Phase I Trial of Iodine-131 Tositumomab With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Relapsed Non-Hodgkin's Lymp
http://www.100md.com
《临床肿瘤学》
the Department of Internal Medicine, Section of Hematology/Oncology, Department of Radiation Oncology, Department of Radiology, Section of Nuclear Medicine, and Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE
ABSTRACT
PATIENTS AND METHODS: Twenty-three patients with chemotherapy-refractory or multiply-relapsed B-cell NHL were treated in a phase I trial combining iodine-131 tositumomab (ranging from 0.30 to 0.75 Gy total-body dose [TBD]) with high-dose BEAM followed by ASCT.
RESULTS: The complete response rate after transplantation was 57%, and the overall response rate was 65%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 38 months (range, 27 to 60 months), the overall survival (OS) rate was 55%, and the event-free survival (EFS) rate was 39%.
CONCLUSION: There were no significant added toxicities apparent with the addition of iodine-131 tositumomab up to a dose of 0.75 Gy TBD to high-dose BEAM chemotherapy followed by ASCT. The EFS and OS were encouraging in this group of chemotherapy-resistant or refractory B-cell NHL patients. A follow-up phase II trial with iodine-131 tositumomab at the dose of 0.75 Gy TBD with BEAM is currently ongoing.
INTRODUCTION
Monoclonal antibodies such as rituximab have recently been added to the transplantation-preparative regimen, used before collecting the autologous stem cells, or in the post-transplant setting as a consolidative therapy.13,14 Additionally, a few pilot trials using radioimmunotherapy either alone or in combination with high-dose chemotherapy followed by stem-cell transplantation have recently been published.15,16 In an initial phase I study, high-dose radioimmunotherapy with iodine-131 tositumomab followed by autologous stem-cell transplantation was administered to patients with relapsed B-cell NHL.15 In subsequent studies, high-dose iodine-131 tositumomab was given with dose-intense etoposide and cyclophosphamide followed by autologous transplantation in an attempt to substitute the iodine-131 tositumomab for total-body irradiation in the transplant regimen.17 The maximum dose of iodine-131 that could be administered with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg in the combination trial was 25 Gy to critical normal organs. The preliminary results from this study were encouraging, with the estimated overall survival (OS) and progression-free survival of all treated patients at 2 years of 83% and 68%, respectively.
The high doses of iodine-131 tositumomab used with this approach require specialized facilities for the administration and radiation isolation for the patients. The phase I trial outlined in this article was designed to combine standard outpatient dosing of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation to take advantage of the additional antilymphoma effects of the radioimmunotherapy with the convenience of outpatient administration.
PATIENTS AND METHODS
Treatment Protocol
Antibody dosimetric dose. The treatment protocol is shown in Figure 1). After more than 1.5 x 106 CD34+ cells/kg of peripheral-blood progenitor cells were obtained after filgrastim mobilization, the patients received their dosimetric dose. This was given on day –19 of the transplantation protocol. Orally administered saturated solution of potassium iodide with two drops three times daily was given for thyroid blockade starting 1 day before the dosimetric dose and was continued for 14 days after the therapeutic dose. The murine monoclonal anti-CD20 (tositumomab; Corixa pharmaceuticals, Seattle, WA; and GlaxoSmithKline, Philadelphia, PA) was radio-iodinated with sodium iodine-131 (specific activity, 296 GBq/mg; New England Nuclear, Boston, MA) by the iodogen method, purified, and tested as described previously.18,19 Patients were premedicated with acetaminophen 650 mg and diphenhydramine 50 mg orally before the administration. Then patients received 450 mg of unlabeled tositumomab intravenously followed by a trace-labeled 5 mCi (35 mg) of iodine-131–labeled tositumomab dose. Vital signs were taken every 15 minutes during the antibody administration. All dosimetric and therapeutic administrations were performed in the outpatient cancer treatment area.
Within 1 hour after the dosimetric dose of iodine-131 tositumomab and before urination, a whole-body quantitative gamma camera image was obtained for baseline readings. Additional scans were performed on day 2, 3, or 4 and day 6 or 7 after the dosimetric dose. Using the information, the radioactive clearance from each patient could be obtained to determine the radioactive millicurie activity of iodine-131 tositumomab required to deliver the desired therapeutic dose 1 week later. The methodology for determining the patient-specific millicurie activity was performed in accordance with the Medical Internal Radiation Dose Primer for Absorbed Dose Calculations.20
Therapeutic infusions. One week later, on day –12 of the transplantation protocol, the therapy dose of iodine-131 tositumomab was administered on an outpatient basis. The patients were again premedicated with acetaminophen 650 mg and diphenhydramine 50 mg orally. Subsequently, 450 mg of unlabeled tositumomab was administered intravenously over 1 hour. This was followed by the patient-specific dose calculated for administration based on the whole-body gamma camera images. Patients were treated in a phase I dosing schema starting at 0.30 Gy total-body dose (TBD) and escalating by 0.15 Gy every three patients up to a maximum of 0.75 Gy TBD of iodine-131 tositumomab. Additional patients were added at the maximum-tolerated dose (MTD), which was 0.75 Gy TBD. The millicurie dose for the therapeutic dose was calculated on the basis of actual body weight for patients weighing ≤ 137% of their lean body weight and at 137% of the lean body weight for those patients weighing more than 137% of their lean body weight. Vital signs were taken every 15 minutes during the infusion of the antibody.
Outpatient release criteria were used from the Nuclear Regulatory Commission guidelines.21 These criteria authorize patient release according to a dose-based limit, which is the dose to individuals exposed to the patient (< 0.5 roetgen-equivalent-man). The dose-based limit addresses the public safety issue of radioactivity, which is governed by the Nuclear Regulatory Commission.
High-dose chemotherapy administration. Starting on day –6 of the transplantation protocol, patients received carmustine 300 mg/m2 intravenously, on days –5 to –2 they received etoposide 100 mg/m2 bid (eight doses total) and cytarabine 100 mg/m2 bid (eight doses total), and on day –1 they received melphalan 140 mg/m2 once intravenously. The following day (day 0), the patients received their previously collected unpurged autologous peripheral-blood progenitor cells. The patients received hematopoietic growth factors with either sargramostim (Leukine, granulocyte-macrophage colony-stimulating factor; Berlex, San Francisco, CA) 250 μg/m2 or filgrastim (Neupogen, granulocyte colony-stimulating factor; Amgen, Thousand Oaks, CA) 5 μg/kg subcutaneously starting on day 0 after the transplantation and continuing until the absolute neutrophil count was ≥ 500 μL for 3 consecutive days. Patients received 2 U of irradiated packed RBCs if their hemoglobin level was ≤ 8 g/dL and a single donor-irradiated platelet count if their platelet count was less than 20,000 μL. In addition, they received standard broad-spectrum antibiotic therapy for associated neutropenic fever and antifungal antibiotics for persistent fevers according to a standard transplantation protocol.
Statistical Analysis
Evaluation of toxicity. Toxic effects were assessed by using the National Cancer Institute Common Toxicity Criteria.22
Follow-up. Patients were assessed for their disease involvement before the stem-cell transplantation, at day +100 after the transplantation, and at yearly intervals after the transplantation. Patients received computed tomography of the chest, abdomen, and pelvis, physical examinations, CBC count, and chemistry profiles at these time points. In addition, if the patients had a positive bone marrow at any point, it was repeated, and optional tests also included a positron emission tomography scan or gallium scan. The patients were tested for HAMA development at baseline, day +100, 6 months, and yearly for 3 years. In addition, the patients had baseline thyroid-stimulating hormone tested, and it was repeated at day +100 and yearly thereafter. If the patients had evidence of unexplained cytopenias, a bone marrow evaluation for cytogenetics and analysis were obtained.
Statistical analysis. One of the major objectives of this study was to estimate the maximum dose of iodine-131 tositumomab (up to the 0.75 Gy TBD) when combined with a standard carmustine, etoposide, cytarabine, and melphalan (BEAM) transplant protocol. The MTD was defined as the maximum dose associated with a targeted true toxicity rate of no greater than 25% above the expected rate with BEAM alone up to the maximum dose of 0.75 Gy. Secondary objectives included the examination of potential efficacy with evaluation of the remission rate, event-free survival (EFS) and OS rates. For these purposes, the CR rate was defined as the complete disappearance of all lymph nodes greater than 1.5 cm and bone marrow positivity, and a partial response was defined as ≥ 50% reduction in the bidimensional sum of the products of all lymph nodes. Responses were evaluated according to the International Workshop Response Criteria.23 EFS and OS were calculated using the method of Kaplan and Meier.24 EFS was defined as all patients who were alive at last follow-up with no documented relapse or progression of their disease. OS was defined as all patients who were alive at their last follow-up, whether their disease had progressed or not.
RESULTS
Toxicity
The grade 3 and 4 toxicities by dose level are listed in Table 2. All patients had the expected severe myelosuppression (neutrophils < 0.5 x 109/L and platelets < 20 x 109/L) after the transplantation procedure. The median time to neutrophil engraftment (the first of 3 consecutive days of neutrophils ≥ 0.5 x 109/L) was 10 days, the median time to platelet independence (the first of 7 consecutive days with a platelet count ≥ 20,000 μL) was 12 days, and the median time to RBC transfusion independence (the first of 30 consecutive days of a hemoglobin level ≥ 8 gm/dL) was 9 days. These were similar to historical control patients receiving BEAM alone, in which the median time to neutrophil engraftment was 10 days, the median time to platelet engraftment was 12 days, and the median time to RBC transfusion independence was 10 days (P = not significant). Nonhematologic toxicity was similar to controls as well, with an excess of 90% of patients having a neutropenic fever. Six patients had pulmonary abnormalities on chest radiographs, which were transient. In addition, two patients had transient renal insufficiency owing to hemoglobinemia (n = 1) or sepsis syndrome (n = 1). One patient had cardiac arrhythmias, which were transient. The median mucositis score was reported as 16 according to the oral mucositis scale.25 This was slightly higher but not statistically different from the median mucositis score of 14 in the historical control patients treated with BEAM alone. There were no deaths within the first 100 days after the transplantation procedure.
Determination of MTD
Doses were escalated by 0.15 Gy TBD according to the protocol, starting at 0.30 Gy TBD of iodine-131 tositumomab. Three assessable patients were treated at each dose level before proceeding to the next dose level. The patients needed to reach at least 6 weeks after transplantation before proceeding to the next dose, so that the engraftment of the patients at that dose could be evaluated. If an additional eligible patient was seen before that time was reached, they were added at the lower dose cohort. If no unexpected grade 3 or 4 toxicities were identified in the patients, the next dose cohort was initiated. The maximum dose in the protocol was 0.75 Gy TBD for the iodine-131 tositumomab administration. No unexpected grade 3 or 4 toxicities were seen in this study, and therefore the MTD was 0.75 Gy TBD, and six additional patients were added at this dose level.
Response to Therapy
The response rate was assessed at day +100 after the transplant. The CR rate was six (26%) of 23 patients, and the CR undetermined was seven (30%) of 23 patients. The total CR rate was 13 (57%) of 23 patients. The partial response rate was two (9%) of 23 patients, for an OS rate of 15 (65%) of 23 patients.
OS and EFS
With a median follow-up of 38 months (range, 27 to 60 months), 11 patients developed progressive disease. Eight of these patients have died, and three patients remain alive after progression. One patient died of septic shock at 34 months after transplantation with prolonged cytopenias owing to MDS without evidence of NHL progression. The 3-year EFS rate is 39% (Fig 2), and the 3-year OS rate is 55% (Fig 3).
Long-Term Complications
Eight patients (35%) developed asymptomatic HAMA (3 to 12 months after therapy), and no patients developed hypothyroidism. Two patients developed MDS at 26 and 29 months after transplantation. One of the patients died of progressive lymphoma at 32 months after transplantation, and the other patient died of sepsis without lymphoma progression at 34 months after transplantation. Both patients had cytogenetic abnormalities at the time of MDS development consistent with alkylating agent exposure, cumulative chemotherapy, and/or radiotherapy, with monosomy 5 and monosomy 7, respectively. Both patients who developed MDS had been heavily treated before transplantation. One patient had received cyclophosphamide, doxorubicin, vincristine, and prednisone x 6; navelbine x 1; fludarabine, mitoxantrone, and dexamethasone x 4; rituximab x 4; and etoposide, prednisone, cytarabine, and cisplatin x 4. The other patient who developed MDS had received localized radiation therapy 36 Gy to the groin; cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone x 2; localized radiation therapy (36 Gy) to the axilla; cyclophosphamide, mitoxantrone, vincristine, and prednisone x 6; and dexamethasone, cytarabine, and cisplatin x 2. This rate of MDS is similar to that published previously for heavily treated patients who receive high-dose chemotherapy and autologous stem-cell transplantation for lymphoma with standard chemotherapy and/or chemoradiotherapy protocols.26,27 However, the contribution of the radioimmunoconjugate to the development of MDS is unknown at this time.
DISCUSSION
Radiolabeled monoclonal antibodies have recently emerged as an effective new treatment for patients with relapsed B-cell lymphomas.18,19 Studies using radioimmunotherapy at nonmyeloablative doses have produced response rates of 60% to 80% for iodine-131 and yttrium-90–labeled anti-CD20 antibodies.18,29 The median duration of responses varied from 6 to 18 months in these trials; however, some CRs have been maintained for up to 8 years.30
Because myelotoxicity is the major toxicity associated with radioimmunotherapy, it is an ideal candidate to combine with high-dose chemotherapy and autologous stem-cell transplantation. The majority of the early studies combining radioimmunotherapy with transplantation have included high-dose myeloablative iodine-131 tositumomab either alone16 or in combination with high-dose etoposide and cyclophosphamide.17 The single-agent myeloablative regimen tested in patients with a variety of relapsed lymphomas produced OS rates and progression-free survival rates of 68% and 42%, respectively.31 The combination regimen of etoposide and cyclophosphamide with myeloablative iodine-131 tositumomab and autologous stem-cell transplantation produced OS and progression-free survival rates of 83% and 68%, respectively, in patients with chemotherapy-sensitive relapsed NHL.17 In addition, high-dose yttrium-90 ibritumomab has also recently been used as part of a conditioning regimen for autologous stem-cell transplantation, with promising results.32
However, a concern with these high-dose myeloablative regimens is the radiation safety concerns and specialized facilities necessary for the administration of these agents. In addition, the cost associated with an escalated dose of radioimmunotherapy may be prohibitive. In an effort to include radioimmunotherapy as part of a transplantation conditioning regimen at standard outpatient dosing, this regimen was developed. This trial was a phase I trial combining standard dose iodine-131 tositumomab in a dose-escalation format (0.30 to 0.75 Gy) with a standard BEAM transplantation protocol.
This pilot trial was conducted in patients who had good end organ function and were able to obtain adequate autologous stem cells for transplantation. However, these patients had multiply pretreated aggressive lymphomas, and many of these patients would not be considered for a standard autologous transplant because of the lymphoma resistant state. The results obtained were quite promising, with a total CR rate of 57% and an OR rate of 65%. In addition, with a follow-up of 38 months, the OS rate is 55% and the EFS rate is 39%. In most prior studies in such chemotherapy-resistant lymphoma patients, the results of transplantation demonstrate between 10% and 20% survival at a comparable time point.7,8 We have been encouraged by these preliminary results and the limited additional toxicity of the addition of outpatient iodine-131 tositumomab to the transplantation program. A larger phase II study adding 0.75 Gy TBD iodine-131 tositumomab to BEAM and autologous transplantation in patients with chemotherapy-sensitive relapsed diffuse large B-cell lymphoma is ongoing at our institution. A large phase III study to compare this technique with current standard autologous transplantation techniques, such as the addition of rituximab to the transplantation regimen, will be needed to document any additional efficacy of this approach.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
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2. Shipp MA, Harrington DP, Klatt MM, et al: Identification of major prognostic subgroups of patients with large cell lymphoma treated with m-BACOD or M-BACOD. Ann Intern Med 104:757-765, 1986
3. Gordon LI, Harrington D, Andersen J, et al: Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin's lymphoma. N Engl J Med 327:1342-1349, 1992
4. Velasquez WS, Lew D, Grogan TM, et al: Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501. J Clin Oncol 21:1996-2003, 2003
5. Horning SJ: Treatment approaches to the low-grade lymphomas. Blood 83:881-884, 1994
6. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333:1540-1545, 1995
7. Philip T, Armitage JO, Spitzer G, et al: High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults and intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 316:1493-1498, 1987
8. Vose JM, Zhang MJ, Rowlings PA, et al: Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: A report from the autologous blood and marrow transplant registry. J Clin Oncol 19:406-413, 2001
9. Sutcliffe SB, Gospodarowicz MK, Bush RS, et al: Role of radiation therapy in localized non-Hodgkin's lymphoma. Radiother Oncol 4:211-223, 1985
10. Mac Manus MP, Hoppe RT: Is radiotherapy curative for stage I and II low-grade follicular lymphoma Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 14:1282-1290, 1996
11. Horning SJ, Negrin RS, Chao JC, et al: Fractionated total-body irradiation, etoposide, and cyclophosphamide plus autografting in Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol 12:2552-2558, 1994
12. Gutierrez-Delgado F, Maloney D, Press O, et al: Autologous stem cell transplantation for non-Hodgkin's lymphoma: Comparison of radiation-based and chemotherapy-only preparative regimens. Bone Marrow Transplant 28:455-461, 2001
13. Gianni AM, Magni M, Martelli M, et al: Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). Blood 102:749-755, 2003
14. Horwitz SM, Negrin RS, Blume KG, et al: Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin's lymphoma. Blood 103:777-783, 2004
15. Press OW, Eary J, Appelbaum FR, et al: Radiolabeled antibody therapy of B cell lymphomas with autologous bone marrow support. N Engl J Med 329:1219-1224, 1993
16. Press OW, Eary JF, Appelbaum FR, et al: A phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet 346:336-340, 1995
17. Press OW, Eary JF, Gooley T, et al: A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. Blood 96:2934-2942, 2000
18. Vose JM, Wahl RL, Saleh M, et al: Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol 18:1316-1323, 2000
19. Kaminiski MS, Zelenetz AD, Press OW, et al: Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol 19:3918-3928, 2001
20. Loevinger R, Budinger TF, Watson EE: MIRD Primer for Absorbed Dose Calculations. Reston, VA, The Society of Nuclear Medicine Inc, 1988
21. Siegel JA: Revised Nuclear Regulatory Commission regulations for release of patients administered radioactive materials: Outpatient iodine-131 Anti-B1 therapy. J Nucl Med 39:28S-33S, 1998
22. National Cancer Institute: NCI toxicity criteria. http://ctep.cancer.gov
23. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI Sponsored International Working Group. J Clin Oncol 17:1244-1253, 1999
24. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
25. Sonis ST, Oster G, Fuchs H, et al: Oral mucositis and the clinical and economic outcomes of hematopoietic stem cell transplantation. J Clin Oncol 19:2201-2205, 2001
26. Darrington DL, Vose JM, Anderson JR, et al: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem cell transplantation for lymphoid malignancies. J Clin Oncol 12:2527-2534, 1994
27. Metayer C, Curtis RE, Vose J, et al: Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: A multicenter case-control study. Blood 101:2015-2023, 2003
28. Stiff P, Dahlberg S, Forman SJ, et al: Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: Value of augmented preparative regimens—A Southwest Oncology Group trial. J Clin Oncol 16:48-55, 1998
29. Witzig TE, White CA, Wiseman GA, et al: Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell non-Hodgkin's lymphoma. J Clin Oncol 17:3793-3803, 1999
30. Coleman M, Kaminski MS, Knox SJ, et al: The Bexxar Therapeutic regimen (tositumomab and iodine I 131 tositumomab) produced durable complete remissions in heavily pretreated patients with non-Hodgkin's lymphoma (NHL), rituximab-relapsed/refractory disease, and rituximab-nave disease. Blood 102:29, 2003 (abstr 89a)
31. Lui SY, Eary JF, Petersdorf SH, et al: Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem cell rescue. J Clin Oncol 16:3270-3278, 1998
32. Nademanee A, Molina A, Forman SJ, et al: A phase I/II trial of high-dose radioimmunotherapy (RIT) with Zevalin in combination with high-dose etoposide (VP-16) and cyclophosphamide (Cy) followed by autologous stem cell transplant (ASCT) in patients with poor-risk or relapsed B-cell non-Hodgkin's lymphoma (NHL). Blood 100:182, 2002 (abstr 679a)(Julie M. Vose, Philip J. )
ABSTRACT
PATIENTS AND METHODS: Twenty-three patients with chemotherapy-refractory or multiply-relapsed B-cell NHL were treated in a phase I trial combining iodine-131 tositumomab (ranging from 0.30 to 0.75 Gy total-body dose [TBD]) with high-dose BEAM followed by ASCT.
RESULTS: The complete response rate after transplantation was 57%, and the overall response rate was 65%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 38 months (range, 27 to 60 months), the overall survival (OS) rate was 55%, and the event-free survival (EFS) rate was 39%.
CONCLUSION: There were no significant added toxicities apparent with the addition of iodine-131 tositumomab up to a dose of 0.75 Gy TBD to high-dose BEAM chemotherapy followed by ASCT. The EFS and OS were encouraging in this group of chemotherapy-resistant or refractory B-cell NHL patients. A follow-up phase II trial with iodine-131 tositumomab at the dose of 0.75 Gy TBD with BEAM is currently ongoing.
INTRODUCTION
Monoclonal antibodies such as rituximab have recently been added to the transplantation-preparative regimen, used before collecting the autologous stem cells, or in the post-transplant setting as a consolidative therapy.13,14 Additionally, a few pilot trials using radioimmunotherapy either alone or in combination with high-dose chemotherapy followed by stem-cell transplantation have recently been published.15,16 In an initial phase I study, high-dose radioimmunotherapy with iodine-131 tositumomab followed by autologous stem-cell transplantation was administered to patients with relapsed B-cell NHL.15 In subsequent studies, high-dose iodine-131 tositumomab was given with dose-intense etoposide and cyclophosphamide followed by autologous transplantation in an attempt to substitute the iodine-131 tositumomab for total-body irradiation in the transplant regimen.17 The maximum dose of iodine-131 that could be administered with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg in the combination trial was 25 Gy to critical normal organs. The preliminary results from this study were encouraging, with the estimated overall survival (OS) and progression-free survival of all treated patients at 2 years of 83% and 68%, respectively.
The high doses of iodine-131 tositumomab used with this approach require specialized facilities for the administration and radiation isolation for the patients. The phase I trial outlined in this article was designed to combine standard outpatient dosing of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation to take advantage of the additional antilymphoma effects of the radioimmunotherapy with the convenience of outpatient administration.
PATIENTS AND METHODS
Treatment Protocol
Antibody dosimetric dose. The treatment protocol is shown in Figure 1). After more than 1.5 x 106 CD34+ cells/kg of peripheral-blood progenitor cells were obtained after filgrastim mobilization, the patients received their dosimetric dose. This was given on day –19 of the transplantation protocol. Orally administered saturated solution of potassium iodide with two drops three times daily was given for thyroid blockade starting 1 day before the dosimetric dose and was continued for 14 days after the therapeutic dose. The murine monoclonal anti-CD20 (tositumomab; Corixa pharmaceuticals, Seattle, WA; and GlaxoSmithKline, Philadelphia, PA) was radio-iodinated with sodium iodine-131 (specific activity, 296 GBq/mg; New England Nuclear, Boston, MA) by the iodogen method, purified, and tested as described previously.18,19 Patients were premedicated with acetaminophen 650 mg and diphenhydramine 50 mg orally before the administration. Then patients received 450 mg of unlabeled tositumomab intravenously followed by a trace-labeled 5 mCi (35 mg) of iodine-131–labeled tositumomab dose. Vital signs were taken every 15 minutes during the antibody administration. All dosimetric and therapeutic administrations were performed in the outpatient cancer treatment area.
Within 1 hour after the dosimetric dose of iodine-131 tositumomab and before urination, a whole-body quantitative gamma camera image was obtained for baseline readings. Additional scans were performed on day 2, 3, or 4 and day 6 or 7 after the dosimetric dose. Using the information, the radioactive clearance from each patient could be obtained to determine the radioactive millicurie activity of iodine-131 tositumomab required to deliver the desired therapeutic dose 1 week later. The methodology for determining the patient-specific millicurie activity was performed in accordance with the Medical Internal Radiation Dose Primer for Absorbed Dose Calculations.20
Therapeutic infusions. One week later, on day –12 of the transplantation protocol, the therapy dose of iodine-131 tositumomab was administered on an outpatient basis. The patients were again premedicated with acetaminophen 650 mg and diphenhydramine 50 mg orally. Subsequently, 450 mg of unlabeled tositumomab was administered intravenously over 1 hour. This was followed by the patient-specific dose calculated for administration based on the whole-body gamma camera images. Patients were treated in a phase I dosing schema starting at 0.30 Gy total-body dose (TBD) and escalating by 0.15 Gy every three patients up to a maximum of 0.75 Gy TBD of iodine-131 tositumomab. Additional patients were added at the maximum-tolerated dose (MTD), which was 0.75 Gy TBD. The millicurie dose for the therapeutic dose was calculated on the basis of actual body weight for patients weighing ≤ 137% of their lean body weight and at 137% of the lean body weight for those patients weighing more than 137% of their lean body weight. Vital signs were taken every 15 minutes during the infusion of the antibody.
Outpatient release criteria were used from the Nuclear Regulatory Commission guidelines.21 These criteria authorize patient release according to a dose-based limit, which is the dose to individuals exposed to the patient (< 0.5 roetgen-equivalent-man). The dose-based limit addresses the public safety issue of radioactivity, which is governed by the Nuclear Regulatory Commission.
High-dose chemotherapy administration. Starting on day –6 of the transplantation protocol, patients received carmustine 300 mg/m2 intravenously, on days –5 to –2 they received etoposide 100 mg/m2 bid (eight doses total) and cytarabine 100 mg/m2 bid (eight doses total), and on day –1 they received melphalan 140 mg/m2 once intravenously. The following day (day 0), the patients received their previously collected unpurged autologous peripheral-blood progenitor cells. The patients received hematopoietic growth factors with either sargramostim (Leukine, granulocyte-macrophage colony-stimulating factor; Berlex, San Francisco, CA) 250 μg/m2 or filgrastim (Neupogen, granulocyte colony-stimulating factor; Amgen, Thousand Oaks, CA) 5 μg/kg subcutaneously starting on day 0 after the transplantation and continuing until the absolute neutrophil count was ≥ 500 μL for 3 consecutive days. Patients received 2 U of irradiated packed RBCs if their hemoglobin level was ≤ 8 g/dL and a single donor-irradiated platelet count if their platelet count was less than 20,000 μL. In addition, they received standard broad-spectrum antibiotic therapy for associated neutropenic fever and antifungal antibiotics for persistent fevers according to a standard transplantation protocol.
Statistical Analysis
Evaluation of toxicity. Toxic effects were assessed by using the National Cancer Institute Common Toxicity Criteria.22
Follow-up. Patients were assessed for their disease involvement before the stem-cell transplantation, at day +100 after the transplantation, and at yearly intervals after the transplantation. Patients received computed tomography of the chest, abdomen, and pelvis, physical examinations, CBC count, and chemistry profiles at these time points. In addition, if the patients had a positive bone marrow at any point, it was repeated, and optional tests also included a positron emission tomography scan or gallium scan. The patients were tested for HAMA development at baseline, day +100, 6 months, and yearly for 3 years. In addition, the patients had baseline thyroid-stimulating hormone tested, and it was repeated at day +100 and yearly thereafter. If the patients had evidence of unexplained cytopenias, a bone marrow evaluation for cytogenetics and analysis were obtained.
Statistical analysis. One of the major objectives of this study was to estimate the maximum dose of iodine-131 tositumomab (up to the 0.75 Gy TBD) when combined with a standard carmustine, etoposide, cytarabine, and melphalan (BEAM) transplant protocol. The MTD was defined as the maximum dose associated with a targeted true toxicity rate of no greater than 25% above the expected rate with BEAM alone up to the maximum dose of 0.75 Gy. Secondary objectives included the examination of potential efficacy with evaluation of the remission rate, event-free survival (EFS) and OS rates. For these purposes, the CR rate was defined as the complete disappearance of all lymph nodes greater than 1.5 cm and bone marrow positivity, and a partial response was defined as ≥ 50% reduction in the bidimensional sum of the products of all lymph nodes. Responses were evaluated according to the International Workshop Response Criteria.23 EFS and OS were calculated using the method of Kaplan and Meier.24 EFS was defined as all patients who were alive at last follow-up with no documented relapse or progression of their disease. OS was defined as all patients who were alive at their last follow-up, whether their disease had progressed or not.
RESULTS
Toxicity
The grade 3 and 4 toxicities by dose level are listed in Table 2. All patients had the expected severe myelosuppression (neutrophils < 0.5 x 109/L and platelets < 20 x 109/L) after the transplantation procedure. The median time to neutrophil engraftment (the first of 3 consecutive days of neutrophils ≥ 0.5 x 109/L) was 10 days, the median time to platelet independence (the first of 7 consecutive days with a platelet count ≥ 20,000 μL) was 12 days, and the median time to RBC transfusion independence (the first of 30 consecutive days of a hemoglobin level ≥ 8 gm/dL) was 9 days. These were similar to historical control patients receiving BEAM alone, in which the median time to neutrophil engraftment was 10 days, the median time to platelet engraftment was 12 days, and the median time to RBC transfusion independence was 10 days (P = not significant). Nonhematologic toxicity was similar to controls as well, with an excess of 90% of patients having a neutropenic fever. Six patients had pulmonary abnormalities on chest radiographs, which were transient. In addition, two patients had transient renal insufficiency owing to hemoglobinemia (n = 1) or sepsis syndrome (n = 1). One patient had cardiac arrhythmias, which were transient. The median mucositis score was reported as 16 according to the oral mucositis scale.25 This was slightly higher but not statistically different from the median mucositis score of 14 in the historical control patients treated with BEAM alone. There were no deaths within the first 100 days after the transplantation procedure.
Determination of MTD
Doses were escalated by 0.15 Gy TBD according to the protocol, starting at 0.30 Gy TBD of iodine-131 tositumomab. Three assessable patients were treated at each dose level before proceeding to the next dose level. The patients needed to reach at least 6 weeks after transplantation before proceeding to the next dose, so that the engraftment of the patients at that dose could be evaluated. If an additional eligible patient was seen before that time was reached, they were added at the lower dose cohort. If no unexpected grade 3 or 4 toxicities were identified in the patients, the next dose cohort was initiated. The maximum dose in the protocol was 0.75 Gy TBD for the iodine-131 tositumomab administration. No unexpected grade 3 or 4 toxicities were seen in this study, and therefore the MTD was 0.75 Gy TBD, and six additional patients were added at this dose level.
Response to Therapy
The response rate was assessed at day +100 after the transplant. The CR rate was six (26%) of 23 patients, and the CR undetermined was seven (30%) of 23 patients. The total CR rate was 13 (57%) of 23 patients. The partial response rate was two (9%) of 23 patients, for an OS rate of 15 (65%) of 23 patients.
OS and EFS
With a median follow-up of 38 months (range, 27 to 60 months), 11 patients developed progressive disease. Eight of these patients have died, and three patients remain alive after progression. One patient died of septic shock at 34 months after transplantation with prolonged cytopenias owing to MDS without evidence of NHL progression. The 3-year EFS rate is 39% (Fig 2), and the 3-year OS rate is 55% (Fig 3).
Long-Term Complications
Eight patients (35%) developed asymptomatic HAMA (3 to 12 months after therapy), and no patients developed hypothyroidism. Two patients developed MDS at 26 and 29 months after transplantation. One of the patients died of progressive lymphoma at 32 months after transplantation, and the other patient died of sepsis without lymphoma progression at 34 months after transplantation. Both patients had cytogenetic abnormalities at the time of MDS development consistent with alkylating agent exposure, cumulative chemotherapy, and/or radiotherapy, with monosomy 5 and monosomy 7, respectively. Both patients who developed MDS had been heavily treated before transplantation. One patient had received cyclophosphamide, doxorubicin, vincristine, and prednisone x 6; navelbine x 1; fludarabine, mitoxantrone, and dexamethasone x 4; rituximab x 4; and etoposide, prednisone, cytarabine, and cisplatin x 4. The other patient who developed MDS had received localized radiation therapy 36 Gy to the groin; cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone x 2; localized radiation therapy (36 Gy) to the axilla; cyclophosphamide, mitoxantrone, vincristine, and prednisone x 6; and dexamethasone, cytarabine, and cisplatin x 2. This rate of MDS is similar to that published previously for heavily treated patients who receive high-dose chemotherapy and autologous stem-cell transplantation for lymphoma with standard chemotherapy and/or chemoradiotherapy protocols.26,27 However, the contribution of the radioimmunoconjugate to the development of MDS is unknown at this time.
DISCUSSION
Radiolabeled monoclonal antibodies have recently emerged as an effective new treatment for patients with relapsed B-cell lymphomas.18,19 Studies using radioimmunotherapy at nonmyeloablative doses have produced response rates of 60% to 80% for iodine-131 and yttrium-90–labeled anti-CD20 antibodies.18,29 The median duration of responses varied from 6 to 18 months in these trials; however, some CRs have been maintained for up to 8 years.30
Because myelotoxicity is the major toxicity associated with radioimmunotherapy, it is an ideal candidate to combine with high-dose chemotherapy and autologous stem-cell transplantation. The majority of the early studies combining radioimmunotherapy with transplantation have included high-dose myeloablative iodine-131 tositumomab either alone16 or in combination with high-dose etoposide and cyclophosphamide.17 The single-agent myeloablative regimen tested in patients with a variety of relapsed lymphomas produced OS rates and progression-free survival rates of 68% and 42%, respectively.31 The combination regimen of etoposide and cyclophosphamide with myeloablative iodine-131 tositumomab and autologous stem-cell transplantation produced OS and progression-free survival rates of 83% and 68%, respectively, in patients with chemotherapy-sensitive relapsed NHL.17 In addition, high-dose yttrium-90 ibritumomab has also recently been used as part of a conditioning regimen for autologous stem-cell transplantation, with promising results.32
However, a concern with these high-dose myeloablative regimens is the radiation safety concerns and specialized facilities necessary for the administration of these agents. In addition, the cost associated with an escalated dose of radioimmunotherapy may be prohibitive. In an effort to include radioimmunotherapy as part of a transplantation conditioning regimen at standard outpatient dosing, this regimen was developed. This trial was a phase I trial combining standard dose iodine-131 tositumomab in a dose-escalation format (0.30 to 0.75 Gy) with a standard BEAM transplantation protocol.
This pilot trial was conducted in patients who had good end organ function and were able to obtain adequate autologous stem cells for transplantation. However, these patients had multiply pretreated aggressive lymphomas, and many of these patients would not be considered for a standard autologous transplant because of the lymphoma resistant state. The results obtained were quite promising, with a total CR rate of 57% and an OR rate of 65%. In addition, with a follow-up of 38 months, the OS rate is 55% and the EFS rate is 39%. In most prior studies in such chemotherapy-resistant lymphoma patients, the results of transplantation demonstrate between 10% and 20% survival at a comparable time point.7,8 We have been encouraged by these preliminary results and the limited additional toxicity of the addition of outpatient iodine-131 tositumomab to the transplantation program. A larger phase II study adding 0.75 Gy TBD iodine-131 tositumomab to BEAM and autologous transplantation in patients with chemotherapy-sensitive relapsed diffuse large B-cell lymphoma is ongoing at our institution. A large phase III study to compare this technique with current standard autologous transplantation techniques, such as the addition of rituximab to the transplantation regimen, will be needed to document any additional efficacy of this approach.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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