Iodine I-131 tositumomab is a well tolerated and effective therapy for recurrent low-grade and transformed low-grade non-Hodgkin lymphoma (NHL). Hematologic reserve after radioimmunotherapy (RIT) is an important consideration when subsequent therapy is required.
One hundred fifty-five patients who received treatment with I-131 tositumomab were assessed, and 68 patients had progressive disease after RIT. The median age (n = 68 patients) was 59 years (range,18–82 yrs), and patients received a median of 2 pre-RIT regimens (range,1–8 regimens), including 66% who received anthracycline, 19% who received platinum, and 50% who received fludarabine.
The median time to disease progression (among progressors) was 168 days (range, 19–771 days). At the time they developed recurrent disease, patients had median white blood cell count (WBC) of 4.9 K cells/μL (range, 1.1–21.4 K cells/μL), a median absolute neutrophil count (ANC) of 3.25 K cells/μL (range, 0.59–8.20 K cells/μL), a median platelet count of 130 K cells/μL (range, 9–440 K cells/μL), and there was no significant difference between pre-RIT and recurrence values except for the platelet count (P < 0.05). No patient demonstrated a WBC < 1.0 K cells/μL or an ANC < 0.5 K cells/μL, although 1 patient had a platelet count < 10 K cells/μL. Twenty-four patients subsequently received no further chemotherapy; and, in 21 patients (88%), hematologic parameters appeared to allow subsequent chemotherapy if necessary (blood counts: National Cancer Institute Grade 0–2). Among 44 patients (65%) who received further chemotherapy (median, 2 regimens; range, 1–4 regimens), 19 patients (43%) were treated with anthracyclines, 17 patients (39%) were treated with platinum, 10 patients (23%) were treated with fludarabine, and 13 patients (30%) underwent stem cell transplantation. Disease improvement occurred in most patients, although 18 patients died (40%) after further chemotherapy, predominantly from refractory lymphoma.
There has been a significant increase in the incidence of and mortality from non-Hodgkin lymphoma (NHL) over the last 4 decades, including NHL with indolent or low-grade (LG) histology.1 Many patients with LG NHL have an indolent clinical course, but most present with disseminated disease that requires systemic therapy.2 The majority of patients respond to their initial therapy; however, recurrences are common and are associated with increasing resistance to treatment over time.3 The median survival of patients with LG NHL has been reported in the range of 8–10 years.4 Available management options include “watch and wait” for asymptomatic patients; involved-field radiation for localized disease; single alkylating agent chemotherapy, such as chlorambucil; combinations with anthracyclines, such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); purine analogues, such as fludarabine; platinum-containing regimens; intensive strategies, such as autologous or allogeneic stem cell transplantation; and, most recently, antibody-based therapies, such as rituximab (anti-CD20) either alone or in combination with chemotherapy.5–12
Recent advances in the treatment of LG NHL include radioimmunotherapy (RIT) in the form of radiolabeled monoclonal antibodies.13 These compounds augment the antitumor effects of the antibody moiety with the added activity of targeted radiation provided by the radioisotope. Clinical trials have demonstrated the benefits of this approach using two such agents that have been approved by the United States Food and Drug Administration: yttrium-90 ibritumomab tiuxetan and iodine I-131 tositumomab.14, 15 Those studies demonstrated high overall response (OR) and complete response (CR) rates, and randomized studies comparing each of these agents with their unlabeled counterparts have confirmed the advantages of RIT.16, 17 Durable CRs also have been noted, particularly with iodine I-131 tositumomab, in patients with postchemotherapy recurrent or chemotherapy-refractory LG NHL and transformed LG NHL, including rituximab-refractory disease.18
The clinical activity of RIT in patients with disease that has recurred after or has become resistant to rituximab and/or chemotherapy supports its use in these settings, particularly given the limited availability of alternative treatment options. Like with other cancer therapies, however, application of this modality earlier in the course of the disease may provide even greater clinical benefit, particularly before resistance has emerged. Although limited data are available using yttrium-90 ibritumomab tiuxetan as primary therapy for NHL, results from several studies have suggested that the early use of iodine I-131 tositumomab as part of initial treatment is associated with high OR and CR rates and with durable remissions.19, 20 One concern about this approach, however, is that the radiation dose delivered to the normal bone marrow as part of RIT potentially may diminish bone marrow reserve. Therefore, some clinicians and patients are concerned that RIT may limit the ability to administer subsequent therapy, including chemotherapy and stem cell harvest and transplantation. To address this issue, we assessed the hematologic status at recurrence and subsequent therapy in a cohort of patients who were treated with iodine I-131 tositumomab at our center. The findings suggest that treatment with iodine I-131 tositumomab does not have an adverse impact on blood counts at the time of disease recurrence in the majority of patients and that further treatment generally can be administered.
MATERIALS AND METHODS
We reviewed 155 patients who were treated with iodine I-131 tositumomab on 6 Institutional Review Board-approved trials (with informed consent) at the Weill Medical College of Cornell University/New York Presbyterian Hospital. At the time of this analysis, 87 patients had not progressed after RIT, whereas 68 patients (44%) had either failed to respond or developed recurrent disease after a response to iodine I-131 tositumomab therapy and constitute the study population for this report.
All patients received standard iodine I-131 tositumomab therapy (65 centigrays or 75 centigrays, based on platelet counts)15 on 1 of 6 clinical trials, all of which included monitoring of safety and efficacy endpoints after treatment. Subsequent therapy after patients developed disease progression after RIT was not defined by protocol and was chosen and administered at the discretion of the treating physician. The studies in which patients received RIT are outlined in Table 1. Study RIT-II-002 was a multicenter, randomized study that compared unlabeled tositumomab with tositumomab plus radiolabeled tositumomab in patients with recurrent/refractory LG NHL or transformed LG NHL.17 Only patients who received radiolabeled tositumomab (n = 9 progressors) were included in this analysis. Study RIT-II-004 (n = 2 patients) was a multicenter study that evaluated iodine I-131 tositumomab in chemotherapy-refractory LG NHL or transformed LG NHL.15 Most patients in this report were from study CP-98-020 (n = 41 patients), which was an expanded access study of iodine I-131 tositumomab in patients with LG NHL or transformed LG NHL. Study CP-98-025 (n = 11 patients) was a single-center trial that used an abbreviated course of 3 cycles of fludarabine followed by iodine I-131 tositumomab in patients with previously untreated LG NHL.21 Study CP-99-032 (n = 1 patient) was a multicenter, Phase II study that evaluated iodine I-131 tositumomab in patients with diffuse large B-cell NHL who were in response after standard CHOP chemotherapy. Finally, Study CP-99-036 (n = 4) was a multicenter study that evaluated 6 cycles of cyclophosphamide, vincristine, and prednisone chemotherapy followed by iodine I-131 tositumomab as initial therapy for patients with LG NHL. Data were available and were compiled as part of these studies with regard to prior NHL treatments; pre-RIT, post-RIT, and postdisease progression hematologic status; and time to disease progression after RIT. In addition, long-term follow-up data included information on subsequent treatment regimens and limited data on outcomes (namely, whether a response occurred). Data on hematologic toxicity of subsequent therapy and duration of response to such treatment were unavailable in sufficient patients for meaningful analysis, because these events were not captured as part of the original protocol. Some patients continued their post-RIT care at our institution, whereas others received subsequent treatment with other oncologists who were contacted for available information.
Table 1. Studies in which Patients Received Radioimmunotherapy
Expanded-access study for recurrent/refractory LG or transformed LG NHL
Previously untreated LG NHL
Previously untreated, diffuse, large B-cell NHL
Previously untreated LG NHL
Of 155 patients on 6 separate studies, 68 patients had no objective response to RIT (n = 33 patients) or had an objective response followed by disease progression (n = 35 patients). Baseline characteristics of the study population at the time of RIT study entry are included in Table 2. Most patients had follicular lymphoma; in 18% of patients, the disease had transformed to an aggressive histology. Before RIT, 49% of patients had lymphomatous involvement of the bone marrow. Most patients had received significant prior cytotoxic therapy, with a median of 2 prior regimens (range, 1–7 regimens), and 35% of patients had received ≥ 3 prior myelosuppressive regimens. Of 68 patients, 66% had previously received anthracyclines, 19% had received platinum, and 50% had received fludarabine (Fig. 1). External-beam radiation and monoclonal antibody therapy had been administered to 15% and 32% of patients, respectively, prior to RIT.
Table 2. Patient Demographics and Baseline Characteristics (N = 68)
No. of patients
RIT: radioimmunotherapy; BM: bone marrow; NHL: non-Hodgkin lymphoma.
Median age in yrs (range)
Diffuse large B cell
No. days post-RIT to progression; Median (range)
No. pre-RIT chemotherapy regimens: Median (range)
One or two regimens
Three or more regimens
Received prior radiation therapy
Received prior antibody treatment
Had pre-RIT BM NHL involvement
The median time to disease progression from the administration (Day 0) of iodine I-131 tositumomab in this population (n = 68 patients) was 168 days (range, 19–771 days). Eleven patients progressed prior to Week 10, before hematologic recovery from RIT generally is expected. In this time frame, cytopenias may reflect a short-term (transient) effect on the bone marrow rather than long-term bone marrow compromise. Median blood counts at baseline (prior to RIT) and at disease progression are outlined in Table 3. Eight patients (12%) had a National Cancer Institute (NCI) Grade 3–4 platelet count, including 1 patient with Grade 4 toxicity (< 10 K/μL) at the time of disease progression 30 days after the therapeutic dose (Fig. 2). Seven percent of patients had a white blood cell count (WBC) that fell within NCI Grade 3 WBC toxicity range, 3% of patients had an absolute neutrophil count (ANC) within the NCI Grade 3 toxicity range, and 3% of patients had hemoglobin levels within the NCI Grade 3 toxicity range. No patient demonstrated NCI Grade 4 WBC, ANC, or hemoglobin toxicity at the time of disease progression. Overall, 10 patients had some type of Grade 3 or Grade 4 hematologic toxicity at the time of disease progression.
Table 3. Comparison of Blood Counts Before Radioimmunotherapy and at the Time of Disease Progression (N = 68)a
All P values for pre-RIT versus post-RIT counts were nonsignificant except for PLT (P < 0.05).
Median days from RIT to disease progression = 168 days (range, 19–771).
Post-RIT (disease recurrence)
Forty-four patients (65%) went on to receive cytotoxic therapy after disease progression (Fig. 3). Twenty-four patients (35%) received no further cytotoxic therapy at the time of analysis (median, 1.6 yrs postrecurrence; range, 0.3–3.5 yrs) for a variety of reasons (Table 4). Therapy was not indicated in four patients due to a lack of disease-associated symptoms. Radiation therapy was used to treat localized disease in five patients, and six patients received rituximab (one patient received both modalities), and one patient was treated on a vaccine protocol. Seven patients died from rapidly progressive disease, and two patients died from causes unrelated to lymphoma. In all but 3 of 24 patients (12%), disease status rather than hematologic parameters appeared to determine the choice of subsequent treatment, because blood counts were acceptable to permit chemotherapy (NCI Grade 0–2 values). Of the 3 patients who had Grade 3 hematologic values at recurrence, 2 patients had progressed early (before Week 13), and all 3 patients had received substantial prior chemotherapy (2–7 prior treatment regimens).
Table 4. Patients without Subsequent Cytotoxic Chemotherapy (N = 24)
One patient received both radiation therapy and unlabeled antibody.
No treatment indicated (asymptomatic)
Treated with radiation therapy (localized disease)
Died from progression of disease (refractory disease)
Vaccine protocol therapy
The 44 patients who received further chemotherapy received a median of 1 subsequent cytotoxic chemotherapy regimen (range, 1–4 regimens) after their disease recurred. In many patients, these were myelosuppressive regimens that included anthracyclines, platinum, fludarabine, and autologous or allogeneic stem cell transplantation (Fig. 4). In patients who underwent autologous stem cell transplantation subsequent to RIT, stem cell collection was performed either before RIT (three patients) or after RIT, and details on harvest results and engraftment are not available. Outcomes observed after the administration of cytotoxic chemotherapy are presented in Table 5. Approximately 50% of patients either completed treatment and were in response after chemotherapy or still were receiving treatment (and were not evaluable for response) at the time of the data analysis. Three patients who received chemotherapy died either from causes that were not lymphoma-related or from complications related to allogeneic stem cell transplantation. Eighteen patients had disease that did not respond to subsequent chemotherapy and died of progressive disease. Post-RIT, this group received a median of 1 and 2 cycles (range, 1–8 cycles) of a median of 1 subsequent regimen (range, 1–3 regimens). To assess whether post-RIT cytopenias may have compromised the amount of subsequent therapy (and led to an unfavorable outcome), we reviewed the hematologic status at recurrence of this subset of 18 patients. Thirteen patients had blood counts at recurrence (NCI Grade 0–2) post-RIT that normally would allow for the administration of cytotoxic chemotherapy. Five patients had blood counts in the Grade 3–4 toxicity range at recurrence, which may well have impacted the ability to deliver appropriate doses of cytotoxic treatment. Three of those 5 patients had received 3–8 cycles (median, 4 cycles) prior to RIT, and 2 patients were early progressors before Week 13 during the expected post-RIT, transient cytopenia period.
Table 5. Outcomes Observed in 44 Patients who Received Subsequent Cytotoxic Chemotherapy
Cycles were not included for continuous regimens (therefore, some patients are listed as having 0 cycles), autologous or allogeneic stem cell transplantation was considered 1 cycle for this analysis.
Refractory disease; died
Unrelated death or toxicity due to allo-SCT
Tositumomab with iodine I-131 tositumomab is an effective treatment modality for patients with recurrent and refractory LG NHL and transformed LG NHL. It is associated with a high OR rate (47–64%) and a CR rate (20–38%) and can induce durable remissions across multiple studies, even in heavily pretreated populations.15, 17, 22–24 It also has the potential to offer utility in other B-cell malignancies and is under active investigation in a number of disease settings, both alone and in combination with chemotherapeutic agents. Although its activity in both recurrent and refractory LG NHL is clear, the application of iodine I-131 tositumomab in patients with less resistant tumors earlier in the course of their disease potentially may offer additional benefit. In these settings, RIT may provide even higher response rates and an increased number of durable remissions while allowing patients to avoid some of the toxicities of chemotherapy, such as alopecia, cardiac toxicity, and neuropathy. A recently published study demonstrated the effectiveness of iodine I-131 tositumomab in the first and second recurrence settings, with OR and CR rates of 76% and 49%, respectively.25 In addition, Kaminski and colleagues reported OR and CR rates of 95% and 75%, respectively, in patients with previously untreated, advanced-stage follicular NHL.19 One concern about the use of RIT in general as initial therapy or after first or second recurrence relates to a potential impact on bone marrow reserve that may cause persistent cytopenias and interfere with the ability to deliver subsequent chemotherapy when required. Additional issues involve the risk of secondary malignancies and myelodysplasia, which appear to be comparable to those observed with standard chemotherapeutic regimens.26, 27 Retrospective data also have been reported regarding subsequent chemotherapy after yttrium-90 ibritumomab tiuxetan therapy.28 Iodine I-131 tositumomab is a newly approved agent that differs in part by the use of patient-specific dosing through dosimetry, which potentially limits bone marrow radiation exposure.29 In addition, unlike yttrium-90 ibritumomab tiuxetan, it is not a heavy metal and, thus, does not deposit in bone. Our report provides data suggesting that hematologic status at the time of recurrence after iodine I-131 tositumomab in pretreated patients allows for the delivery of subsequent cytotoxic therapies, when required, in > 90% of patients with recurrent disease. Because the other patients at our institution continued in response posthematologic recovery after iodine I-131 tositumomab, it should be recognized that the percentage of all patients treated with RIT (not just progressors) presumably would be higher. In addition, it seems intuitive that patients who receive iodine I-131 tositumomab as initial therapy or in first or second recurrence will have even better hematologic reserve when the need for further therapy arises. Because some patients clearly have long-term bone marrow toxicity with chemotherapy (including persistent cytopenias that interfere with later treatment), it is unclear whether any different outcomes would have been observed if our patients had been treated with alternative options.
We recognize that there are limitations to this study. First, a major variable is the impact of physician preference and perception in the selection of specific subsequent therapies (and the exclusion of others), which may have affected later outcomes. This issue is unavoidable, because it is impractical to define in advance (e.g., in a prospective trial) which treatment will be prescribed after a future recurrence that may not occur until several years later. Second, this was a retrospective study. More specific information on subsequent chemotherapy courses, including frequency of dose reductions and dose delays, would be of interest. Because our patients were “off study” from their principal clinical trial after recurrence, there was some limitation in what follow-up information was available, particularly in patients who received subsequent therapy elsewhere. Planned prospective trials that investigate this issue should provide more information, but results will not be forthcoming for several years. Third, all patients in this analysis had received chemotherapy prior to RIT. It is impossible to isolate long-term bone marrow effects due to prior chemotherapy from bone marrow effects that are related to RIT. Therefore, our data may overestimate the effects of RIT on bone marrow reserve, because any observed toxicity may relate in part to other prior myelosuppressive therapies.
Despite these caveats, our findings provide important information regarding hematologic status at recurrence after iodine I-131 tositumomab in a population of patients who generally had received multiple prior chemotherapy regimens (range, 1–8 regimens) prior to RIT. At the time of disease recurrence, this group of patients demonstrated blood counts that were unchanged from pre-RIT levels, except for a modest but statistically significant decrease in platelet counts. In some patients, clinical status did not warrant the initiation of cytotoxic therapy at the time of recurrence. Overall, two-thirds of the patients with progressive disease received subsequent chemotherapy that included anthracyclines, platinum, and fludarabine-containing regimens, all of which are associated commonly with myelosuppression. It is reassuring to note that, for patients who received chemotherapy, approximately 50% either achieved a clinical response (and, thus, could at least receive sufficient treatment to respond) or were in the process of receiving treatment at the time of this analysis. Three patients either died from unrelated causes or from stem cell transplantation-related complications, and 18 patients died from refractory disease. Within this later group, there was evidence in five patients that blood counts at recurrence were low enough that full-dose chemotherapy may not have been administered. However, 2 of those 5 patients had disease progression before expected hematologic recovery post-RIT (usually within 7–13 weeks), at a time when immediate chemotherapy administration may be problematic. For the remaining patients, it appears that the refractory nature of their lymphoma, rather than a compromise in hematologic reserve, may have been responsible for their adverse outcomes.
In summary, in a heavily pretreated population of patients with LG NHL and transformed LG NHL, recurrence after iodine I-131 tositumomab therapy generally is associated with an acceptable hematologic status that allows for the administration of subsequent therapy, including chemotherapy and stem cell transplantation. This information suggests that the use of iodine I-131 tositumomab earlier in the course of NHL treatment should not preclude subsequent therapy and should be explored further. Additional studies are warranted and are underway both to evaluate the efficacy and to include prospective monitoring of treatment subsequent to recurrence after RIT.