Advances in Radioimmunotherapy Treatment: Options for Refractory Non-Hodgkin's Lymphoma
Richard Wahl, MD, Director of Nuclear Medicine, Vice Chairman Department of Radiology, Henry N. Wagner Jr. Professor of Nuclear Medicine, Professor of Oncology, Johns Hopkins School of Medicine, The Johns Hopkins University, Baltimore, Maryland
The 50th Annual Meeting of the Society of Nuclear Medicine in New Orleans provided new data indicating reasons for optimism in the treatment of non-Hodgkin's lymphomas with radio-immunotherapy. Non-Hodgkin's lymphoma (NHL) is a disease that varies widely in its aggressiveness. The histologically less aggressive, or indolent, tumors are generally incurable, despite an apparently benign histology. With each successive treatment, response rates diminish and duration of response shortens.1 Though the disease is quite variable, NHL eventually becomes more chemotherapy-resistant or transforms into higher-grade lesions. Some long-term survival has been noted, but for the most part no single treatment has shown a clear improvement in survival.
Targeted immunotherapy and radioimmunotherapy are new treatment strategies for patients with NHL. Treatment with a chimeric anti-CD20 monoclonal antibody, rituximab, yields objective responses in approximately 50% of patients with relapsed/refractory low-grade NHL for a median duration of about one year. However, virtually all patients relapse.
Patients with relapsed/refractory low-grade NHL, with or without transformation, are in need of novel therapies that offer not only a higher response rate but also the opportunity for durable responses without further cytotoxic chemotherapy. Evidence from 5 clinical trials of tositumomab and iodine-131 (131I-tositumomab) (Bexxar) suggests that this immunotherapy/radiotherapy combination may provide such benefits in a proportion of these very challenging patients.2 Bexxar is a murine monoclonal antibody that also binds CD20 (with high affinity and specificity) on normal and malignant lymphocytes. It has a dual-action approach that combines the tumor-targeting ability of a cytotoxic monoclonal antibody with the therapeutic potential of radiation. This drug also has a dual level of specificity: specific targeting to CD20-positive tumor cells and a patient-specific dosing regimen where the injected mCi dose is optimized based on the specific patient's own pharmacokinetics (determined from imaging a tracer dose).
Several papers were presented showing very encouraging results for Bexxar. According to the results of a presented analysis, long-term durable responses can be achieved in 30% of all patients treated with this agent—even those who have undergone 3 and even up to 8 prior therapies.2 Of the patients who achieved durable responses (one year or longer), 76% showed complete responses and their time to progression was nearly 5 years. In some patients, time to progression exceeded 8 years. Given that NHL has a tendency to relapse even more frequently and with shorter response durations with successive therapies—and that this was such a difficult patient population—these findings are quite unexpected and exciting.
Investigators who presented these studies showed not only that Bexxar delivered long-term durable remissions in many patients, but also that precise targeting based on patient-specific dosimetry was possible with this agent, thus minimizing toxicity to the bone marrow. Patients with thrombocytopenia and obese patients were effectively and safely treated by customizing (often by attenuating) the treatment dose.3,4 Reassuringly, we heard from other researchers that there appears to be little risk due to radiation exposure to healthcare personnel administering Bexxar.5 The details of these informative and timely studies are described in this Radioimmunotherapy Express Report.
Clinical Trial Data Show Long-term Durable Response with Bexxar
According to an analysis of data from 5 clinical trials of Bexxar, long-term durable remissions are possible in a substantial proportion of patients with NHL after a single short course of therapy. The analysis, presented by Richard Wahl, MD, Director of Nuclear Medicine, Vice Chairman Department of Radiology, Henry N. Wagner Jr. Professor of Nuclear Medicine, Professor of Oncology, Johns Hopkins School of Medicine, The Johns Hopkins University, Baltimore, Maryland began with an evaluation of 250 patients (mean age 52 years; range 23 to 82 years) with relapsed or refractory disease who had participated in Bexxar clinical trials. Of these 250 patients, 76 (30%) met the definition for durable response (any responding patient with an independent, blinded assessment of response and time to progression of 12 months or greater). The median follow-up for these patients was 44.6 months and ranged up to 8 years. All 76 responders received a prescribed dose of Bexxar 75 cGy to the total body.
The analysis showed that for the 76 durable responders, the rate of response was—by protocol definition—100%, and the median duration of response was 58.4 months (95% Confidence Interval (CI), 36.5-not reached), Dr. Wahl reported. The rate of complete response was 76% (58/76) with a median duration of response of 59.1 months (95% CI, 47.2-not reached). The median time to progression was 60.1 months (95% CI, 37.9-not reached).
"These results were based on a single therapeutic administration of Bexxar, and we saw a response duration of five years. The longest response we've seen has been over eight years," observed Dr. Wahl.
The patient characteristics of this patient group make the rate and duration of response all the more interesting and encouraging, Dr. Wahl noted. Most of the respondents had received 3 prior chemotherapy regimens and one-third had received more than 4 prior chemotherapy treatments. Thirty-eight percent of the patients had demonstrated no response to their last chemotherapy treatment. Eighty percent had low-grade NHL and 20% had transformed disease. Approximately 50% of the patients had bulky disease.
In an attempt to gain assurance that the beneficial effect of long-term responses did not simply result from the selection of patients with good prognostic factors, ten prognostic factors recognized to be important in NHL were examined in the 76 durable responders and in the remaining 174 patients. These included age >60 years, ≥4 prior chemotherapies, no response to last chemotherapy, prior radiotherapy, Stage IV disease, transformed histology, bone marrow involvement, elevated levels of lactate dehydrogenase (LDH), disease ≥5 cm, and modified International Prognostic Index (IPI) score ≥3.
"Using these factors, we found that 80% of durable responders to Bexxar had at least three poor prognostic features and 30% had five or more factors. However, a number of poor prognostic factors were less prevalent in the durable responder group, suggesting that prognostic factors defined in the chemotherapy experience in non-Hodgkin's lymphoma also apply to radioimmunotherapy," Dr. Wahl pointed out.
Factors found to be associated with less durable response were older age (>60 years), ≥4 prior chemotherapies, lack of response to last chemotherapy, elevated LDH, bulky disease, and modified IPI score ≥3. Dr. Wahl also indicated that nonfollicular histology was also predictive of a less favorable response, indicating that the underlying substrate is important.
"Basically, the patients who tended to have more aggressive disease and poor prognosis factors tended to have less durable responses," summarized Dr. Wahl.
Dr. Wahl said he hopes that specific biological characteristics will eventually emerge that will better characterize which patients will most benefit from Bexxar. "My hope is that the natural history of non-Hodgkin's lymphoma may be changing in a select group of patients as a result of this treatment," remarked Dr. Wahl.
Bexxar in Rituximab-refractory Follicular and Transformed NHL
Donald Podoloff, MD, of Texas Medical Center, Houston, Texas reported long-term, durable responses with Bexxar in 43% of patients (N = 35) with rituximab-refractory disease.6 This outcome was seen "despite poor prognostic factors and a stringent definition of progressive disease," stated Dr. Podoloff.
The subset was drawn from a multicenter study of Bexxar therapy in patients with low-grade (follicular small cleaved or mixed-cell, small lymphocytic), transformed low-grade, or de novo follicular large-cell NHL. Patients were included in the present retrospective analysis if they failed to respond to rituximab or had progressive disease within 6 months of therapy.
Dr. Podoloff reported that the overall response rate was 63% and median duration of response was 25.3 months (95% CI, 10.6-not reached) (Table 1). Complete responses were achieved in 29% of patients, the median duration of which had not yet been reached (95% CI, 28.3 months-not reached). Median time to progression for all patients was 11.8 months (range, 5.5 to 17.7 months). With a follow-up of 40 months, 8 patients (23%) remain in complete remission, Dr. Podoloff reported. These results led Dr. Podoloff to conclude, "Bexxar therapy is highly effective in heavily pretreated patients with low-grade and transformed low-grade non-Hodgkin's lymphoma, including those with rituximab-refractory disease."
Therapy With Bexxar in Patients with Thrombocytopenia
Also presented were results of a study showing that NHL patients with mild thrombocytopenia can be safely and effectively treated with Bexxar using an attenuated 65 cGy total body dose.3 The study was presented by Stanley J. Goldsmith, MD, Director of Nuclear Medicine, New York Presbyterian Hospital, and Professor of Radiology, Weill Medical College of Cornell University, New York, New York.
In previous studies, patients with mild thrombocytopenia (platelet count 100,000/mm3-149,999/mm3) were found to be at risk for grade 4 neutropenia and thrombocytopenia at the standard 75 cGy dose of Bexxar. In subsequent studies, such patients have received an adjusted total body dose of 65 cGy. The present study evaluated the safety and efficacy of Bexxar 65 cGy in 190 patients with mild thrombocytopenia at baseline (22% of the 870 patients in the clinical trials and an expanded access program). The patients generally had the same characteristics as the larger population, with substantial proportions of patients demonstrating a number of poor-prognosis factors such as high modified IPI ≥3 (52.3%), transformed NHL (15.8%), and bulky disease (41.3%). Their median absolute neutrophil count (ANC) was 972 cells/mm3 and median platelet count was 46,000/mm3.
In this thrombocytopenic subgroup, Bexxar at 65 cGy produced the following toxicity profile: grade 3/4 neutropenia 50% (grade 4 neutropenia, 21%); grade 3/4 thrombocytopenia 52% (grade 4 thrombocytopenia, 27%); and grade 4+ thrombocytopenia (<10,500/mm3) 5%. Supportive care was required by 31.8% of patients. Despite the 50% rate of hematologic toxicity, severe infections developed in only 3.7% and grade 3/4 gastrointestinal bleeding in only 1.6%. Adverse events occurred in 24.2% of patients.
Importantly, the attenuated dose of Bexxar for patients with mild thrombocytopenia at baseline was associated with an overall response rate of 48% (median duration of response 15.5 months; range, 5.6 months-not reached) and a complete response rate of 25% (median duration of response has not been reached); therefore, efficacy was not seemingly compromised by the reduced dose, but this was not a randomized study. The low incidence of clinical consequences associated with observed hematologic toxicity, and the good response rates, are similar to what is observed in patients with normal platelet counts receiving the 75 cGy dose, Dr. Goldsmith pointed out.
"We conclude that the incidence of grade 4 neutropenia and thrombocytopenia is acceptable in this group, and can be managed with supportive care. This study validates the dosage adjustment of Bexxar 65 cGy in patients with mild thrombocytopenia," advised Dr. Goldsmith.
Efficacy and Safety of Bexxar in Obese Patients
An analysis of Bexxar trial data showed the therapy to be safe and effective when adjusted for lean body mass in obese NHL patients.4 As background, Dr. Wahl noted that some obese patients have developed grade 4 thrombocytopenia and neutropenia on 75 cGy of Bexxar, which was determined to be caused by a lack of substantial distribution of radioantibodies into adipose tissue.
"Including the total body weight in the dose calculation increased the risk of toxicity in obese patients, so we adjusted the administered dose for obese patients to 137% of their calculated lean body mass. Using this protocol, patients' lean body mass received the desired 75 cGy total body dose," Dr. Wahl explained.
Toxicity data were analyzed for 172 obese patients (median weight 96 kg; range, 55 to 172 kg) who received 65 or 75 cGy of Bexxar, and for 698 non-obese patients (median weight 76 kg; range, 40 to 123 kg) who participated in one of 5 Bexxar clinical trials or the Expanded Access Program. Efficacy data from 23 obese patients and 164 non-obese patients were also compared.
Adverse events were significantly greater among non-obese patients (89.5% vs 83.7%; P = .05) as were grade 3/4 adverse events (68.1% vs 55.2%; P = .002). Grade 3/4 thrombocytopenia occurred in 39.2% of non-obese patients compared with 24.6% of obese patients (P<.001), and grade 3/4 neutropenia was observed in 42.7% versus 36.8%, respectively (P = .189). The incidence of grade 4 thrombocytopenia and neutropenia was similar between the treatment groups.
The overall response rate was 53% (87/164) in non-obese and 70% (16/23) in obese patients (P = .205), with complete responses reported in 30% (49/164) and 39% (9/23), respectively (P = .511). Median duration of response for non-obese patients was 13.2 months (95% CI, 10.6-36.5) in responders and 59.1 months (95% CI, 36.5-not reached) for complete responders. For obese patients, median duration of response has not been reached in responders or complete responders. Time to progression in the obese patients was 12.1 months (95% CI, 4.7-not reached) compared with 6.1 months (95% CI, 5.4-9.7) in the non-obese patients (P = .162).
Dr. Wahl noted that the demographics were similar in the obese and non-obese groups, except that non-obese subjects had a significantly higher median of prior chemotherapy regimens (3 vs 2; P = .002), which may have contributed to observed differences in toxicity.
In conclusion, Dr. Wahl advised the results of the present study demonstrated that adjusting the Bexxar dose for lean body mass provides obese patients with a well-tolerated regimen that has potential for complete and durable response.
Bexxar Administration Safe to Health Care Workers
A multicenter study that monitored a multidisciplinary group of health care workers involved in administering Bexxar concluded that the agent can be administered safely, with little or no risk to health care personnel.5 The study was conducted over a period of 4.6 years at 4 institutions and involved radiopharmacists, nuclear medicine technologists, nurses, and physicians. Participants were monitored for whole-body radiation exposure using personnel radiation film badges that were collected monthly. Radiation doses to personnel during months in which Bexxar therapy was administered were compared with those measured during months of no Bexxar therapy.
Altogether, the study monitored 20 health care workers who administered a total of approximately 13 Ci of Bexxar to 147 patients with relapsed and refractory low-grade and transformed low-grade NHL. Health care workers received 0 to 3.8 mRem per month of additional whole-body radiation dose attributable to the scanning of patients, and an additional dose of 4-10 mRem per month during compounding and/or administration of Bexxar. The average Bexxar therapy-related exposure per month per healthcare worker was 5.8 mRem.
This study demonstrated that the preparation and administration of Bexxar do not pose a measurable health risk to health care personnel; health care workers receive minimal (approximately 0.1% of the annual permissible dose) additional whole-body radiation.
The 50th Annual Meeting of the Society of Nuclear Medicine provided new and expanded information regarding the safety and efficacy of iodine-131 anti CD20 therapy. These data along with other previously-presented data indicate that Bexxar can yield long-term, durable remissions in patients with low-grade non-Hodgkin's lymphoma, even in relapsed/refractory and poor-prognosis patients. Tailored dosing is possible and routinely performed with Bexxar; an attenuated dose will safely and effectively treat patients with mild thrombocytopenia at baseline, and a dose adjusted for lean body mass will yield equivalent and safe outcomes in obese patients. Of interest to health care workers, whole-body radiation exposure is minimal and little or no risk is posed by preparing and administering this agent. In summary, data from the meeting show this form of therapy offers considerable promise for patients with non-Hodgkin's lymphoma.
1. Gallagher CJ, Gregory WM, Jones AE, et al. Follicular lymphoma: prognostic factors for response and survival. J Clin Oncol. 1986;4:1470-1480.
2. Wahl RL, Goldsmith S, Kaminski M, Stewart P, Kroll S. Bexxar produces a meaningful therapeutic benefit in the form of durable responses of 5 years in patients with relapsed and refractory low grade-non-Hodgkin's Lymphoma. J Nucl Med. 2003;44(suppl):31P. Abstract 99.
3. Goldsmith SJ, Kostakoglu L, Wahl R, et al. Bexxar (tositumomab and iodine I 131 tositumomab) is well tolerated and efficacious in heavily pretreated patients with non-Hodgkin's lymphoma (NHL) and mild thrombocytopenia. J Nucl Med. 2003;44(suppl):33P. Abstract 105.
4. Wahl R, Goldsmith SJ, Zasadny KR, Alavi A, Divgi C, Hankins J. Efficacy and safety of Bexxar (tositumomab and iodine I 131 tositumomab) in obese patients with low-grade non-Hodgkin's lymphoma. J Nucl Med. 2003;44(suppl):415P. Abstract 1478.
5. Harwood SJ, Rutar F, Sullivan G, Avionitis V. Bexxar radioimmunotherapy can be safety administered by health care professionals with minimal whole body exposure. J Nucl Med. 2003;44(suppl):327P. Abstract 1171.
6. Podoloff DA, Wahl RL, Griffeth LK. Radioimmunotherapy (RIT) with tositumomab and iodine I 131 tositumomab (Bexxar) provides long-term responses in patients with rituximab-refractory follicular and transformed non-Hodgkin's lymphoma. J Nucl Med. 2003;44(suppl):414P. Abstract 1477.