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(A) Schematic representation of the occurrence and duration of at least grade-3 neutropenia. (B) Schematic representation of the occurrence and duration of at least grade-3 thrombocytopenia. No adverse events greater than grade 2 were observed with the administration of the 4-weekly course of rituximab and the dosimetry evaluations (weeks 0 through 6). Patients received the therapeutic dose of 90 Y-ibritumomab tiuxetan on day 43. *Patient 3 did not receive 90 Yibritumomab tiuxetan.
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This report presents updated time-to-event variables from a multicenter phase II trial of reduced-dose 90Y ibritumomab tiuxetan in patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL) and mild thrombocytopenia (platelet counts of 100 to 149 x 10(9) platelets/L). Patients received a single co...
Contexts in source publication
Context 1
... data from the first cohort showed no differ- ences in the radiation-absorbed dose for the whole body, liver, and left kidney before and after a 4-weekly course of rituximab, except for the spleen, in which a reduction was observed in all patients (before rituximab: mean 55.2 rads/ mCi, range 34-77; after rituximab: mean 40, range 29-47; p: 0.06, Wilcoxon signed-rank test). The radiation-absorbed dose to the bone marrow calculated from blood radioactiv- ity, increased in 3 patients from 1.53 (mean; range, 1.2-1.9) to 5.37 rads/mCi (mean; range, 2.9-8.8), did not change in 1 patient with low tumor burden, and decreased in 1 patient with rituximab-refractory disease, high tumor burden, and rapid clinical progression. The dosimetry results for the en- tire study have been reported. 19 In consultation with the FDA, dose-escalation was held, and the protocol was amended to allow enrollment of pa- tients at a lower dose level (0.3 mCi/kg) and exclude patients with rituximab-resistant disease (no response to rituximab or relapse within 6 months). Six patients were enrolled at a lower dose level (cohort -1, 0.3 mCi/kg): 1 patient experi- enced grade-4 neutropenia, whereas grade-3 leukopenia, neutropenia, and thrombocytopenia were seen in 2, 3, and 3 patients, respectively (Fig. 2). Four patients received growth factors at their nadir, and 1 patient received transfusions (of both platelets and red blood cells). Possibly related non- neutropenic cellulitis and sinusitis occurred in 1 patient each and resolved with ...
Context 2
... and toxicity. Cohort 1 ( 90 Y-ibritumomab tiuxetan, 0.4 mCi/kg) enrolled 5 patients. Dose-escalation was held after the significant hematologic toxicities observed in those patients: 1 patient developed grade-4 and 3 developed grade-3 reversible thrombocytopenia; 4 patients developed grade-4 reversible leukopenia and neutropenia; and 1 patient developed grade-4 febrile neutropenia (Fig. 2). One patient in this cohort did not receive the study drug due to the toxicity observed in the previous patients, but was included in the dosimetry and antitumor efficacy studies; this patient expe- rienced only reversible grade-2 neutropenia with rituximab infusions. No nonhematologic toxicities were observed, and no toxicities greater than grade 2 were observed with ritux- imab. All 4 patients who received the full course of radio- immunotherapy received growth factors at the nadir, and 2 patients received ...
Context 3
... those who developed hematologic toxicities, the median duration of at least grade-3 leukopenia, neutropenia, and thrombocytopenia (first date in grade 3 to first date of improvement to grade 2 or better) was 12 (range, 7-37), 10 (range, 7-30), and 12 (range, 3-44) days, respectively. No significant differences were observed in the duration of cy- topenias among the patients who received 0.4 and 0.3 mCi/ kg of 90 Y-ibritumomab tiuxetan: the median duration of at least grade-3 leukopenia, neutropenia, and thrombocytope- nia was 12 (range, 7-37), 10 (range, 7-28), and 12 (range, 6- 29) days, respectively, in the 0.4 mCi/kg cohorts, versus 7 (range, 7-7), 9 (range, 7-30), and 7 (range, 5-44) days, re- spectively, in the 0.3 mCi/kg cohort (Fig. ...
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To determine whether the therapeutic effect of (90)Y-ibritumomab might be enhanced by a full course of rituximab followed by single dose of (90)Y-ibritumomab, the trial included pre- and post-rituximab treatment imaging with (111)In-ibritumomab and blood pharmacokinetics. Comparison of the pre- and post-rituximab imaging and blood data allowed for...
Bone Marrow Transplantation is a high quality, peer-reviewed journal covering all aspects of clinical and basic haemopoietic stem cell transplantation.
Nonmyeloablative allogeneic transplantation (NMAT) infrequently cures active chemoresistant, bulky, or aggressive B-cell lymphoma (B-cell non-Hodgkin lymphoma [B-NHL]). We hypothesized that ⁹⁰Y-ibritumomab tiuxetan-based NMAT would facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft....
This study aimed at identifying clinical factors for predicting hematologic toxicity after radioimmunotherapy with (90)Y-ibritumomab tiuxetan or (131)I-tositumomab in clinical practice.
Hematologic data were available from 14 non-Hodgkin lymphoma patients treated with (90)Y-ibritumomab tiuxetan and 18 who received (131)I-tositumomab. The percentage...
Non-Hodgkin’s lymphoma (NHL) comprises both indolent forms, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), and aggressive forms, including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). FL and DLBCL are the most common subtypes of indolent and aggressive NHL, respectively. Although these lymphomas exhibi...
Citations
... While using conventional treatments as the first line seem to make it hard to later-use RIT in its highest effectiveness, using RIT as the first line does not preclude using other alternatives in case of relapse. There are some studies which show that using different further therapies in patients who have previously received RIT is not precluded by RIT [25,[40][41][42]. Chemotherapy or stem cell transplantation has been reported as alternative treatment options following RIT [43,44], however, only the patients who have enough cell counts are eligible for subsequent cytotoxic therapy. ...
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy. The estimated deaths and new cases of NHL in the USA in 2018 have reached 19,910 and 74,680, respectively, with 5-year survival rate of 71%. Therapeutic interventions for NHL consist of chemotherapy, radiation therapy and immunotherapy. Radioimmunotherapy (RIT) is a potential alternative treatment for NHL that is currently used in different lines of treatment. Studies show that nuclear medicine physicians and radiation oncologists are not yet certain about the proper line for administration of RIT. Herein, we have reviewed the efficiency and toxicity of RIT as the first line of treatment, and discussed potential novel indications, and strategies such as modifying induction therapy and using rituximab maintenance to optimize the efficiency of RIT as the first line of treatment. Our review indicates that it is more logical to postpone conventional therapies to the second or third lines of treatment instead of RIT.
... RIT alone is associated with hematologic toxicities. However, hematologic toxicities observed following RIT can be overcome using SC infusion [25, 26]. In the current study, toxicity profiles of the patients in the Z-BuCyE group were comparable with those of the BuCyE group patients, although 1 patient in the Z-BuCyE group died from VOD. Ibritumomab tiuxetan appears to be safely incorporated into myeloablative regimens, as life-threatening hematologic toxicities associated with RIT and HDC were rescued with ASCT, which was demonstrated by only 1 patient who experienced septicemia. ...
Radioimmunotherapy agents have a highly significant role in autologous stem cell transplantation as they improve tolerability and increase the efficacy of the conditioning regimen.
We retrospectively analyzed the efficacy and toxicity of yttrium-90 ibritumomab tiuxetan (Zevalin) combined with intravenous busulfan, cyclophosphamide, and etoposide (Z-BuCyE) compared with those of BuCyE alone followed by autologous stem cell transplantation in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). The efficacy, toxicity, and engraftment characteristics were compared between 19 patients who received Z-BuCyE and 19 historical controls who received BuCyE.
The 2 treatment groups shared similar baseline characteristics. The median time to platelet engraftment (>20×10(9)/L) and neutrophil engraftment (>0.5×10(9)/L) did not significantly differ between the Z-BuCyE group (12 days and 10 days, respectively) and the BuCyE group (12 days and 10 days, respectively). No significant differences were observed between the groups with respect to toxicities and treatment-related mortality. The median follow-up period was 30.4 months, and median event-free survival was generally better in the Z-BuCyE group (12.5 months) vs. the BuCyE group (6.2 months, P=0.236). No significant difference in overall survival between the groups was noted.
Adding ibritumomab tiuxetan to BuCyE high-dose chemotherapy may benefit patients with relapsed or refractory B-cell NHL with no risk of additional toxicity.
... The unbound fraction of free 90 Y 3 + is a potential source of radiotoxic effects for non-tumour cells and normal tissues [9]. As also reported by Kutzner et al. [10] free 90 Y 3 + accumulates in bone [11,12] with unwanted irradiation of bone marrow already involved in the toxicity associated with 90 Y-Zevalin RIT, which is primarily haematological, even if transient and reversible [13][14][15][16]. ...
90Y-ibritumomab tiuxetan (90Y-Zevalin) is currently approved for radioimmunotherapy of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. The radioimmunoconjugate may be administered to the patient only if the radiolabelling yield is higher than 95%.
To evaluate different methods of quality control testing for an accurate and rapid determination of radiolabelling yield in the clinical routine.
Five beta-counting systems, involved in determining the yield of radiolabelled 90Y-Zevalin, were compared: an autoradiography system (AS), a thin-layer chromatography (TLC) scanner system, a dose calibrator (DC), a liquid scintillation analyser (LSA) and high-performance liquid chromatography (HPLC). These instruments were also analysed in terms of efficiency, spatial resolution, analysis time, operating procedure level, cost and availability.
Radiolabelling yields were comparable among all instruments except for DC whose values were dubious. Efficiency was 1.5+/-0.11 MDLU.s for the AS (where DLU means digital light unit), 3.5+/-0.2 kcps for the TLC analyser, 0.74+/-0.02 MBq for the DC, 15+/-0.12 kcps for LSA and 180+/-0.07 kcps for HPLC. Spatial resolution was 1 mm for AS and 5 mm for the TLC analyser. The quality control test needed 8 min with AS and DC, 15 min with TLC and LSA, and 50 min with HPLC.
The short analysis time, high sensitivity, simultaneous detection of multiple radioactive strips and low cost offered by AS make it a suitable tool for radioactivity analysis and quantification in a radiopharmacy laboratory.
... 11 Data from the 4 registration trials of the ibritumomab tiuxetan regimen show a high OR rate in patients with recurring or refractory B-cell NHL. 7,8,12,13 To determine the durability of these responses and to characterize the role of patient and disease factors in patients with a long-term response (LTR), we evaluated data on the patients in the 4 registration trials in whom the time to progression (TTP) after treatment with the ibritumomab tiuxetan regimen was 12 months or longer. ...
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.
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.
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.
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.
... Therapeutic monoclonal antibodies (MoAbs) against the CD20 antigen present on mature B cells yield response rates of 30-50% in patients with relapsed B-cell NHL [3]. In addition, when MoAbs against CD20 are conjugated to the h-emitting isotope 131 I or 90 Y and used in patients, long-term responses in up to 86% of the patients have been observed [4][5][6][7]. ...
Radioimmunotherapy has proven clinically effective in patients with non-Hodgkin's lymphoma. Radioimmunotherapy trials have so far been performed with beta-emitting isotopes. In contrast to beta-emitters, the shorter range and high linear energy transfer (LET) of alpha particles allow for more efficient and selective killing of individually targeted tumor cells. However, there are several obstacles to the use of alpha-particle immunotherapy, including problems with chelation chemistry and nontarget tissue toxicity. The alpha-emitting radioimmunoconjugate (227)Th-DOTA-p-benzyl-rituximab is a new potential anti-lymphoma agent that might overcome some of these difficulties. The present study explores the immunoreactivity, in vivo stability and biodistribution, as well as the effect on in vitro cell growth, of this novel radioimmunoconjugate. To evaluate in vivo stability, uptake in balb/c mice of the alpha-particle-emitting nuclide (227)Th alone, the chelated form, (227)Th-p-nitrobenzyl-DOTA and the radioimmunoconjugate (227)Th-DOTA-p-benzyl-rituximab was compared in a range of organs at increasing time points after injection. The immunoreactive fraction of (227)Th-DOTA-p-benzyl-rituximab was 56-65%. During the 28 days after injection of radioimmunoconjugate only, very modest amounts of the (227)Th had detached from DOTA-p-benzyl-rituximab, indicating a relevant stability in vivo. The half-life of (227)Th-DOTA-p-benzyl-rituximab in blood was 7.4 days. Incubation of lymphoma cells with (227)Th-DOTA-p-benzyl-rituximab resulted in a significant antigen-dependent inhibition of cell growth. The data presented here warrant further studies of (227)Th-DOTA-p-benzyl-rituximab.
... Therapeutic monoclonal antibodies (MoAbs) against the CD20 antigen present on mature B cells yield response rates of 30 -50% in patients with relapsed B-cell NHL [3]. In addition, when MoAbs against CD20 are conjugated to the h-emitting isotope 131 I or 90 Y and used in patients, long-term responses in up to 86% of the patients have been observed [4][5][6][7]. ...
Radioimmunotherapy has proven clinically effective in patients with non-Hodgkin's lymphoma. Radioimmunotherapy trials have so far been performed with β-emitting isotopes. In contrast to β-emitters, the shorter range and high linear energy transfer (LET) of α particles allow for more efficient and selective killing of individually targeted tumor cells. However, there are several obstacles to the use of α-particle immunotherapy, including problems with chelation chemistry and nontarget tissue toxicity. The α-emitting radioimmunoconjugate 227Th-DOTA-p-benzyl-rituximab is a new potential anti-lymphoma agent that might overcome some of these difficulties. The present study explores the immunoreactivity, in vivo stability and biodistribution, as well as the effect on in vitro cell growth, of this novel radioimmunoconjugate. To evaluate in vivo stability, uptake in balb/c mice of the α-particle-emitting nuclide 227Th alone, the chelated form, 227Th-p-nitrobenzyl-DOTA and the radioimmunoconjugate 227Th-DOTA-p-benzyl-rituximab was compared in a range of organs at increasing time points after injection. The immunoreactive fraction of 227Th-DOTA-p-benzyl-rituximab was 56–65%. During the 28 days after injection of radioimmunoconjugate only, very modest amounts of the 227Th had detached from DOTA-p-benzyl-rituximab, indicating a relevant stability in vivo. The half-life of 227Th-DOTA-p-benzyl-rituximab in blood was 7.4 days. Incubation of lymphoma cells with 227Th-DOTA-p-benzyl-rituximab resulted in a significant antigen-dependent inhibition of cell growth. The data presented here warrant further studies of 227Th-DOTA-p-benzyl-rituximab.
... For the purposes of this systematic review, that regimen will be referred to as standard 90 Y-RIT. One randomized controlled trial (6,7,32,33), six single-arm phase II trials (8)(9)(10)(13)(14)(15)(16), and two single-arm phase I/II trials (11,12) were identified that examined standard 90 Y-RIT. Three of the trials have been reported in abstract form only in either the conference proceedings of ASCO or ASH (13)(14)(15). ...
... Six of the trials have also been fully published (6,8,9,11,12,16). Both the randomized trial (6) and the single-arm phase II trial reported by Wiseman et al (9) have had updated results fully published (7,10). The randomized SYSTEMATIC REVIEW -page 3 trial (6) has also had two reports published detailing biodistribution and dosimetry for patients who received 90 Y-RIT (32,33). ...
... (7). A comparable duration of median time-to-progression periods was noted in single-arm trials of relapsed lymphoma patients, with results ranging from 1.6 months to 12.9+ months (8)(9)(10)(11)13,14). Time-to-progression was also reported by Knox et al (12) and ranged from 3-29+ months. ...
Introduction:
Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immuno conjugate. Clinical trials of (90)Y-IT as a first-line stand-alone treatment in follicular lymphoma (FL) and/or marginal zone lymphoma (MZL) showed high efficacy. However, long-term survival outcomes and toxicities are not well-defined.
Methods:
We report a retrospective single-institution, multi-center study of (90)Y-IT in previously untreated low grade (LG)-FL and MZL at Mayo Clinic Cancer Center between January 2000 and October 2019. We selected patients with LG-FL and MZL who received standard-dose (90)Y-IT as a single agent in the first line setting.
Results:
The cohort (n = 51) consists of previously untreated LG-FL (n = 41) or MZL (n = 10). Median follow-up was 5.3 years (95% CI; 4.2, 6.2). Overall response rate (ORR) was 100% with complete response rate (CR) of 94%. Continuous CR was observed in 59% patients who had more than 2 years of follow-up. Long-term CR (>7 years) was seen in 25% of patients. Median progression free survival (mPFS) for the whole cohort was not reached (NR) (95% CI; 4.9, NR). Bulky disease was associated with shorter median PFS of 3.5 years (CI 95%; 0.8, 4.9) compared to non-bulky disease NR (CI 95%; 5.8, NR), P = .02. The incidence of grade 3 or higher thrombocytopenia, neutropenia and anemia were 47%, 37%, and 4% respectively. No therapy-related myelodysplasia or acute myeloid leukemia were observed.
Conclusion:
Long real-life follow-up showed that single-agent (90)Y-IT is highly efficacious with durable long-term survival in previously untreated LG-FL and MZL without significant risk for secondary malignancies.
Background:
We herein provide an overview of the clinical laboratory tests that should be performed before, during and after using therapeutic monoclonal antibodies (mAbs) and the clinical laboratory tests that may be affected by mAbs.
Methods:
The labels of FDA-approved therapeutic mAbs were downloaded from DailyMed (the official website for drug labels) and were used as the sources of data for this review.
Results:
It was found that most of the labels provided information relevant to the clinical laboratory tests, including the tests needed before mAbs treatment to check the patients' background status and to identify potentially sensitive patients, the tests needed during or after the treatment to evaluate the patients' response, and the mAbs that may lead to false positive or negative results for clinical laboratory tests.
Conclusions:
The present findings will be of interest to physicians, laboratory scientists, those involved in drug development and surveillance and individuals making health care policy.
