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1.  Yttrium-90 Ibritumomab Tiuxetan Doses Calculated to Deliver up to 15 Gy to Critical Organs May Be Safely Combined With High-Dose BEAM and Autologous Transplantation in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma 
Journal of Clinical Oncology  2009;27(10):1653-1659.
Purpose
To determine the maximum-tolerated radiation-absorbed dose (RAD) to critical organs delivered by yttrium-90 (90Y) ibritumomab tiuxetan in combination with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with autologous transplantation.
Patients and Methods
Eligible patients had relapsed or refractory CD20+ non-Hodgkin's lymphoma (NHL). Individualized 90Y activities were based on dosimetry and were calculated to deliver cohort-defined RAD (1 to 17 Gy) to critical organs with three to six patients per cohort. The therapeutic dose of 90Y ibritumomab tiuxetan was followed by high-dose BEAM and autologous transplantation.
Results
Forty-four patients were treated. Thirty percent of patients had achieved less than a partial remission to their most recent therapy and would not have been eligible for autologous transplantation at most centers. The toxicity profile was similar to that associated with high-dose BEAM chemotherapy. Two dose-limiting toxicities occurred at the 17 Gy dose level, which made 15 Gy the recommended maximum-tolerated RAD. Although eight patients received at least twice the conventional dose of 0.4 mCi/kg, a weight-based strategy at 0.8 mCi/kg would have resulted in a wide range of RAD; nearly 25% of patient cases would have received 17 Gy or more, and many would have received less than 10 Gy. With a median follow-up of 33 months for all patients, the estimated 3-year progression-free and overall survivals were 43% and 60%, respectively.
Conclusion
Dose-escalated 90Y ibritumomab tiuxetan may be safely combined with high-dose BEAM with autologous transplantation and has the potential to be more effective than standard-dose radioimmunotherapy. Careful dosimetry is required to avoid toxicity and undertreatment.
doi:10.1200/JCO.2008.19.2245
PMCID: PMC2668971  PMID: 19255322
2.  Biodistribution, radiation dosimetry and scouting of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin’s lymphoma using 89Zr-ibritumomab tiuxetan and PET 
Purpose
Positron emission tomography (PET) with 89Zr-ibritumomab tiuxetan can be used to monitor biodistribution of 90Y-ibritumomab tiuxetan as shown in mice. The aim of this study was to assess biodistribution and radiation dosimetry of 90Y-ibritumomab tiuxetan in humans on the basis of 89Zr-ibritumomab tiuxetan imaging, to evaluate whether co-injection of a therapeutic amount of 90Y-ibritumomab tiuxetan influences biodistribution of 89Zr-ibritumomab tiuxetan and whether pre-therapy scout scans with 89Zr-ibritumomab tiuxetan can be used to predict biodistribution of 90Y-ibritumomab tiuxetan and the dose-limiting organ during therapy.
Methods
Seven patients with relapsed B-cell non-Hodgkin’s lymphoma scheduled for autologous stem cell transplantation underwent PET scans at 1, 72 and 144 h after injection of ~70 MBq 89Zr-ibritumomab tiuxetan and again 2 weeks later after co-injection of 15 MBq/kg or 30 MBq/kg 90Y-ibritumomab tiuxetan. Volumes of interest were drawn over liver, kidneys, lungs, spleen and tumours. Ibritumomab tiuxetan organ absorbed doses were calculated using OLINDA. Red marrow dosimetry was based on blood samples. Absorbed doses to tumours were calculated using exponential fits to the measured data.
Results
The highest 90Y absorbed dose was observed in liver (3.2 ± 1.8 mGy/MBq) and spleen (2.9 ± 0.7 mGy/MBq) followed by kidneys and lungs. The red marrow dose was 0.52 ± 0.04 mGy/MBq, and the effective dose was 0.87 ± 0.14 mSv/MBq. Tumour absorbed doses ranged from 8.6 to 28.6 mGy/MBq. Correlation between predicted pre-therapy and therapy organ absorbed doses as based on 89Zr-ibritumomab tiuxetan images was high (Pearson correlation coefficient r = 0.97). No significant difference between pre-therapy and therapy tumour absorbed doses was found, but correlation was lower (r = 0.75).
Conclusion
Biodistribution of 89Zr-ibritumomab tiuxetan is not influenced by simultaneous therapy with 90Y-ibritumomab tiuxetan, and 89Zr-ibritumomab tiuxetan scout scans can thus be used to predict biodistribution and dose-limiting organ during therapy. Absorbed doses to spleen were lower than those previously estimated using 111In-ibritumomab tiuxetan. The dose-limiting organ in patients undergoing stem cell transplantation is the liver.
doi:10.1007/s00259-011-2008-5
PMCID: PMC3276758  PMID: 22218876
Immuno-PET; Molecular imaging; Radioimmunotherapy; Ibritumomab tiuxetan; 89Zr; 90Y; Dosimetry; Lymphoma
3.  Outcomes after 90Yttrium-ibritumomab tiuxetan-BEAM in diffuse large B-cell lymphoma: a meta-analysis 
Cancer Medicine  2014;3(4):927-938.
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are chemosensitive. The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) is commonly used as a conditioning regimen. The addition of yttrium-90 (90Y)-ibritumomab tiuxetan (Zevalin®) to BEAM (Z-BEAM) is increasingly being used to improve outcomes and overcome refractory disease. We conducted a literature review and meta-analysis in order to evaluate the clinical effects of Z-BEAM followed by ASCT in patients with DLBCL. A literature search was conducted for randomized controlled trials and observational studies of Z-BEAM as a conditioning regimen for ASCT in adult patients with DLBCL. Extracted data included baseline patient demographics, overall response (ORR), complete response (CR), overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), median time to ANC and platelet engraftment, and rate of myelodysplastic syndrome. Mixed-effects models were used to determine estimates. Ten studies (N = 328) were included in the meta-analysis. The 2-year OS and PFS were 84.5% (n = 328) and 67.2% (n = 285), respectively. Outcomes were superior in patients with nontransformed lymphoma. Posttransplant, ORR and CR rates were 72.6% and 68.5%, respectively. The NRM rate was 6.3% and the incidence rate of myelodysplastic syndrome was 2.5%. Two-year OS was significantly associated with pretransplant ORR (P = 0.008, τ2 = 0). There was no significant association between PFS and pretransplant response. Z-BEAM is safe and effective as a conditioning regimen in relapsed/refractory DLBCL.
doi:10.1002/cam4.247
PMCID: PMC4303160  PMID: 24740968
90Y-Ibritumomab tiuxetan; autologous transplantation; DLBCL; meta-analysis; radioimmunotherapy; Z-BEAM
4.  The Novel Expanded Porphyrin, Motexafin Gadolinium, Combined with Ytrrium-90 Ibritumomab Tiuxetan for Relapsed/Refractory Non-Hodgkin Lymphoma: Pre-Clinical Findings and Results of a Phase I Trial 
Purpose
Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium (MGd) is a novel anti-cancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation.
Experimental Design
We performed pre-clinical studies examining MGd combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of MGd concurrently with standard yttrium-90 (90Y)-ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin lymphoma.
Results
In HF1 lymphoma cells, MGd and rituximab resulted in synergistic cytotoxicity (combination index 0.757) through a mitochondrial-mediated caspase-dependent pathway, while cell death in Ramos and SUDHL4 cells was additive. MGd/rituximab combined with radiation (1–3Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47–87), and histologies were: marginal-zone (n=1), mantle-cell (n=3), diffuse large-cell (n=6), and follicular lymphoma (n=18). 86% of all patients were rituximab-refractory. Therapy was well-tolerated and no dose limiting toxicity was seen. Overall response rate (ORR) was 57% (complete remission (CR) 43%) with median time-to-treatment failure (TTF) of 10 months (1–48+) and median duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n=14), ORR was 86% (CR 64%) with median TTF of 14 months (2–48+).
Conclusions
This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Further, tumor responses with 90Y-ibritumomab tiuxetan/MGd were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma.
doi:10.1158/1078-0432.CCR-09-0905
PMCID: PMC2763343  PMID: 19825958
lymphoma; radioimmunotherapy; rituximab-refractory; oxidative stress; MGd
5.  Phase II Study of Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Immunochemotherapy Followed by Yttrium-90–Ibritumomab Tiuxetan in Untreated Mantle-Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499 
Journal of Clinical Oncology  2012;30(25):3119-3126.
Purpose
To test the hypothesis that consolidation therapy with yttrium-90 (90Y) –ibritumomab tiuxetan after brief initial therapy with four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated mantle-cell lymphoma would be a well-tolerated regimen that would improve outcomes compared with historical R-CHOP data.
Patients and Methods
Patients ≥ 18 years old with histologically confirmed mantle-cell lymphoma expressing CD20 and cyclin D1 who had not received any previous therapy and had an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were eligible. The study enrolled and treated 57 patients, of whom 56 patients were eligible. Fifty-two patients (50 eligible patients) received 90Y-ibritumomab tiuxetan. The study design required 52 eligible patients to detect a 50% improvement in the median time to treatment failure (TTF) compared with that reported for six cycles of R-CHOP.
Results
With 56 analyzed patients (median age, 60 years; men, 73%), the overall response rate was 82% (55% complete response/complete response–unconfirmed). With a median follow-up of 72 months, the median TTF was 34.2 months. The median overall survival (OS) has not been reached, with an estimated 5-year OS of 73% (79% for patients ≤ age 65 years v 62% for patients > age 65 years; P = .08 [log-rank test]). There were no unexpected toxicities.
Conclusion
R-CHOP given for four cycles followed by 90Y–ibritumomab tiuxetan compared favorably with historical results with six cycles of R-CHOP in patients with previously untreated mantle-cell lymphoma. This regimen was well tolerated and should be applicable to most patients with this disease.
doi:10.1200/JCO.2012.42.2444
PMCID: PMC3732008  PMID: 22851557
6.  Update on the rational use of 90Y-ibritumomab tiuxetan in the treatment of follicular lymphoma 
OncoTargets and therapy  2009;2:199-208.
The development of radiolabeled antibodies against CD20 has facilitated targeted treatment of follicular lymphoma (FL). By using 90Y-ibritumomab tiuxetan (Zevalin®), a radionuclide (yttrium-90, linked by the chelator tiuxetan to the antibody ibritumomab) is brought into the vicinity of lymphoma cells. By the so-called cross-fire effect, this beta emitter has the capacity to destroy not only the lymphoma cells having bound the antibody, but also neighboring lymphoma cells. Currently this antibody is licensed in the European Union for use in relapsed or refractory FL. It is anticipated that this drug will also be approved for use as consolidation therapy after successful first-line treatment. Here we first will review the published literature supporting the use of 90Y-ibritumomab tiuxetan in the aforementioned indications and emerging data showing applicability of ibritumomab tiuxetan as sole first-line therapy for FL, as well as in the transplant setting. Possible strategies of incorporating ibritumomab tiuxetan into the treatment algorithm of FL are discussed.
PMCID: PMC2886339  PMID: 20616907
follicular lymphoma; 90Y-ibritumomab tiuxetan
7.  First report on a prospective trial with yttrium-90–labeled ibritumomab tiuxetan (Zevalin) in primary CNS lymphoma 
Neuro-Oncology  2009;11(4):423-429.
Most patients with primary CNS lymphoma (PCNSL) relapse after primary therapy. Standard salvage treatment has not yet been established in PCNSL. Anti-CD20 immunotherapy has expanded treatment options in systemic B-cell lymphoma; however, its use is limited by reconstitution of the blood–brain barrier after tumor shrinkage. The aim of this phase II trial was to evaluate the therapeutic efficacy, toxicity, and biodistribution of yttrium-90 (90Y) ibritumomab tiuxetan in PCNSL. Ten patients with relapsed PCNSL were included in a phase II trial and treated with the 90Y-labeled anti-CD20 antibody ibritumomab tiuxetan. Nine patients actually received the planned radioimmunotherapy. In six patients, biodistribution of the antibody was measured by indium-111 (111In) ibritumomab tiuxetan whole-body scans and single-photon-emission CT (SPECT) of the brain. All patients were evaluated for toxicity and response at least 4 weeks after therapy. Four patients responded: one patient had a complete response lasting 30+ months, and three patients had short-lived responses of ≤4 weeks. Five patients progressed, and one patient did not receive treatment due to an infection prior to 90Y-antibody administration. Target accumulation of the antibody was demonstrated in four of the six patients examined by SPECT imaging with 111In ibritumomab tiuxetan. All patients experienced grade 3/4 hematotoxicity but no acute neurotoxicity. Penetration of a therapeutic antibody into PCNSL and significant clinical activity was shown. Because of limited response duration and considerable hematotoxicity, future investigations should focus on a multimodal approach with additional chemotherapy and preferably autologous stem cell support.
doi:10.1215/15228517-2008-108
PMCID: PMC2743222  PMID: 19060176
90Y ibritumomab tiuxetan; CNS lymphoma; imaging; PCNSL; Zevalin
8.  FCR (Fludarabine, Cyclophosphamide, Rituximab) regimen followed by 90yttrium ibritumomab tiuxetan consolidation for the treatment of relapsed grades 1 and 2 follicular lymphoma: a report of 9 cases 
Background
This retrospective analysis is focused on the efficacy and safety of radioimmunotherapy (RIT) with Zevalin® in nine patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete remission or partial remission with FCR.
Methods
The median age was 63 yrs (range 46-77), all patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m2x 3 days), C (1 gr/m2 day 1) and R (375 mg/m2 day 4) for 4 cycles. Who achieved at least a partial remission, with < 25% bone marrow involvement, was treated with 90Yttrium Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg up to a maximum dose 1184 MBq, at 3 months after the completion of FCR. The patients underwent a further restaging at 12 weeks after 90Y-RIT with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy.
Results
Nine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR 7 patients obtained CR and 2 PR; after 90Y-RIT two patients in PR converted to CR 12 weeks later. With median follow up of 34 months (range 13-50) the current analysis has shown that overall survival (OS) is 89% at 2 years, 76% at 3 years and 61% at 4 years. The most common grade 3 or 4 adverse events were hematologic, one patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungal infection.
Conclusions
Our experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with grades 1 and 2 FL with no unexpected toxicities. A longer follow up and a larger number of patients with relapsed grades 1 and 2 FL are required to determine the impact of this regimen on long-term duration of response and PFS.
doi:10.1186/1756-9966-30-16
PMCID: PMC3041690  PMID: 21303501
9.  Radioimmunotherapy of B-Cell Non-Hodgkin’s Lymphoma 
Frontiers in Oncology  2013;3:177.
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: 131I-tositumomab (Bexxar®), and 90Y-ibritumomab tiuxetan (Zevalin®). 131I-tositumomab is available in the United States, and 90Y-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.
doi:10.3389/fonc.2013.00177
PMCID: PMC3708100  PMID: 23875170
radioimmunotherapy; monoclonal antibody; CD20; CD22; dosimetry
10.  Review of 90Y-ibritumomab tiuxetan as first-line consolidation radio-immunotherapy for B-cell follicular non-Hodgkin’s lymphoma 
Several studies have indicated that radioimmunotherapy is an effective and clinically relevant complementary therapeutic approach for patients with B-cell non-Hodgkin’s lymphoma (NHL) and may convert partial to complete response when given as consolidation after induction chemotherapy. Yttrium-90(90Y)-ibritumomab tiuxetan (90Y-IT, Zevalin®, Y2B8) has documented efficacy for both indolent and aggressive NHL. Patients considered eligible for 90Y-IT treatment should satisfy several screening criteria. A recently completed randomized study for patients with follicular lymphoma has demonstrated that 90Y-ibritumomab consolidation also produced a marked prolongation of the median time to progression from 13.5 to 37 months, while partial responders seem to derive relatively more benefit. Other published and ongoing studies explore a similar use for patients with aggressive lymphoma. Studies are comparing the use of 90Y-IT consolidation with the anti-CD20 antibody rituximab maintenance, which is also gaining acceptance. In conclusion, the documented benefit of radioimmunotherapy should be viewed in the context of the goals of treatment and the changing standards of care for lymphoma.
PMCID: PMC3004670  PMID: 21188131
radioimmunotherapy; 90Y-ibritumomab tiuxetan; follicular lymphoma; consolidation
11.  A Phase I Trial of Immunostimulatory CpG 7909 Oligodeoxynucleotide and 90Yttrium Ibritumomab Tiuxetan Radioimmunotherapy for Relapsed B-cell Non-Hodgkin Lymphoma 
American journal of hematology  2013;88(7):589-593.
Radioimmunotherapy (RIT) for relapsed indolent non-Hodgkin lymphoma produces overall response rates (ORR) of 80% with mostly partial remissions. Synthetic CpG oligonucleotides change the phenotype of malignant B-cells, are immunostimulatory, and can produce responses when injected intratumorally and combined with conventional radiation. In this phase I trial we tested systemic administration of both CpG and RIT. Eligible patients had biopsy-proven previously treated CD20+ B-cell NHL and met criteria for RIT. Patients received rituximab 250 mg/m2 days 1,8, and 15; 111In-ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of 90Y-ibritumomab tiuxetan day 15. The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (six patients each) and 0.48 mg/kg (12 patients) IV over 2 hours without dose limiting toxicity. The ORR was 93% (28/30) with 63% (19/30) complete remission (CR); median progression free survival of 42.7 months (95% CI 18-NR); and median duration of response (DR) of 35 months (4.6-76+). Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1β, in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation.
doi:10.1002/ajh.23460
PMCID: PMC3951424  PMID: 23619698
lymphoma; radioimmunotherapy; rituximab; ibritumomab tiuxetan; CpG 7909
12.  Matched-cohort analysis of autologous hematopoietic cell transplantation with radioimmunotherapy- versus total body irradiation-based conditioning for poor-risk diffuse large cell lymphoma 
We conducted a matched-cohort analysis of autologous transplant conditioning regimens for diffuse large cell lymphoma in 92 patients treated with either radioimmunotherapy (RIT) or total body irradiation (TBI)-based conditioning regimens. The RIT regimen consisted of 0.4 mCi/kg of 90Y-ibritumomab tiuxetan plus BEAM (BCNU, etoposide, cytarabine, melphalan). The TBI-based regimen combined fractionated TBI at 1200 cGy, with etoposide and cyclophosphamide. Five factors were matched between 46 patient pairs: age at transplant +/−5yrs, disease status at salvage, number of prior regimens, year of diagnosis +/−5yrs, and year of transplant +/−5yrs. Patients in the TBI group had higher rates of cardiac toxicity and mucositis, while Z-BEAM patients had a higher incidence of pulmonary toxicity. Overall survival at 4 years was 81.0% for the Z-BEAM and 52.7% for the TBI group (P = 0.01). The 4-year cumulative incidence of relapse/progression was 40.4% and 42.1% for Z-BEAM and TBI, respectively (P = 0.63). Non-relapse mortality was superior in the Z-BEAM group: 0% compared to 15.8% for TBI at 4 years (P < 0.01). Our data demonstrate that RIT-based conditioning had a similar relapse incidence to TBI, with lower toxicity, resulting in improved overall survival, particularly in patients with ≥2 prior regimens.
doi:10.1016/j.bbmt.2011.07.016
PMCID: PMC3433244  PMID: 21801706
radioimmunotherapy; diffuse large cell lymphoma; autologous hematopoietic cell transplantation; BEAM; TBI; DLCL
13.  Radioimmunotherapy based conditioning regimens for stem cell transplantation 
Seminars in hematology  2008;45(2):118-125.
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 non-myeloablative doses of RIT combined with high-dose chemotherapy. Myeloablative RIT has been shown to be feasible and efficacious using escalated doses of I-131-Tositumomab (Bexxar), Y-90-ibritumomab tiuxetan (Zevalin), and I-131-rituximab with or without chemotherapy followed by autologous stem cell transplant (ASCT). The second approach predominantly has used standard doses of Y-90-ibritumomab tiuxetan or I-131 Tositumomab plus BEAM chemotherapy followed ASCT. RIT targeting CD-45, CD-33 and CD-66 prior to allogeneic transplantation has also 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.
doi:10.1053/j.seminhematol.2008.02.002
PMCID: PMC2460561  PMID: 18381107
Radioimmunotherapy; stem cell transplantation; CD20; CD45; I-131; Y-90
14.  Gemcitabine, Etoposide, Cisplatin, and Dexamethasone in Patients With Refractory or Relapsed Non-Hodgkin's Lymphoma 
Background/Aims
To date, an effective salvage chemotherapy regimen for the treatment of refractory or relapsing non-Hodgkin's lymphoma (NHL) has not been discovered. This study was conducted to evaluate the efficacy and safety of gemcitabine, etoposide, cisplatin, and dexamethasone in relapsed or refractory NHL patients.
Methods
All patients had histologically proven relapsed or refractory NHL. Treatments consisted of gemcitabine 700 mg/m2 by continuous i.v. on days 1 and 8; etoposide 40 mg/m2 by i.v. on days 1-4; cisplatin 60 mg/m2 by i.v. on day 1; or dexamethasone 40 mg by i.v. on days 1-4 (GEPD) every 21 days. The primary end point was the patient response rate following two cycles of treatment. After two cycles, stem cells were harvested using mobilizing regimens (ESHAP or GEPD plus filgrastim), and this was followed by autologous stem cell transplantation or four additional cycles of GEPD.
Results
Between January 2005 and January 2006, 20 patients (13 males and 7 females) were enrolled in the study. The median age was 53 (range 16-75) years. The most common histology was diffuse large B-cell lymphoma (n=10). The median follow-up duration was 5.2 (range 1.0-16.0) months. After two cycles, the overall response rate was 50.0% (10/20), including two complete responses and eight partial responses. The dose-limiting toxicity was myelosuppression. Grade IV neutropenia and thrombocytopenia occurred in 13 (65.0%) and 6 patients (30.0%), respectively. The median number of CD34-positive cells collected was 6.0 (range, 2.8-11.6) ×106/kg. Of the 17 patients < 66 years of age, 4 (23.5%) proceeded to autologous stem cell transplantation.
Conclusions
GEPD chemotherapy in patients with refractory or relapsed NHL was effective as a salvage therapy and helpful for stem cell harvest followed by autologous transplantation.
doi:10.3904/kjim.2009.24.1.37
PMCID: PMC2687646  PMID: 19270480
Non-Hodgkin's lymphoma; Refractory or relapsed; Gemcitabine
15.  A possible coincidence of cytomegalovirus retinitis and intraocular lymphoma in a patient with systemic non-Hodgkin’s lymphoma 
Virology Journal  2013;10:18.
Purpose
To present a possible coincidence of cytomegalovirus retinitis and intraocular lymphoma in a patient with systemic non-Hodgkin’s lymphoma.
Case presentation
A 47-year-old woman presented with decreased visual acuity associated with white retinal lesions in both eyes. A history of pneumonia of unknown aetiology closely preceded the deterioration of vision. Five years previously the patient was diagnosed with follicular non-Hodgkin’s lymphoma. She was treated with a chemotherapy regimen comprised of cyclophosphamide, adriamycin, vincristin, and prednisone with later addition of the anti-CD20 antibody rituximab. She experienced a relapse 19 months later with involvement of the retroperitoneal lymph nodes, and commenced treatment with rituximab and 90Y-ibritumomab tiuxetan. A second relapse occurred 22 months after radioimmunotherapy and was treated with a combination of fludarabine, cyclophosphamide, and mitoxantrone followed by rituximab. The patient experienced no further relapses until the current presentation (April, 2010).
Pars plana vitrectomy with vitreous fluid analysis was performed in the right eye. PCR testing confirmed the presence of cytomegalovirus in the vitreous. Atypical lymphoid elements, highly suspicious of malignancy were also found on cytologic examination. Intravenous foscarnet was administered continually for three weeks, followed by oral valganciclovir given in a dose of 900 mg twice per day. In addition, the rituximab therapy continued at three monthly intervals. Nevertheless, cessation of foscarnet therapy was followed by a recurrence of retinitis on three separate occasions during a 3-month period instigating its reinduction to the treatment regime after each recurrence.
Conclusions
Cytomegalovirus retinitis is an opportunistic infection found in AIDS patients as well as in bone marrow and solid organ transplant recipients being treated with systemic immunosuppressive drugs. This case presents a less common incidence of cytomegalovirus retinitis occurring in a patient with non-Hodgkin’s lymphoma. We demonstrated a possible coexistence of cytomegalovirus retinitis and intraocular lymphoma in this particular patient. The final diagnosis was based on clinical manifestations together with the course of uveitis and its response to treatment alongside the results of vitreous fluid analysis. This report highlights the importance of intraocular fluid examination in cases with nonspecific clinical manifestations. Such an examination allows for the detection of simultaneously ongoing ocular diseases of differing aetiologies and enables the prompt initiation of effective treatment.
doi:10.1186/1743-422X-10-18
PMCID: PMC3551720  PMID: 23295015
Cytomegalovirus; Cytomegalovirus retinitis; Foscarnet; Non-Hodgkin’s lymphoma; Rituximab; Valganciclovir
16.  90Y-Ibritumomab tiuxetan followed by reduced-intensity conditioning and allogeneic stem-cell transplantation in patients with advanced follicular lymphoma 
Bone marrow transplantation  2011;46(12):1503-1509.
RIC HSCT is a potentially curative therapeutic option for patients with advanced FL but disease relapse remains the most common cause of failure. Radioimmunoconjugates administered prior to RIC allogeneic HSCT may enhance cytoreduction and allow more time for graft versus lymphoma effect to develop without the associated toxicity of a myeloablative HSCT. We performed a retrospective study to describe the outcomes of patients with relapsed, refractory or transformed FL who received 90Y ibritumomab tiuxetan followed by fludarabine and low-dose busulfan RIC allogeneic HSCT at the Dana-Farber Cancer Institute between 2006 and 2009, inclusively. Twelve patients were identified with a median age of 55 (40–66) years and a median number of lines of therapy of 5 (2–10). Two patients (17%) had transformed to a more aggressive histology and 5 (42%) had chemorefractory FL. Cumulative incidences of grade II–IV acute GVHD at 100 days were 17% (± 11%) and chronic GVHD at 12 months were 63% (±19%). Two-year non-relapse mortality was 18% (± 12%). Two-year OS and progression-free survival (PFS) were 83% (± 11%) and 74% (± 13%), respectively. This treatment is associated with favorable outcomes including acceptable rates of GVHD and relapse in advanced FL patients and warrants prospective studies.
doi:10.1038/bmt.2010.339
PMCID: PMC3139703  PMID: 21258420
Follicular lymphoma; Allogeneic hematopoietic stem cell transplantation; Radioimmunotherapy; 90Y-ibritumomab tiuxetan
17.  RIT with Y90-Ibritumomab Tiuxetan in Follicular Non-Hodgkin Lymphoma: Evaluation of Recent Outcomes in a Single Institution 
Journal of Oncology  2012;2012:412742.
Background. Based on historical data we reviewed our hospital clinical database to analyse our updated information and therapy outcomes of follicular non-Hodgkin lymphoma (F-NHL) patients treated with 90Y-Ibritumomab tiuxetan. Patients and Methods. Between 2005 and 2011, 56 F-NHL patients were included in a clinical protocol conducted by a multidisciplinary team and treated in the same centre. All patients received 0.3 or 0.4 mCi/kg IV (88%) of 90Y-IT; response evaluation was performed 12 weeks after. Results. M/F 44.6%/55.4%, mean age 61.45 years (30–85); ECOG 0-1 96.9%. According to FLIPI score, distribution were good: 58.5%, intermediate: 29.2%, and poor: 12.3%. Previous therapies: >2: 40% (26). ORR was 94.6% (53/56). CR: 85.7%; CR according to previous disease: relapsed disease: 90% (27/30), refractory disease: 42.85% (3/7), consolidation with CR: 92.85% (13/14), and consolidation with PR: 100% (5/5). Global PR and NR were 8.9% (5) and 5.3% (3), respectively. Mean OS 63.86 months with a mean follow-up time of 57 months (2–73). Mean TTP: 52.65 months (95% CI: 43.83–61.48). Median OS and TTP were not achieved. No hospital submissions or deaths were registered. Conclusions. This study confirms the safety and high efficacy of 90Y-IT in F-NHL patients, RIT in early stage of disease could improve outcomes.
doi:10.1155/2012/412742
PMCID: PMC3463194  PMID: 23049552
18.  Brazilian experience using high dose sequential chemotherapy followed by autologous hematopoietic stem cell transplantation for malignant lymphomas 
Objective
To evaluate the use of high-dose sequential chemotherapy in a Brazilian population.
Methods
High-dose cyclophosphamide followed by autologous hematopoietic stem cell transplantation is an effective and feasible therapy for refractory/relapsed lymphomas; this regimen has never before been evaluated in a Brazilian population. All patients (106 with high-grade non-Hodgkin lymphoma and 77 with Hodgkin's lymphoma) submitted to this treatment between 1998 and 2006 were analyzed. Chemotherapy consisted of the sequential administration of high-dose cyclophosphamide (4 or 7 g/m2) and granulocyte-colony stimulating factor (300 µg/day), followed by peripheral blood progenitor cell harvesting, administration of etoposide (2g/m2) and methotrexate (8 g/m2 only for Hodgkin's lymphoma) and autologous hematopoietic stem cell transplantation.
Results
At diagnosis, non-Hodgkin lymphoma patients had a median age of 45 (range: 8-65) years old, 78% had diffuse large B-cell lymphoma and 83% had stage III/IV disease. The Hodgkin's lymphoma patients had a median age of 23 (range: 7-68) years old, 64.9% had the nodular sclerosis subtype and 65% had stage III/IV disease. Nine Hodgkin's lymphoma patients (13%) and 10 (9%) non-Hodgkin lymphoma patients had some kind of cardiac toxicity. The overall survival, disease-free survival and progression-free survival in Hodgkin's lymphoma were 29%, 59% and 26%, respectively. In non-Hodgkin lymphoma, these values were 40%, 49% and 31%, respectively. High-dose cyclophosphamide-related mortality was 10% for Hodgkin's lymphoma and 5% for non-Hodgkin lymphoma patients. High-dose cyclophosphamide dosing had no impact on toxicity or survival for both groups.
Conclusions
Despite a greater prevalence of poor prognostic factors, our results are comparable to the literature. The incidence of secondary neoplasias is noteworthy. Our study suggests that this approach is efficient and feasible, regardless of toxicity-related mortality.
doi:10.5581/1516-8484.20110118
PMCID: PMC3459363  PMID: 23049359
Transplantation, autologous; Hodgkin disease/drug therapy; Lymphoma; Lymphoma, non-Hodgkin; Antineoplastic Combined Chemotherapy Protocols/administration & dosage; Cyclophosphamide/administration & dosage; Hematopoietic stem cell transplantation
19.  Current approaches to the treatment of non-Hodgkin's lymphoma 
Hematology Reports  2011;3(3 Suppl):e3.
Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has long been a standard treatment for lymphoma. Improvements to the efficacy of this regimen can be made by increasing the doses of doxorubicin and cyclophosphamide, as in the chemotherapeutic regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP), and by reducing the standard dosing interval, as seen with the CHOP-14 regimen. Adding the immunotherapeutic agent rituximab (R) to either CHOP or ACVBP has been shown to improve outcomes significantly, such that six cycles of R-CHOP plus two cycles of ritux-imab are as effective as eight cycles of R-CHOP, and R-CHOP-21 appears to be at least as effective as the more dose-intense R-CHOP-14. In patients who have several adverse prognostic factors, R-ACVBP plus autologous stem-cell transplantation has been shown to produce good treatment outcomes. The use of positron emission tomography scanning before and early in treatment should allow prediction of long-term outcomes, and therefore the adaptation of treatment to individual prognosis and treatment needs. In patients with follicular lymphoma, rituximab has been shown to improve the efficacy of conventional chemotherapies. In addition, rituximab alone or yttrium-90-ibritumomab tiuxetan are effective maintenance therapies in this condition.
doi:10.4081/hr.2011.s3.e3
PMCID: PMC3269215  PMID: 22586511
non-Hodgkin's lymphoma; treatment; chemotherapy; rituximab.
20.  Autologous transplantation in poor risk Hodgkin's disease using high dose melphalan/etoposide conditioning with non-cryopreserved marrow rescue. The Newcastle and Northern Region Lymphoma Group. 
British Journal of Cancer  1993;67(2):383-387.
This study aimed to assess the safety and efficacy of using high dose melphalan and etoposide followed by autologous, non-cryopreserved marrow rescue in advanced Hodgkin's disease (HD). Seventeen patients with poor risk Hodgkin's disease from a single centre underwent autologous bone marrow transplant (ABMT) using high dose melphalan and etopside conditioning. Two patients had primary progressive resistant disease (PD), two were in fourth relapse, six in second or third complete remission (CR), one patient had good partial response (GPR) (> 75% reduction in initial bulk) to primary therapy and six were in first complete remission. The patients transplanted in first CR all has a Scotland and Newcastle Lymphoma Group (SNLG) Prognostic Index (Proctor et al., 1991) which indicated they were in a poor risk prognostic group. Melphalan and etoposide both have a short half life enabling ABMT to be accomplished using unmanipulated marrow stored at 4 degrees C. The marrow was returned to the patient within 56 h of harvest. Complete haematological reconstitution occurred in 16/17 patients, the rate of engraftment reflecting the amount of previous chemotherapy. One patient died of progressive Hodgkin's disease before full engraftment could occur. In patients autografted in first remission, the median number of days with neutropenia (< 0.5 x 10(9) l-1 neutrophils) was 19 (range 9-33) and, in those in subsequent remission, 27 days (range 18-36). The median number of days to 50 x 10(9) l-1 platelets in the same groups were 29 (21-80) and 50 (41-74) respectively. The number of days in hospital post transplant in both groups was similar; median 22 (15-27) and 23 (17-37) respectively. There were no procedural deaths and none of the patients transplanted in first, second or third CR have relapsed (median follow up 21 months). The two patients transplanted with progressive disease showed only temporary responses. The two patients transplanted in fourth relapse went into CR; one is still alive and in CR 15 months post transplant, but the other relapsed 18 months post transplant. This form of intensification therapy with marrow rescue has been shown to be effective and of low toxicity and now forms part of a randomised controlled trial in poor risk Hodgkin's patients as identified by the SNLG index (Proctor et al., 1992).
PMCID: PMC1968195  PMID: 8431371
21.  Radioimmunotherapy with 131I-Rituximab in a Patient with Diffuse Large B-Cell Lymphoma Relapsed After Treatment with 90Y-Ibritumomab Tiuxetan 
We report a case that demonstrates the efficacy of radioimmunotherapy (RIT) with radioiodinated rituximab (131I-rituximab) for relapsed diffuse large B-cell lymphoma (DLBCL). A 79-year-old male patient with DLBCL initially achieved a complete response (CR) after six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. However, the lymphoma relapsed 20 months later. Although the patient had achieved a second and a third CR after two cycles of 90Y-ibritumomab tiuxetan, he experienced a third relapse approximately 3 years later. Between March and June 2011, the patient received three cycles of 131I-rituximab. Although he had achieved partial response after the second cycle, the disease progressed after the third cycle, and the total progression–free survival was thus 5 months. The patient suffered only relatively mild toxicity (grade 1 thrombocytopenia) during treatment. RIT with 131I-rituximab is therefore potentially effective in patients with relapsed DLBCL, even after the failure of 90Y-ibritumomab tiuxetan therapy.
doi:10.1007/s13139-013-0229-1
PMCID: PMC4035173  PMID: 24900126
131I-rituximab; Rituximab; Radioimmunotherapy; Diffuse large B-cell lymphoma; Refractory
22.  Autologous Peripheral Blood Stem Cell Transplantation in Children with Refractory or Relapsed Lymphoma: Results of Children’s Oncology Group Study A5962 
Purpose
This prospective study was designed to determine the safety and efficacy of cyclophosphamide, BCNU and etoposide (CBV) conditioning and autologous peripheral blood stem cell transplant (PBSCT) in children with relapsed or refractory Hodgkin and non-Hodgkin lymphoma (HL and NHL).
Patients and Methods
Patients achieving CR or PR after 2–4 courses of reinduction underwent a G-CSF mobilized PBSC apheresis with a target collection dose of 5×106 CD34+/kg. Those eligible to proceed received autologous PBSCT after CBV (7200 mg/m2, 450–300 mg/m2, 2400 mg/m2).
Results
Forty-three of 69 patients (30/39 HL, 13/30 NHL) achieved a CR/PR after reinduction. Thirty-eight patients (28 HL, 10 NHL) underwent PBSCT. All initial 6 patients who received BCNU at 450 mg/m2 experienced grade III or IV pulmonary toxicity compared to none of the subsequent 32 receiving 300 mg/m2 (p<0.0001). The probability of OS at 3 years for all patients is 51% and for transplanted patients is 64%. The 3-year EFS is 38% (45% for HL; 30% NHL). The 3-year EFS in transplanted patients is 66% (65% HL; 70% NHL). Initial duration of remission of ≥ 12 vs < 12 months was associated with a significant increase in OS (3 ys OS 70% vs 34%) (p=0.003).
Conclusion
BCNU at 300 mg/m2 in a CBV regimen prior to PBSCT is well tolerated in relapsed or refractory pediatric lymphoma patients. A short duration (< 12 months) of initial remission is associated with a poorer prognosis. Lastly, a high percentage of patients achieving a CR/PR after reinduction therapy can be salvaged with CBV and autologlous PBSCT.
doi:10.1016/j.bbmt.2010.07.002
PMCID: PMC3072756  PMID: 20637881
autologous transplant; PBSCT; CBV; lymphoma; NHL; HL
23.  Advances and application of radioimmunotherapy in non-Hodgkin lymphoma 
The activity of radio-immuno conjugate in Non-Hodgkin Lymphoma (NHL) has resulted in FDA approval of two antibodies, Y90 Ibritumomab tiuxetan and I131 tositumomab. Both these agents target CD20, a receptor widely expressed in B-Cell NHL. These immunoconjugates deliver their radioactive payload to the malignant clone in the bone marrow and lymph node. Their use has been associated with modest improvement in survival end points among several lymphoma histologies. The promising effect on disease control as well as their efficacy in disease relapse is encouraging in low grade lymphoma. Radioimmunotherapy (RIT) is increasingly being explored in the setting of consolidation as well as conditioning regimens prior to stem cell transplantation. Here, we summarize the clinical use, complications and future applications of RIT in NHL.
PMCID: PMC3384399  PMID: 22762027
Radioimmunotherapy; non-Hodgkin lymphoma; stem cell transplantation; CD20 target
24.  Efficacy of 90Y ibritumomab-tiuxetan treatment in a case of resistant gastric MALT non-Hodgkin’s lymphoma 
Treatment modalities for resistant/relapsing gastric mucosa associated lymphoid tissue (MALT) non-Hodgkin’s lymphoma (NHL) are not yet well standardized. In the past, most patients were treated surgically with a gastrectomy, while, more recently, radiotherapy and systemic approaches (chemotherapy and immunotherapy) have been used with improving results.
Here, we report the case of a patient affected by MALT NHL resistant to antibiotics, chemotherapy and immunotherapy, who achieved a durable complete remission after radio-immunotherapy treatment with Zevalin (90Y ibritumomab-tiuxetan), administered in a single-standard dose. This observation must be confirmed on a larger series but suggests that radio-immunotherapy may be a valid approach in treating relapsing MALT NHL patients, or those resistant to conventional therapies, so avoiding more aggressive and toxic approaches.
doi:10.3332/eCMS.2008.79
PMCID: PMC3234051  PMID: 22275968
25.  90Yttrium ibritumomab tiuxetan in the treatment of non-Hodgkin’s lymphoma: current status and future prospects 
Biologics : Targets & Therapy  2007;1(3):215-227.
After nearly three decades with little change in the treatment for B-cell non-Hodgkin’s lymphoma, the addition of immunotherapy has had a profound effect on the treatment of this group of diseases. A more subtle addition to the armentarium has been the radiolabeled monoclonal antibodies, 90yttrium ibritumomab tiuxetan and 131iodine tositumomab. Unfortunately these drugs have been underutilized. This is, in part, because of the need for coordination between specialties, concern about long-term effects, possible limitations on the tolerance of subsequent therapies and, in part, because of reimbursement factors. In this review, the studies in relapsed and refractory disease are discussed and the very promising results reported from phase II studies using radioimmunotherapy as first-line. Potential mechanisms of resistance to monoclonal antibodies are postulated based on alterations in cell signaling pathways that have been observed in lymphoma cell lines resistant to rituximab. It is anticipated that as mechanisms of resistance are better understood for both unlabeled and labeled monoclonal antibodies, biomarkers will not only predict their efficacy but also lead to the development of therapies to overcome resistance.
PMCID: PMC2721318  PMID: 19707332
immunotherapy; radioimmunotherapy; ibritumomab; zevalin; non-Hodgkin lymphoma

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