Radionuclide Therapy of Lymphomas

  • Heather A. JaceneEmail author
  • Sree Tirumani
  • Richard L. WahlEmail author
Living reference work entry


Radioimmunotherapy is an effective therapy for NHL in a variety of settings and is well tolerated. Current studies continue to investigate the role of NHL at various time points in the management of patients with NHL. The limited clinical use of RIT seems to have been driven by economics rather than by a lack of clinical effectiveness. As new radiolabeled agents and indications and nonradioactive agents are being investigated, probably in parallel with nonradioactive agents, close collaborations between medical oncologists and nuclear medicine physicians/radiologists are paramount for optimal integration of these agents into the overall treatment schema for patients with lymphoma.

Radioimmunotherapy (RIT) for treatment of non-Hodgkin lymphoma (NHL) has been undergoing investigations since the early 1990s and became available for clinical use to treat relapsed/refractory NHL in the early 2000s. Since then, the indications for the use of RIT in NHL have been expanded. RIT for NHL is an effective therapy; however, the use in clinical practice has been limited as there are multiple other competing nonradioactive therapies for NHL, several developed in the past few years.

This chapter will provide a review of the current and possible future roles of RIT in patients with lymphoma.


Radioimmunotherapy RIT Zevalin Bexxar Lymphoma 





Acute myelogenous leukemia


Complete response


Chemotherapy regimen based on cyclophosphamide,doxorubicin, vincristine, and prednisone


Diffuse large B-cell lymphoma


United States Food and Drug Administration


Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)


Human anti-chimeric antibodies


Human anti-mouse antibodies


International prognostic index


Myelodysplastic syndrome


Maximum tolerated dose


Non-Hodgkin’s lymphoma


Progression-free survival


Partial response






Southwest Oncology Group

Rationale and Mechanism of Action

The rationale for the use of radioimmunotherapy (RIT) in cancer is that radiolabeled monoclonal antibodies will specifically target and irradiate tumor cells while sparing normal tissues. The specific tumor targeting of RIT theoretically allows higher doses of radiation to be delivered to tumor compared to external beam radiation because there are less effects of the radiation on normal tissues with RIT. Two radiolabeled anti-CD20 monoclonal antibodies, yttrium-90 (90Y)-ibritumomab tiuxetan and iodine-131 (131I)-tositumomab, are approved by the United States Food and Drug Administration (FDA) for the treatment of NHL as part of the Zevalin® (Spectrum Pharmaceuticals, Irvine, CA [1]) and Bexxar® (GlaxoSmithKline [2]) therapeutic regimens, respectively.

90Y-ibritumomab tiuxetan is composed of the radioisotope 90Y and the murine monoclonal antibody ibritumomab. 131I-tositumomab is composed of the 131I radioisotope and the murine monoclonal antibody tositumomab. Both components contribute to the drugs’ mechanism of action. The antibodies recognize slightly different epitopes of the extracellular domain of the CD20 antigen, which is found on the surface of pre-B lymphocytes, mature B-lymphocytes, and >90% of B-cell NHLs [3, 4]. Formation of the antibody-antigen complex results in induction of apoptosis, complement-dependent cytotoxicity, and antibody-dependent cytotoxicity [5, 6]. The radioisotopes emit β- radiations, which deposit enough energy in the tumor to result in cell death. Because the distribution of the radiolabeled antibody within a tumor can be heterogeneous [7], an additional advantage of RIT is that the β- emissions of the radiolabel can also target the surrounding malignant cells via the cross-fire effect and thus result in killing of residual microscopic disease in cells that the unlabeled antibody did not reach.

Efficacy and Safety of RIT in Recurrent NHL

In clinical trials investigating 90Y-ibritumomab tiuxetan and 131I-tositumomab in patients with recurrent NHL, overall response rates ranged from 60% to 83%, with complete response (CR) rates of 15–52%[8, 9, 10, 11, 12, 13, 14, 15]. The median duration of response with RIT ranges from 6 to 16 months for all responders, but seems to be associated with the quality of the initial response. At the time of publication of several studies, the median duration of response for patients who achieved a CR was much longer than for those achieving a less robust response, and had not yet been reached. Higher response rates were reported for RIT compared to the unlabeled anti CD-20 antibody. In a cross-over study of 131I-tositumomab, 42% of patients non-responsive to unlabeled tositumomab achieved a CR after receiving a therapeutic dose of 131I-tositumomab [16]. Again, a partial explanation for the improved overall response rates with the radioactive monoclonal antibodies is that the addition of the radioactivity probably allows more cells to be targeted and killed due to the cross-fire effect.

Although the initial results of the studies investigating RIT in recurrent NHL (mostly follicular) were excellent, the initial studies preceded the widespread use of the anti CD-20 mouse-human chimeric antibody, rituximab. These trials included mostly patients who were rituximab-naïve and studies were needed to show efficacy of RIT in the group of patients previously treated with unlabeled rituximab. Rituximab is now a routine component of B-cell lymphoma regimens. Two important studies showed excellent efficacy (overall response rates, 65–74%; complete response rates, 15–42%), durations of response, and progression-free survival (6.8–12.4 months) of RIT in patients with a prior history of rituximab therapy compared to the prior studies of rituximab-naïve patients [8, 13]. In addition, responses to radioimmunotherapy were seen in patients who appeared to be refractory to rituximab therapy.

Numerous prognostic factors have been evaluated in an attempt to identify which patients are most likely to respond to RIT. In individual studies, factors reported to be associated with response are low-grade follicular histology, non-bulky disease, no bone marrow involvement, fewer prior regimens, normal serum lactate dehydrogenase levels, lower IPI, higher total body radiation dose, and no prior history of transplant [8, 9, 10, 11, 12, 13, 14, 15]. Of all of these, low-grade follicular histology and non-bulky disease at the time of treatment are the most reliable predictors, especially in patients who had received no or minimal prior therapy for lymphoma.

In patients with NHL, RIT is generally well tolerated. The most common adverse events are serious cytopenias, notably declines in platelets and white blood cells, which are experienced by a majority of patients. Sixty to 70% of patients enrolled in clinical trials developed grade III/IV thrombocytopenia and/or neutropenia. Count nadirs typically occurred between 4 and 7 weeks post-RIT, and cytopenias may last for approximately 30 days. Consequently, monitoring of complete blood counts is required for at least 10–12 weeks post-therapy. Hematologic support is required for ~15–32% of patients after RIT [1, 2]. Notably, count nadirs occur later than typically seen with cytotoxic chemotherapies.

Additional non-hematologic short-term side effects are usually mild and may include fatigue, asthenia, nausea, and fever. There are several long-term side effects of which prescribing nuclear medicine physicians/radiologists, oncologists and patients must also be aware of [1, 2, 17, 18]. In patients with recurrent NHL treated with RIT, human anti-mouse or chimeric antibodies are found in 4–11%. Acute side effects due to HAMA/HACA (such as serum sickness-like illness) are not typically seen in this population due to a history of prior therapies and relative immune compromise, but could affect future treatment decisions (treatment with additional monoclonal antibody, eligibility for clinical trials) or interfere with certain laboratory evaluations. In studies in which 131I-tositumomab RIT has been used as the initial therapy of lymphoma, HAMA rates have been even higher. Hypothyroidism has been reported to occur in ~18% of patients who receive 131I-tositumomab, despite attempted thyroid blockade prior to therapy with cold iodine; this occurrence is probably less frequent with careful attention to thyroid blockade.

Secondary myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) has been reported in 2–4% of patients with recurrent NHL who received RIT [1, 2, 17, 18]. Nevertheless, the patients in these studies were heavily pretreated; thus, the role of RIT versus exposure to prior cytotoxic agents and a history of NHL in the development of MDS/AML remains unresolved. Czuczman et al. [17] retrospectively reviewed the data from 746 patients previously treated with 90Y-ibritumomab tiuxetan from 1996 to 2002 who were participating in clinical trials and compassionate use trials. Nineteen patients (2.5%) developed MDS/AML at a median of 5.6 years (1.4–13.9 years) after RIT. The annualized incidences of MDS/AML after NHL diagnosis (0.3% per year) and after treatment (0.7% per year) were not more than expected in heavily pretreated patients with NHL. At a median follow-up of 5.1 years, no cases of MDS/AML were reported in 76 patients with untreated follicular NHL treated with 131I-tositumomab as front-line therapy [19]. This patient population is generally at higher risk for the development of MDS/AML and should be monitored carefully.

Front-Line and Consolidation Therapy with RIT

RIT has also been investigated in front-line and consolidation settings. In both instances, single doses of RIT are effective and can produce long-term remissions. In 76 untreated patients with follicular NHL, Kaminski et al. reported a 95% overall response rate and 75% complete response rate to a single dose of 131I-tositumomab [19]. The estimated median progression-free survival rate at 5 years was 59% and progression-free survival was 6.1 years, with 5 years of follow-up. The relapse rate decreased progressively with time from the first RIT, and the long-term observations suggest that the quality of initial response may be important for subsequent relapse. HAMA was seen with greater frequency in this patient population.

A pivotal, multicenter phase III trial of 90Y-ibritumomab tiuxetan by Morschhauser et al. (FIT trial) led to the approval of 90Y-ibritumomab tiuxetan in the United States in the consolidation setting in 2009 [20] and long-term follow-up results have since been published [21]. Patients with untreated advanced follicular NHL received first-line chemotherapy, and if a response (complete, complete unconfirmed, or partial) was attained, patients were randomized to no treatment or 90Y-ibritumomab tiuxetan consolidation. In the updated results of the FIT trial and similar to the initial publication, median progression-free survival (PFS) was significantly longer for patients in the 90Y-ibritumomab tiuxetan consolidation arm (n = 207) versus the no treatment arm (n = 202) (4.1 years versus 1.1 years, p < 0.001) [21]. More patients in the 90Y-ibritumomab tiuxetan arm who achieved a PR to first-line chemotherapy converted to CR/CRu than in the no treatment arm (77.2% versus 17.5%, p < 0.001) [20] and in long-term follow-up the benefit of 90Y-ibritumomab tiuxetan was better in this group than in those who achieved a CR. Time to next treatment was 8.1 years in the 90Y-ibritumomab tiuxetan arm versus 3 years in the control arm (p < 0.001) [21]. Response rates to second-line therapy and 8-year overall survival rates were the same in both arms, which the authors attributed to salvage therapy [21]. The major criticism of this study is the lack of a comparison arm with maintenance rituxumab, which has also been shown to improve PFS, and the lack of rituximab in the chemotherapy alone arms in this trial [22, 23]. Press et al. with the Southwest Oncology Group (SWOG) reported similar encouraging results in a phase II study using 131I-tositumomab in the consolidation setting after six cycles of CHOP. In 90 patients, the overall and complete response rates were 91% and 69%, respectively, and 5-year progression-free survival was 67%. These outcomes were higher versus historical studies with CHOP alone [24]. Based on these results, a phase III study of CHOP/rituximab versus CHOP/131I-tositumomab was conducted in patients with previously untreated follicular lymphoma (SWOG S0016). Patients were randomly assigned to six cycles of CHOP with rituximab (n = 267) or six cycles of CHOP and a single dose of therapeutic 131I-tositumomab (n = 265). After a median of 4.9 years of follow-up, no difference in PFS or OS survival was seen between the CHOP-R and CHOP-RIT groups [25]. The Spanish intergroup PETHEMA/GELTAMO/GELCAB conducted a randomized phase II trial comparing consolidation with 90Y-ibritumomab tiuxetan (n = 63) and maintenance rituximab (n = 61) after a response to R-CHOP in patients with grades 1-3a follicular lymphoma. Thirty-six month PFS survival was higher in the maintenance rituximab group than the RIT group (86% versus 64%, p = 0.01) [26]. Overall survival was similar between the two arms at the time of follow-up in that study. Overall, it seems that consolidation or maintenance anti-CD20 therapy is helpful in terms of PFS and the optimal regimen remains to be determined. Press et al. also raised additional questions about maintenance rituximab versus RIT and a combination of these to further optimize PFS [25].

As in the recurrent setting, RIT is also very well tolerated in the front-line and consolidation settings. Hematologic side effects were again the most common, but more modest compared to the recurrent setting [19, 20, 21]. One difference is the occurrence of HAMA (~50% in Kaminski’s initial treatment with RIT study [19]) and the observation of associated clinical symptoms. A flu-like illness (fever, chills, myalgias, arthalgias) developed in 26% of patients with HAMA [19]. Symptoms were moderate and resolved without sequelae in 3–4 days. An association with shorter progression-free survival was suggested in post-hoc analysis for patients who developed very high HAMA levels (>5 times the lowest level found in the first 7 weeks). No cases of MDS/AML were reported by Kaminski et al. using 131I-tositumomab [19]; however, in the long-term follow-up of the FIT trial, the annualized incidence of rate of MDS/AML was higher in the 90Y-ibritumomab tiuxetan consolidation arm than controls (0.50% versus 0.07%, p = 0.42) [21]. The eight patients who developed MDS/AML received various subsequent treatments, and a common cytogenetic abnormality (−7 and/or 5q deletion) was found in six. The rate of MDS/AML was similar to those reported in other studies investigating RIT and non-RIT treatment [17, 25], but certainly raises a concern given that all eight patients with MDS/AML were in the RIT arm.

Logistics of RIT Regimens and Practical Considerations

The logistics of administering RIT, including determining which patients are eligible for treatment, are described and reviewed in the agents package inserts as well as by Wahl, Wagner et al. and by Goldsmith [1, 2, 27, 28, 29].

First, patient eligibility for RIT must be determined. This is largely determined by indication and the ability to safely administer the agents. Patients must have CD20+ lymphoma and the currently approved indications are listed in Table 1. The use of RIT has been evaluated for other indications (i.e., diffuse large B-cell lymphoma, less common indolent lymphomas, mantle cell lymphoma). In these cases, RIT is best administered in the clinical trial setting and on an individual basis in close consultation with the referring oncologist, and with full informed consent of the patient who is made aware of the potential risks and benefits.
Table 1

Clinical indications for radioimmunotherapy of lymphomas


90Y-ibritumomab tiuxetan

CD20+ relapsed or refractory low-grade, follicular, or transformed NHL, including patients with rituximab-refractory NHL

Relapsed or refractory low-grade or follicular B-cell NHL

Previously untreated follicular NHL who achieve partial or complete response to first-line chemotherapy

The minimum laboratory requirements for treatment are shown in Table 2. The minimum recommended platelet requirement is 100,000/mm3 and absolute neutrophil requirement is 1,500/mm3. The prescribed therapeutic activities for both 90Y-ibritumomab tiuxetan and 131I-tositumomab are based on platelet count (Table 2). Patients with a prior history of transplant can be treated safely, although reduced doses of RIT may be considered [10, 30, 31]. In order to avoid extensive and prolonged toxicity to the bone marrow, patients should have <25% of the marrow involved with lymphoma at the time of RIT. Traditionally, this is ascertained by marrow biopsy within 6–8 weeks before RIT, but [18F]FDG PET may provide complementary information as well. Pertinent medical history also includes, but is not limited to, allergies to medications, reactions to prior administrations of monoclonal antibody therapy, and concurrent medications (e.g., anti-platelet and anti-clotting agents).
Table 2

General eligibility and dosing for radioimmunotherapy of lymphomas

General eligibility criteria

For both agents:

 Tumor-expressing CD20

 Platelet count ≥100,000/mm3

 Absolute neutrophil count ≥1,500/mm3

 <25% lymphomatous marrow involvement

 Other pertinent medical history:



  Past infusion reactions to antibody therapy

For 131I-tositumomab:

 Baseline creatinine level

 Ability to follow radiation safety precautions

Therapeutic dosing of RIT


Platelet count ≥150,000/mm3


90Y-ibritumomab tiuxetan

0.4 mCi/kg


75 cGy total body radiation dose

Platelet count =100,000–150,000/mm3


90Y-ibritumomab tiuxetan

0.3 mCi/kg


65 cGy total body radiation dose

There are additional considerations for 131I-tositumomab. Creatinine levels should be assessed because free radioiodine is renally excreted and there is potential for a high radiation dose to the uro-epithelium in a patient with renal obstruction. Radiation safety issues, including home environment, must also be assessed and this may play a role in deciding which agent to use for RIT (discussed below). Radiation safety precautions to be followed are reproduced in the review article by Goldsmith [27].

Until very recently, the regimens for both 90Y-ibritumomab tiuxetan and 131I-tositumomab consisted of two steps in the United States. For both regimens, the first step consisted of imaging studies and the second step consisted of the administration of the therapeutic radiolabeled antibody. The schemas for each are shown in Fig. 1, and although similar, the major difference is the method for determining the amount of radioactivity to administer for the therapeutic dosage.
Fig. 1

Schemes for Zevalin® and Bexxar® therapeutic regimens adapted from prescribing information. The infusions of unlabeled and labeled antibody are administered intravenously and preceded by pre-medications to decrease infusion reactions and side effects. Biodistribution with 111In-ibritumomab tiuxetan is no longer required in the United States prior to therapy with 90Y-ibritumomab tiuxetan (Zevalin®)

Because 90Y is a pure β emitter, imaging studies are performed with 111In-ibritumomab tiuxetan (185 MBq, or 5 mCi). The purpose is to assure normal biodistribution of the tracer and avoid inadvertently delivering high radiation doses to normal organs. The incidence of abnormal biodistribution studies with 111In-ibritumomab tiuxetan is low [30]. In the United States, the requirement for 111In-ibritumomab tiuxetan imaging prior to therapeutic 90Y-ibritumomab was removed by the Food and Drug Administration in late 2011. Kylstra et al. presented a meta-analysis of five clinical trials and 9 years of post-approval safety data [32]. There was no difference in incidence of serious adverse events or bone marrow failure in countries performing imaging (United States/Japan) and not performing imaging (rest of world) [32]. The amount of 90Y radioactivity to administer for the therapeutic dosage is calculated based on platelet count and patient weight because, despite some patient-to-patient variability, only modest correlations between pharmacokinetic/dosimetric parameters using 111In-ibritumomab tiuxetan and hematologic toxicity have been demonstrated [31, 33].

Although biodistribution is also assessed, imaging before therapeutic 131I-tositumomab is performed (with 185 MBq 131I-tositumomab) mainly to determine patient-specific kinetics. The amount of radioactivity (in mCi) to achieve a desired total body radiation dose is then calculated based on this patient-specific kinetics, and a single therapeutic amount of 131I-tositumomab is administered [34, 35, 36].

Prior to administration of both the tracer and therapeutic doses of 90Y-ibritumomab tiuxetan and 131I-tositumomab, unlabeled anti-CD20 antibody (rituximab and tositumomab, respectively) is given to increase the tumor radiation dose relative to normal tissue radiation dose, as well as to increase the serum half-life of the radiolabeled antibody [37]. There has been some suggestion that administration of unlabeled antibody may, in some settings, block available tumor CD-20 positive sites and prevent the radiolabeled antibody from binding to tumor [38]. There is some logic to this, and it is noted that in the initial studies showing improved tumor dosimetry with pre-dosing, clinical efficacy of RIT in the recurrent and consolidation settings were performed mostly in rituximab-naïve patients. Regardless, no clinical data yet supports that prior rituximab, or unlabeled tositumomab pre-dosing, decreases the clinical efficacy of RIT [39], and further work on this issue is needed.

There are currently no randomized controlled trials comparing 90Y-ibritumomab tiuxetan and 131I-tositumomab. The clinical efficacy and safety profiles of the single agents, 90Y-ibritumomab tiuxetan and 131I-tositumomab, are similar in the clinical trials reported so far. From a practical standpoint, once a patient is determined to be a candidate for RIT, either agent may be used. However, as of February 2014, commercial production of 131I-tositumomab was discontinued, thus limiting the clinical choice.

Prior to 2014, we used both 131I-tositumomab and 90Y-ibritumomab tiuxetan routinely. When a patient was felt to be a candidate for RIT, one of the agents was chosen based on patient and disease characteristics as well as referring physician preference and familiarity. Differences in the physical properties of the agents and resultant studies, although very limited, helped to guide our decision process [40, 41].

Song et al. [41] performed a Monte-Carlo based dosimetric analysis and found that when compared to 90Y, 131I has a narrower distribution of tumor absorbed doses of radiation and is predicted to be more efficacious in the treatment of lung nodules, particularly those with radii less than 2 cm, presumably because of the shorter path length of 131I (0.8 mm) compared to 90Y (5.3 mm) [27]. This may be of particular relevance in small tumor foci near normal structures, if these findings can be extrapolated beyond the lungs [41].

We also retrospectively evaluated our clinical experience with 90Y-ibritumomab tiuxetan and 131I-tositumomab from 2002 to 2006 and found less severe declines in platelet count with 131I-tositumomab (which is based on patient-specific dosimetry) than with 90Y-ibritumomab tiuxetan (for which dosimetry measures are not performed) [40]. We suggested that 131I-tositumomab may be a more appropriate choice for patients with limited bone marrow reserve or lung metastases, or conditions which might alter the biological clearance rate of the radioantibodies; however, large, randomized, prospective trials would be needed for further evaluation.

The entire patient and clinical situation must be considered when assessing appropriateness for RIT, including radiation safety regulations at the institution and the ability of the patient to follow radiation safety precautions. The choice of RIT agents is currently limited to 90Y-ibritumomab tiuxetan due to commercial availability in the United States. In Australia, 131I-rituximab is available for treatment in select patients.

Subsequent therapies have been well tolerated after RIT. Multiple cycles (up to seven) of chemotherapy and radiation therapy have been given post-RIT [42, 43]. Autologous and allogeneic transplants have been performed after RIT, with adequate stem cell collection occurring after RIT. The toxicity of various subsequent therapies has not been shown to be different after RIT.

Repeat Therapies

Neither 90Y-ibritumomab tiuxetan nor 131I-tositumomab are approved by the FDA for repeat dosing, but repeat dosing for both agents has been studied to a limited extent. A consideration for repeat dosing is the induction of a host immunologic response, because both 90Y-ibritumomab tiuxetan and 131I-tositumomab are mouse antibodies. The chance of developing human anti-mouse antibodies (HAMA) is higher with tositumomab/131I-tositumomab because the pre-dose (and larger protein load) of antibody is also mouse antibody, whereas the pre-dose for 90Y-ibritumomab tiuxetan is the human/mouse chimeric antibody rituximab. Most patients with follicular NHL who receive RIT have also received prior therapies and are somewhat immunocompromised, thus probably decreasing the chance of developing HAMA.

Kaminski et al. reported on 28 of 32 patients with relapsed follicular NHL who received a second dose of 131I-tositumomab after previously responding to 131I-tositumomab for at least 3 months [44]. The median duration of response in this population was similar for the first and second doses of 131I-tositumomab and 10 of the 18 re-responders had a longer duration of response with the repeat dose, 5 of which lasted longer than 1.5 years. Hematologic toxicity was similar after the first and second doses of 131I-tositumomab. Ten percent of patients developed HAMA and 12% had an elevated thyroid-stimulating hormone [44].

A retrospective study was done describing experience with 90Y-ibritumomab tiuxetan retreatment. Eighteen patients were identified from the Biogen-IDEC database. Similar to 131I-tositumomab, the safety and efficacy profiles after the second course of 90Y-ibritumomab tiuxetan were overall similar to the first. There are also several case reports of individuals tolerating and benefiting from repeat doses of RIT [45, 46, 47]. These data suggest that, in selected patients, repeat treatment with RIT may be beneficial.

Others have evaluated administering 90Y-ibritumomab tiuxetan with fractionated or sequential schedules. A phase II study evaluated fractionated 90Y-ibritumomab tiuxetan for initial therapy of follicular lymphoma [48]. Seventy-four patients were enrolled: 55 received both doses of 90Y-ibritumomab tiuxetan 8–12 weeks apart and 17 received only a single dose of 90Y-ibritumomab tiuxetan due to hematologic toxicity, treating physician preference, HAMA, or premorbid condition. Overall response rate was 94.4% with CR/CRu rate of 58.3% after the initial dose, and nine patients improved their response after the second dose. Estimated 3-year overall survival was 95%, and median PFS was 3.35 years. Toxicity was primarily hematologic, as expected, with slightly higher percentage of grade 3–4 toxicity and duration of toxicity with the second dose [48].

Witzig et al. performed a phase I study to determine the maximally tolerated dose (MTD) of two rapidly sequenced doses of 90Y-ibritumomab tiuxetan given 12–24 weeks apart [49]. Eighteen patients were enrolled and dose-limiting hematologic toxicity was seen in the cohort receiving 0.3 mCi/kg for the second dose of 90Y-ibritumomab tiuxetan. The authors concluded that the MTD for the second dose of 90Y-ibritumomab tiuxetan was 0.2 mCi/kg [49]. Consideration of the time from last treatment, response to last treatment, baseline and previous hematologic toxicity and time to recovery, and bone marrow tumor burden are all important considerations in the repeat setting, which again is not an FDA indication.

Barriers to the Use of RIT

Radiolabeled anti-CD20 antibody therapy for low-grade follicular lymphoma is effective and it has a predictable and very tolerable safety profile. Nevertheless, despite improvement in response rates compared to unlabeled rituximab and anti-lymphoma activity in patients with rituximab-refractory disease, these agents are not widely applied in the clinical setting. Limited drug sales led to the discontinuation of production of the 131I-tositumomab agent in 2014. Schaefer et al. conducted two surveys in the United States to identify barriers to use of RIT [50, 51]. The first was an eight-question survey sent to medical oncologists, and 5% (216 of 4,239) responded [51]. The three top concerns were bone marrow damage and limiting future therapies, late side effects and too many effective nonradioactive alternatives. Contrary, the literature supports that subsequent therapies are well tolerated after RIT. There were some differences in concerns amongst oncologists practicing in academic versus nonacademic settings. Nonacademic oncologists had significantly greater concerns regarding adverse economic effects on their own practice, lack of referral centers, complicated referral process and lack of interest by Nuclear Medicine specialists. Despite these concerns, 37% thought that RIT would grow in use in the United States [51].

The second survey was sent to nuclear medicine physicians and radiation oncologists, 4.6% (613 of 13,221) responded [50]. About 40% did not treat NHL with RIT. The biggest concerns among this group was that referring providers wanted to treat patients themselves with nonradioactive drugs and the cost of RIT. Those who thought RIT had a negative future believed that the procedure was time consuming, had concerns about the dosimetry procedure and radiation safety, and the high-cost. Those from academic centers had less concerns about these issues than those in nonacademic settings [50].

Other Settings for RIT

In addition to non-follicular NHL subtypes, the use of RIT is under investigation in several additional clinical situations. In the transplant setting, standard and high dose (myeloablative) RIT has been included in conditioning regimens. The approaches have varied from institution to institution, but results from multiple phase II trials have shown that the addition of RIT is tolerable without increasing toxicity, and the efficacy results have shown promise. They are reviewed by Gisselbrecht et al. [52]. A phase III intergroup study comparing Rituxan/BEAM (n = 113) versus BEXXAR/BEAM (n = 111) conditioning prior to autologous stem cell transplant for persistent or relapsed chemosensitive DLBCL showed similar 2-year PFS and OS between the groups [53].

[18F]FDG-PET for Evaluation of Response to RIT

[18F]FDG uptake in tumors typically drops significantly following RIT [54, 55, 56, 57, 58, 59, 60] (Fig. 2). Large declines in [18F]FDG uptake tend to be seen in patients with the longest progression-free survival [55, 56].
Fig. 2

A 62-year-old man with a history of transformed non-Hodgkin’s lymphoma (NHL). He received five regimens for low-grade NHL and then progressed with transformation to diffuse large B-cell lymphoma after R-CHOP. He was referred for radioimmunotherapy (RIT). At the time of therapy, his platelet count was 180,000/mm3 and the absolute neutrophil count was 3,320/mm3. He received 0.4 mCi/kg 90Y-ibritumomab tiuxetan. The baseline PET/CT scan shows intense [18F]FDG uptake in left supraclavicular lymph nodes (A: top row). At 12 weeks after therapy, the [18F]FDG uptake in lymph nodes resolved, which is consistent with complete response to RIT. The duration of response was 10 months. (Left: CT; Center: PET; Right: Fused PET/CT)

Semi-quantitative parameters on pre-RIT PET have been evaluated as possible predictors of response. In 1991, Okada et al. reported that patients with the worse prognoses after chemotherapy and/or radiotherapy had higher levels of [18F]FDG uptake [57]. Several subsequent studies have not shown a correlation between pre-RIT SUVmax corrected for whole body or lean body weight of the hottest tumor and response [54, 55]; however, a trend for this was very recently reported by Cazaentre et al. [54]. In this study, Cazaentre et al. [54] also found that pre-RIT total lesion glycolysis (a measure of [18F]FDG uptake and tumor volume) was higher for those who did not respond to RIT compared to those who did. Tumor volume has previously been shown to be a prognostic factor for response to RIT and may be more indicative of disease state than the metabolic activity of a single lesion. In a study of 59 patients with follicular NHL treated with 90Y-ibritumomab tiuxetan, post-RIT PET response was the only independent predictive factor for progression-free survival in the multivariate analysis [56].

The optimal timing to obtain a PET scan after RIT is still being defined. We, and others, have performed PET scanning 2–3 months after RIT with several interesting observations. At this time point, it is possible to identify those with a complete response, those with progressive disease (most commonly due to new lesions) and in such instances, management decisions are clear [55, 58]. However, [18F]FDG-PET cannot adequately predict the subsequent outcome of the group of patients who achieves a partial response by the revised IWG at 12 weeks. Some patients may have a continued response, warranting further observation, while others may progress necessitating treatment. Several authors have found longer response durations and time to progression with patients who have a response seen on PET scans performed even earlier, at 4–6 weeks post-RIT [59, 61]. Further prospective studies in larger numbers of patients are needed.

The use of [18F]FDG-PET for evaluating response to RIT has helped to demonstrate an interesting pattern of relapse after RIT. In our own study, we found that progressive disease was only due to “new” lesions in a majority of patients (11/12) who progressed at 12 weeks (Fig. 3) [55]. Aviles et al. found that bulky disease was a negative factor for achieving a CR to RIT, but if a CR was achieved, the site of bulky disease was not at increased risk for recurrence [62]. Lymphoma is more likely to recur outside initial radiation ports after external beam radiation therapy; whereas, recurrence is more likely at initial sites and less frequently at new sites after chemotherapy alone. These data suggest that the quality of the initial response may predict long-term outcome and that progressive disease/relapse may be more likely to occur at new sites of disease rather than at sites of previous involvement.
Fig. 3

A 59-year-old woman with a long history of stage 4 splenic marginal zone lymphoma status post splenectomy and multiple treatments with local external beam radiation and single-agent rituximab was referred for radioimmunotherapy and treated with a 75 cGy total body radiation dose of 131I-tositumomab. The pre-RIT PET/CT scan (a) shows multiple foci of abnormal [18F]FDG uptake in right axillary, upper abdominal, para-aortic, iliac, and inguinal lymph nodes, which is consistent with active lymphoma. There were also numerous subcutaneous nodules present indicating lymphoma. Post-RIT (b), many of the large lymph nodes resolved (e.g., arrows); however, new lymph node lesions (arrowheads) and subcutaneous lesions were seen, suggesting overall progressive disease. The patient refused further systemic chemotherapy but has received further external beam radiation to sites causing local symptoms

Other Radiolabeled Monoclonal Antibodies and Strategies

Several other radiolabeled monoclonal antibodies are currently under investigation [63, 64]. 90Y-veltuzumab (Immunomedics, Inc, Morris Plains, NJ) is a humanized anti-CD20 monoclonal antibody. The potential benefit of the humanized antibody is less HAMA formation. Initial phase I/II clinical studies have been reported with the unlabeled antibody [65] and the therapeutic activity of the radiolabeled agent in animal models of NHL is reported [64].

Epratuzumab is an anti-CD22 monoclonal antibody. CD22 is a B-cell marker found on 60–80% of B-cell malignancies. Epratuzumab has been radiolabeled with 131I and 90Y radioisotopes [64]. In a pilot study of 11 patients with refractory B-cell lymphomas, six patients responded to 131I-epratuzumab, three with a complete response [66]. More responses were seen with follicular and transformed NHL than DLBCL, and toxicity was higher in patients with decreased marrow reserve. A potential disadvantage with 131I-epratuzumab is internalization and a short intracellular half-life. Better tumor dosimetry has been reported for 90Y-epratuzumab. Using a fractionated schedule of 90Y-epratuzumab in 16 patients with NHL, the same group reported overall response rates of 62% and CR rates of 25% [66]. Epratuzumab has also been labeled with Rhenium-186 and administration is feasible in phase I trials [67].

The group at Fred Hutchinson Cancer Research Center in Seattle (WA, USA) has demonstrated therapeutic activity of 131I-anti-CD45 antibodies in NHL B-cell and T-cell xenograft models, with minimal toxicity [68, 69].

In addition to targeting various isotopes, improving approaches and schedules for administration of RIT are areas of active investigation. These approaches were recently reviewed by Sharkey et al. [64]. In the pre-targeting approach, bispecific antibodies recognize both the tumor target and a radiolabeled hapten-peptide. The unlabeled bispecific antibody is given first and allowed to bind to the target. Several days later, the radiolabeled hapten-peptide is given which binds the bispecific antibody. Pre-targeting should help to decrease the serum half-life of the radiolabel in the blood and subsequently exposure of non-tumor hematopoietic tissue and toxicity. Combinations of antibodies targeting different surface antigens may also help to increase the amount of tumor targeting and circumvent the issue of “tumor blocking” by unlabeled antibody.


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Nuclear Medicine/PET-CT, Department of Imaging, Dana-Farber Cancer Institute and Department of Radiology, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  2. 2.Mallinkrodt Institute of RadiologyWashington University School of MedicineSt. LouisUSA

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