, 2007.     

Acute myeloid leukaemia after treatment with (90)Y-ibritumomab tiuxetan for follicular lymphoma

We report here a patient with relapsed follicular lymphoma who developed secondary acute myeloid leukaemia 15 months after radioimmunotherapy (RIT) with (90)Y-ibritumomab tiuxetan, the fifth described case to date. We review the literature for the potential causal relationship between RIT and secondary myelodysplastic syndromes/acute myeloid leukaemia.     

Pharmacotherapy of large B-cell lymphoma

Background: Constituting approximately 30% of lymphoid malignancies, diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma in adults worldwide. The clinical and biologic heterogeneity that exists in DLBCL suggests that this entity might actually be comprised of several distinct neoplasms that could require different therapeutic approaches. DLBCL was considered incurable until combination chemotherapy became available. Objective: Current treatment strategies for the treatment of untreated and relapsed advanced-stage DLBCL are reviewed; novel treatments for DLBCL are discussed. Methods: Relevant literature was identified using the PubMed search engine and by reviewing abstracts from major conference proceedings. Results/conclusion: Recently, novel therapeutic strategies, including the incorporation of immunotherapy to combination chemotherapy, have improved outcome for patients with DLBCL with cure rates exceeding 50%, especially in younger patients.     

Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan

BACKGROUND: Radioimmunotherapy with radiolabeled monoclonal antibodies to CD20 produces a high response rate in patients with recurring non-Hodgkin lymphoma (NHL), but the durability of those remissions is not well defined. METHODS: Data on patients with recurring NHL treated with yttrium Y 90 ibritumomab tiuxetan in 4 clinical trials were reviewed to identify patients with a long-term response, defined as a time to progression of 12 months or longer. RESULTS: Long-term responses were seen in 37% (78/211) of patients. At a median follow-up of 53.5 months (range, 12.7-88.9) the median duration of response was 28.1 months and the median time to progression was 29.3 months. A third of these patients had been treated with at least 3 previous therapies, and 37% of them had not responded to their last therapy. The findings in patients with follicular lymphoma (n=59) were similar to those in the overall population of long-term responders. The estimated overall survival at 5 years was 53% for all patients treated with 90Y ibritumomab tiuxetan and 81% for long-term responders. CONCLUSIONS: A single dose of 90Y ibritumomab tiuxetan can produce durable responses and prolonged overall survival in a substantial number of patients in whom previous therapies have failed.     

Development of radioimmunotherapy for the treatment of non-Hodgkin's lymphoma

The goal of radioimmunotherapy (RIT) is to target radiation to tumor tissue with radiolabeled monoclonal antibodies while limiting toxicity to normal cells. Radionuclide emission properties and the chemical stability of radioimmunoconjugates are important factors that contribute to the effectiveness of RIT. A 1994 review of early clinical trials with RIT in treating non-Hodgkin's lymphoma (NHL) reported a 40% response rate with nonmyeloablative doses of yttrium 90 (90Y) or iodine 131 (131I) antibodies. Of the radiolabeled antibodies currently in pivotal trials or approved by the US Food and Drug Administration, those targeted to the CD20 antigen have produced the highest response rates. Response rates for ibritumomab tiuxetan, the recently approved RIT for NHL, ranged from 74% in rituximab-refractory patients to 80% in the pivotal trial. The iodine-labeled anti-B1 antibody has been evaluated in previously treated and previously untreated patients with NHL. In the pivotal trial, previously treated patients achieved a response rate of 65%, whereas previously untreated patients had a 97% response rate. Radiolabeled anti-HLA DR has been evaluated in NHL patients and has demonstrated a 53% response rate. Murine antibody LL2, which recognizes the CD22 antigen, has been radiolabeled with 90Y and 131I, with response rates ranging from 15% to 33%. The development of radioimmunotherapy has led to meaningful advances in the treatment of B-cell NHL.     

Y90‐Ibritumomab tiuxetan (Y90‐IT) and high‐dose melphalan as conditioning regimen before autologous stem cell transplantation for elderly patients with lymphoma in relapse or resistant to chemotherapy: a feasibility trial (SAKK 37/05)

Standard conditioning regimens for autologous stem cell transplantation (ASCT) are often not tolerated by elderly patients, on one hand. Single high‐dose melphalan, on the other hand, has been shown to be safe and active as a pretransplant preparative regimen in elderly patients. Y⁹⁰‐Ibritumomab tiuxetan (Y⁹⁰‐IT) is well tolerated and feasible in the transplantation setting. We therefore investigated the combination of high‐dose melphalan and Y⁹⁰‐IT as a conditioning regimen for patients ≥65 years of age. Patients with relapsed or resistant CD20‐positive lymphoma in remission after salvage chemotherapy could be enrolled. High‐dose therapy consisted of standard dose Y⁹⁰‐IT (0.4‐mCi/kg body weight) followed by melphalan at escalating doses (100, 140, 170 and 200 mg/m²) and ASCT. The primary objective was to identify the maximum tolerated dose; secondary end points were complete response (CR) rate 100 days after transplantation and toxicity. Twenty patients (median age 72 years) were included. No DLT occurred at any dose level. Thirteen patients completed the treatment, 11 were evaluable for response. Seven patients did not complete treatment because of mobilization failure (n = 3), progressive disease (n = 2), worsening of cardiac function (n = 1), and grade 3 dyspnea (n = 1). Seven patients achieved a CR/complete remission/unconfirmed (CRu) and 2 had stable disease. Five out of 7 responding patients were still alive more than 3 years after transplantation. The 2 patients with SD had a long‐term survival of 3 and 5 years, respectively. Nonhematological grade 3 or higher treatment related adverse events (AEs) were infection (n = 6), including 2 cases of febrile neutropenia, diarrhea (n = 3), mucositis, anorexia, viral hepatitis, hypokalemia, dehydration, and multiorgan failure (n = 1 for each). The combination of Y⁹⁰‐IT and high‐dose melphalan is feasible before ASCT for elderly patients, with promising activity and manageable toxicity.