Radiation dosimetry results for zevalin radioimmunotherapy of rituximab-refractory non-hodgkin lymphoma

Authors

  • Gregory A. Wiseman M.D.,

    Corresponding author
    1. Division of Nuclear Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
    • Division of Nuclear Medicine, Mayo Clinic and Mayo Foundation, Charlton Building, 1-227, 200 First Street S.W., Rochester, MN 55905===

    Search for more papers by this author
    • Fax: (507) 266-4461

  • Bryan Leigh M.D.,

    1. IDEC Pharmaceuticals Corporation, San Diego, California
    Search for more papers by this author
    • Bryan Leigh and Christine A. White are employees and stockholders of IDEC Pharmaceuticals Corporation; Dominick Lamonica, Daniel H. S. Silverman, and Ellen Kornmehl are consultants for IDEC; Richard Sparks is a former IDEC consultant; Ellen Kornmehl has received honoraria from IDEC for commissioned papers; Stewart M. Spies has received speaking honoraria and travel support from IDEC.

  • William D. Erwin M.S.,

    1. Department of Radiology, Northwestern University and Robert H. Lurie Cancer Center, Chicago, Illinois
    Search for more papers by this author
  • Dominick Lamonica M.D.,

    1. Department of Nuclear Medicine, Roswell Park Cancer Center, Buffalo, New York
    Search for more papers by this author
    • Bryan Leigh and Christine A. White are employees and stockholders of IDEC Pharmaceuticals Corporation; Dominick Lamonica, Daniel H. S. Silverman, and Ellen Kornmehl are consultants for IDEC; Richard Sparks is a former IDEC consultant; Ellen Kornmehl has received honoraria from IDEC for commissioned papers; Stewart M. Spies has received speaking honoraria and travel support from IDEC.

  • Ellen Kornmehl M.D.,

    1. Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts
    Search for more papers by this author
    • Bryan Leigh and Christine A. White are employees and stockholders of IDEC Pharmaceuticals Corporation; Dominick Lamonica, Daniel H. S. Silverman, and Ellen Kornmehl are consultants for IDEC; Richard Sparks is a former IDEC consultant; Ellen Kornmehl has received honoraria from IDEC for commissioned papers; Stewart M. Spies has received speaking honoraria and travel support from IDEC.

  • Stewart M. Spies M.D.,

    1. Department of Radiology, Northwestern University and Robert H. Lurie Cancer Center, Chicago, Illinois
    Search for more papers by this author
    • Bryan Leigh and Christine A. White are employees and stockholders of IDEC Pharmaceuticals Corporation; Dominick Lamonica, Daniel H. S. Silverman, and Ellen Kornmehl are consultants for IDEC; Richard Sparks is a former IDEC consultant; Ellen Kornmehl has received honoraria from IDEC for commissioned papers; Stewart M. Spies has received speaking honoraria and travel support from IDEC.

  • Daniel H. S. Silverman M.D.,

    1. Nuclear Medicine, Ahmanson Biochemical Imaging Center, UCLA Medical Center, Los Angeles, California
    Search for more papers by this author
    • Bryan Leigh and Christine A. White are employees and stockholders of IDEC Pharmaceuticals Corporation; Dominick Lamonica, Daniel H. S. Silverman, and Ellen Kornmehl are consultants for IDEC; Richard Sparks is a former IDEC consultant; Ellen Kornmehl has received honoraria from IDEC for commissioned papers; Stewart M. Spies has received speaking honoraria and travel support from IDEC.

  • Thomas E. Witzig M.D.,

    1. Division of Nuclear Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
    Search for more papers by this author
  • Richard B. Sparks Ph.D.,

    1. Oak Ridge Associated Universities, Oak Ridge, Tennessee
    Search for more papers by this author
    • Bryan Leigh and Christine A. White are employees and stockholders of IDEC Pharmaceuticals Corporation; Dominick Lamonica, Daniel H. S. Silverman, and Ellen Kornmehl are consultants for IDEC; Richard Sparks is a former IDEC consultant; Ellen Kornmehl has received honoraria from IDEC for commissioned papers; Stewart M. Spies has received speaking honoraria and travel support from IDEC.

  • Christine A. White M.D.

    1. IDEC Pharmaceuticals Corporation, San Diego, California
    Search for more papers by this author
    • Bryan Leigh and Christine A. White are employees and stockholders of IDEC Pharmaceuticals Corporation; Dominick Lamonica, Daniel H. S. Silverman, and Ellen Kornmehl are consultants for IDEC; Richard Sparks is a former IDEC consultant; Ellen Kornmehl has received honoraria from IDEC for commissioned papers; Stewart M. Spies has received speaking honoraria and travel support from IDEC.


Abstract

BACKGROUND

Zevalin consists of a murine anti-CD20 monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates indium-111 (111In) for imaging and dosimetry and yttrium-90 (90Y) for radioimmunotherapy (RIT). Previous trials involving rituximab-naïve patients have demonstrated excellent targeting of Zevalin to CD20+ B-cell non-Hodgkin lymphoma with minimal uptake in normal organs. The purpose of this trial was to perform 111In-Zevalin imaging in patients with rituximab-refractory tumors to determine normal organ dosimetry.

METHODS

Twenty-seven patients were given an imaging dose of 5 mCi (185 MBq) 111In-Zevalin on Day 0, evaluated with dosimetry, and then given a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y-Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m2 rituximab to clear peripheral B cells and improve Zevalin biodistribution. Residence times for 90Y in blood and major organs were estimated from 111In biodistribution, and the MIRDOSE3 computer software program was used to calculate absorbed radiation doses to organs and red marrow.

RESULTS

Median estimated absorbed radiation doses from 90Y-Zevalin were 8.1 Gray (Gy) (range, 4.2–23.0 Gy) to the spleen, 5.1 Gy (range, 2.6–12.0 Gy) to the liver, 2.0 Gy (range, 1.4–5.3 Gy) to the lungs, 0.22 Gy (range, < 0.01–0.66 Gy) to the kidneys, and 0.74 Gy (range, 0.29–1.2 Gy) to the red marrow. These results are consistent with those from earlier Zevalin trials in rituximab-naïve patients. Hematologic toxicity was manageable and did not correlate with estimates of red marrow or total-body absorbed radiation dose.

CONCLUSIONS

Zevalin treatment of rituximab-refractory follicular NHL patients at 0.4 mCi/kg resulted in acceptable estimates of absorbed radiation dose to organs, similar to those observed in other Zevalin-treated populations. Cancer 2002;94:1349–57. © 2002 American Cancer Society.

DOI 10.1002/cncr.10305

Radioimmunotherapy (RIT) selectively delivers ionizing radiation to tumor cells while limiting the irradiation of normal tissues. Pretreatment dosimetry has been used with RIT to estimate absorbed radiation doses to organs and red marrow, and to ensure that the delivered doses remain within a safe range. However, mounting clinical experience with Zevalin (IDEC Pharmaceuticals Co., San Diego, CA) RIT suggests that dosimetry can be safely eliminated in defined patient populations when standardized weight-adjusted dosing is used.1, 2

Zevalin consists of a murine immunoglobulin IgG1 kappa anti-CD20 monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan (MX-DTPA), which is capable of securely chelating indium-111 (111In) (Amersham Health, Buckinghamshire, United Kingdom) for imaging and dosimetry and yttrium-90 (90Y) (Amersham Health, Buckinghamshire, United Kingdom) for RIT.3 Zevalin targets the CD20 antigen, a 35-kD phosphoprotein present on normal B lymphocytes and the majority of B-cell lymphomas.4, 5 Prior to administering Zevalin, an infusion of unlabeled chimeric anti-CD20 antibody (rituximab) is given to clear peripheral B cells and improve biodistribution of the radiolabeled antibody.

90Y is attractive for use as a therapeutic radionuclide, with several features that are advantageous for clinical RIT. Intermediate- to long-range high-energy beta emissions (maximum energy, 2.3 MeV) are capable of delivering energy 5 mm away from the antibody.6 This extended beta range may be especially advantageous in the treatment of bulky or poorly vascularized tumors. 90Y has a 64-hour half-life, which approximates the biologic half-life of the radiolabeled antibody. Because 90Y has no penetrating gamma irradiation, radiotoxicity to nontarget organs is minimized and patient shielding is unnecessary.

For Zevalin imaging, the medium-energy gamma emitter 111In is employed as a radioconjugate. 111In has optimal imaging characteristics to facilitate dosimetry. Preclinical studies have demonstrated that biodistribution of the 90Y-labeled antibody is reliably predicted by the 111In-labeled antibody.3, 7 The radiolabeled antibody stably retains the 90Y radionuclide in vitro; 96-hour incubation indicates an average of only 1% loss of 90Y per day from the antibody conjugate.3

This report describes the dosimetry results of a multicenter, Phase III, open-label, nonrandomized, controlled trial designed to evaluate the efficacy and safety of Zevalin RIT in patients with rituximab-refractory follicular B-cell non-Hodgkin lymphoma (NHL). The role of pretreatment dosimetry as part of the Zevalin regimen is then discussed for this defined population.

Materials and Methods

Patient Population

This Phase III trial enrolled a total of 57 patients, of whom 27 were assessed with dosimetry. The study population included patients age ≥ 18 years with histologically confirmed follicular NHL (International Working Formulation [IWF] B, C, and D, also defined as revised European-American classification Follicular Center Grades I, II, and III) who were previously treated with rituximab 375 mg/m2 × 4, and who either 1) did not experience a partial response (PR) or complete response (CR) to the most recent treatment and had disease progression at the time of our study, or 2) had disease progression within 6 months of the first rituximab infusion. Patients with either IWF A or transformed B-cell NHL who were treated on the rituximab control arm of an associated clinical trial and did not achieve a PR or CR were also eligible for treatment to expand the safety and dosimetry experience, but were prospectively not to be included in the efficacy analysis. Eligibility required the presence of bidimensionally measurable disease with at least one lesion measuring ≥ 2.0 cm in a single dimension; a prestudy performance status of 0, 1, or 2 according to the World Health Organization scale; acceptable hematologic status within 2 weeks prior to initial treatment (absolute neutrophil count ≥ 1500/mm3, total lymphocyte count < 5000/mm3 for patients with small lymphocytic lymphoma, and platelets ≥ 150,000/mm3); and, for IWF A or transformed NHL, a demonstrable monoclonal CD20-positive B-cell population in lymph nodes or bone marrow. In addition, patients could not be pregnant or lactating, had to follow reliable birth control methods, and had to have a life expectancy of ≥ 3 months. Principal exclusion criteria included bilateral bone marrow biopsies demonstrating ≥ 25% involvement with NHL, prior external beam radiation therapy to ≥ 25% of the patient's bone marrow, the presence of human antimurine antibody (HAMA) or human antichimeric antibody (HACA), prior radioimmunotherapy, or prior myeloablative therapy with autologous bone marrow transplantation or peripheral blood stem cell support. Patients were excluded if they had central nervous system lymphoma, chronic lymphocytic leukemia, lymphoma related to human immunodeficiency virus or acquired immunodeficiency syndrome, abnormal liver (total bilirubin > 2.0 mg/dL) or renal function (serum creatinine > 2.0 mg/dL), pleural invasion and/or effusion with positive cytology for lymphoma, peritoneal invasion and/or ascites with positive cytology for lymphoma, other primary malignancies (other than squamous or basal cell carcinoma of the skin or in situ carcinoma of the cervix) within the last 5 years, or serious nonmalignant disease or infection that would likely compromise the study objectives. Patients could not have concurrent corticosteroid therapy (≥ 40 mg prednisone as a single dose or ≤ 40 mg prednisone for more than six doses), or have received therapy with granulocyte–colony-stimulating factor or granulocyte-macrophage–colony-stimulating factor within 2 weeks prior to treatment, or have undergone major surgery (other than diagnostic therapy) within the prior 4 weeks. The study protocol was approved by the Institutional Review Board at each study site, and written informed consent was obtained from all patients.

Study Design

The original study protocol called for dosimetry to be performed on all patients; however, it was subsequently determined that individualized radiation dosimetry was not necessary for safe treatment at standard doses of 0.4 mCi/kg (15 MBq/kg) 90Y-Zevalin. Thus, the study protocol was amended to eliminate individualized dosimetry as a requirement. As a result, the dosimetry procedures described below were performed for only 27 of the 57 patients treated under this protocol.

Patients (n = 57) first received an infusion of rituximab (Rituxan, MabThera, 250 mg/m2) to clear peripheral B cells and optimize biodistribution of the radiolabeled antibody.8 For patients undergoing dosimetry (n = 27), this was followed immediately by an imaging dose of 5 mCi (185 MBq) 111In-Zevalin. Dosimetry was performed over the following 4–6 days at the clinical site to estimate absorbed radiation doses to organs and red marrow that would result from 90Y-Zevalin treatment. These results were compared with the protocol-defined upper limits of 20 grays (Gy) for uninvolved organs and 3.0 Gy for red marrow. One week following the rituximab and 111In-Zevalin infusions, dosimetry patients meeting these criteria (n = 27) went on to receive infusions of rituximab (250 mg/m2) followed by the therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y-Zevalin up to a maximum dose of 32 mCi (1.2 GBq).

Dosimetry

Initial estimates of absorbed radiation dose were made at the clinical sites using quantitative imaging and blood sampling data with the MIRDOSE3 software program.9 Following the injection of 111In-Zevalin, whole-body scans were performed and blood samples were drawn for dosimetry calculations. Scans were performed at five time points (within 1 hour, between 4 and 6 hours, and on Days 1, 3, and 6) after 111In-Zevalin injection. Anterior and posterior images were acquired using a medium-energy collimator, a 256 × 1024 computer acquisition matrix, and photopeak settings of 172 and 247 keV with 15% windows. Scan speed was 10 cm/min for the first three scans, 7 cm/min for the Day 3 scan, and 5 cm/min for the Day 6 scan. Blood samples were drawn at six time points after 111In-Zevalin infusion, with the times corresponding to the scan times, in addition to a sample at 2 hours postinfusion.

Initial dosimetry calculations were performed at the clinical site to support the treatment decision; subsequently, the Division of Nuclear Medicine, Mayo Clinic, and the Radiation Internal Dose Information Center, Oak Ridge Associated Universities (ORAU), performed centralized dosimetric analyses of all patients.

The methodology used to calculate activity and residence times for the whole body, lungs, liver, spleen, and kidney has been previously described.1, 2 The process involves 1) estimating region of interest (ROI) 111In activity content-versus-time based on geometric mean (GM) counts and a whole-body–averaged attenuation correction factor derived from the first whole-body count (i.e., before the patient has excreted any activity); 2) performing necessary decay corrections to convert 111In activity to 90Y activity; 3) estimating the residence time as the area under the activity-versus-time curve using exponential curve-fitting;10 and 4) estimating dose from residence time using the MIRDOSE3 computer program.9 Dose projections made at clinical sites to support treatment decisions were based on the reference organ masses incorporated into MIRDOSE3. The central dosimetry used patient-specific organ masses for spleen and liver, estimated from organ volume determined by computed tomography (CT).

Residence times in red marrow were derived from blood time-activity curves following the method of Sgouros.11 Whole-blood 111In concentration (μCi/mL) was measured, decay corrected to simulate 90Y concentration, and plotted as a function of time of blood draw. The curve was fit with either a mono- or biexponential function, which was then integrated to obtain cumulated activity per mL of blood (Ăb). The blood residence time (τblood) was then obtained by multiplying the Ăb times the patient-specific blood volume/activity injected.12 Red marrow residence time (τrm) was then estimated as follows:

equation image

Values were obtained for red marrow mass (mrm) by matching the patient's weight with an appropriate phantom in MIRDOSE3 and using the corresponding value (e.g., 1120 grams for a 70-kg adult, 1050 grams for a 54-kg adult, etc.).

Statistical Methods

Summary statistics (median and range) were generated for estimated 90Y absorbed radiation doses using results from the centralized analysis. Two forms of statistical testing were performed. The first used the Wilcoxon rank sum test (comparison of two groups) or the Kruskal-Wallis test (comparison of three or more groups) to test for significant differences in median dosimetry or pharmacokinetic variables by clinical parameters. The second used Pearson linear correlation analyses to investigate potential correlations between radiation dose and hematologic toxicity.

Results

Figure 1 provides an example of anterior whole-body gamma scan images at successive time points used to estimate residence times in regions of interest (ROIs). Although not used for dosimetry calculations, abdominal single photon emission computed tomography (SPECT) and CT views are also provided to illustrate Zevalin uptake within a bulky abdominal mass.

Figure 1.

Serial whole-body anterior gamma camera scans from a representative patient following 111In–Zevalin injection show uptake within a bulky mass. Abdominal single photon emission computed tomography (SPECT) and computed tomography (CT) views correlate uptake with abdominal adenopathy.

A summary of estimated absorbed radiation doses is presented in Table 1. The organ doses are assigned to either of two categories. The first category includes the specific organs for which the absorbed radiation dose is estimated from residence times specifically determined for these ROIs by imaging or blood sampling. Since 90Y is a pure beta emitter, virtually all of the dose to each of these organs is due to 90Y transformations occurring within the target organ (i.e., by self-irradiation). An exception is the calculation of bone marrow dose, which, because of the physical distribution of this tissue, must account for beta energy deposition from 90Y on adjacent bone surfaces. The second category comprises other target organs. The absorbed radiation dose to other organs is estimated from the total-body remainder residence time. This method, as incorporated into MIRDOSE3, assumes that all remaining activity is distributed among these organs in proportion to their mass. For pure beta emitters, this assumption results in equal doses for each of the remainder organs.

Table 1. Summary of 90Y-Zevalin Absorbed Radiation Doses
Target organnDose factorDose
(cGy/mCi)(mGy/MBq)(Gy)
MedianRangeMedianRangeMedianRange
  • 90Y: yttrium-90; mGy: milligrays; cGy: centigrays.

  • a

    All liver and spleen doses adjusted for patient-specific organ mass; one patient had prior splenectomy.

  • b

    Includes adrenals, brain, breasts, gallbladder wall, heart wall, lower large intestine wall, muscle, pancreas, skin, small intestine, stomach, thymus, thyroid, and upper large intestine wall.

Red marrow272.41.0–4.10.650.26–1.100.740.29–1.20
Bone surfaces272.11.0–3.20.570.27–0.860.610.30–0.90
Kidneys270.7< 0.1–2.40.20< 0.01–0.650.22< 0.01–0.66
Livera2717.08.2–40.04.602.20–11.05.102.62–12.00
Lungs277.14.7–16.01.901.30–4.302.001.40–5.30
Spleena2627.013.0–95.07.303.50–26.08.104.20–23.0
Urinary bladder wall273.21.8–4.90.860.49–1.300.920.55–1.40
Ovaries/uterus141.51.3–2.00.410.35–0.540.420.29–0.52
Testes131.61.2–1.80.430.32–0.490.500.36–0.58
Total body272.01.7–2.90.540.46–0.780.610.47–0.77
Other organsb271.51.2–2.00.410.32–0.540.450.29–0.58

For the 27 patients undergoing dosimetry, estimated absorbed radiation doses from 90Y-Zevalin were well below the protocol-defined limits of 3.0 Gy to red marrow and 20 Gy to uninvolved organs. Median estimated absorbed radiation doses from 90Y-Zevalin were 8.1 Gy (range, 4.2–23.0 Gy) to the spleen, 5.1 Gy (range, 2.6–12.0 Gy) to the liver, 2.0 Gy (range, 1.4–5.3 Gy) to the lungs, 0.22 Gy (range, < 0.01–0.66 Gy) to the kidneys, and 0.74 Gy (range, 0.29–1.2 Gy) to the red marrow. Estimated absorbed radiation dose to the spleen exceeded 20 Gy in one patient with clinical and CT scan evidence of spleen involvement by NHL.

Statistical analyses were performed to determine whether blood-derived red marrow or total-body absorbed radiation dose estimates correlated with hematologic toxicity. As described in the statistical methods, both categoric (Kruskal-Wallis test) and continuous (Pearson linear correlation test) variables were evaluated. Hematologic parameters analyzed included both neutrophil and platelet nadir grade, nadir value, and days to recovery. The results for the analyses of hematologic nadir grade and days to recovery (categoric variables) are displayed in Tables 2 and 3. The results for hematologic nadir value and days to recovery (continuous variables) are displayed as scattergrams in Figures 2 and 3. None of these analyses showed significant correlations between dosimetric parameters and hematologic toxicity (P < 0.05). In addition, no significant correlation was noted between dosimetric parameters and response to therapy (Table 4). Neither blood-derived red marrow dose nor total-body dose correlated with the overall response rate (ORR).

Table 2. Correlation Analysis of Red Marrow or Total-Body Absorbed Radiation Dose versus Hematologic Nadir Grade
  ANC nadir gradePlatelet nadir grade
0–234P valuea0–234P valuea
  • ANC: absolute neutrophil count; cGy: centigrays.

  • a

    Kruskal-Wallis test.

n11885202
Red marrow doseMedian (cGy)7382480.1197575400.209
Total-body doseMedian (cGy)6061630.9756461610.961
Table 3. Correlation Analysis of Red Marrow or Total-Body Absorbed Radiation Dose versus Days to Hematologic Recovery
  ANC—Days to recoveryPlatelets—Days to recovery
1–1414–28> 28P valuea1–1414–28> 28P valuea
  • ANC: absolute neutrophil count; cGy: centigrays.

  • a

    Kruskal-Wallis test.

n9321371
Red marrow doseMedian (cGy)8751600.3757377290.251
Total-body doseMedian (cGy)6258650.4896064540.380
Figure 2.

Scattergrams for linear correlation analysis of red marrow radiation absorbed dose versus nadir value for (A) absolute neutrophil count (ANC) and (B) platelet count. No significant linear correlation was observed.

Figure 3.

Scattergrams for linear correlation analysis of red marrow radiation absorbed dose versus days to recovery for (A) absolute neutrophil count (ANC) and (B) platelet count. No significant linear correlation was observed.

Table 4. Correlation Analysis of Red Marrow or Total-Body Absorbed Radiation Dose versus Response to Therapy
 nResponders (CR/PR/CCR)nNonresponders (SD, PD)P valuea
Dose (cGy)Dose (cGy)
MedianMeanMin.Max.MedianMeanMin.Max.
  • CR: complete response; PR: partial response; CCR: complete clinical response; SD: stable disease; PR: progressive disease; cGy: centigrays.

  • a

    Wilcoxon rank-sum test.

Red marrow dose1376.874.328.61151471.66630.794.70.423
Total-body dose136060.748.876.51461.561.447.374.80.662

Analyses were also performed to determine whether the baseline peripheral blood B-cell count correlated with major organ (liver, lung, or spleen) absorbed radiation dose estimates. Data analyzed using the Kruskal-Wallis test produced a significant P value (P = 0.015) for the liver dose estimates (Table 5); however, the results were not continuous. Patients with undetectable B-cell levels and high B-cell levels had lower liver dose estimates than the intermediate group of patients with low B-cell levels. No significant correlation was noted between B-cell levels and absorbed radiation dose estimates to the spleen or lungs.

Table 5. Baseline Peripheral Blood B-Cell Level versus Absorbed Radiation Dose to liver: Kruskal-Wallis Analysis
Baseline B-cell level (× 103/mm3)No. of patientsLiver dose (cGy)
MedianRange
  1. cGy: centigrays.

None10346.54262.40–903.00
Low (< 32)9710.40384.00–1200.00
Normal/High (≥ 32)7543.15352.00–1024.00
Unknown1462.60462.60–462.60
P value0.015

Each of these patients had received prior rituximab therapy. Analyses were performed to determine whether the baseline serum rituximab level, prior to the first rituximab infusion of the Zevalin regimen, correlated with major organ (liver, lung, or spleen) absorbed radiation dose estimates. As shown in Table 6, a higher baseline serum rituximab level correlated with a higher estimated median dose to the lungs. Despite this significant finding, all patients had estimated absorbed radiation dose estimates to the lungs well below lung tolerance. No significant correlation was noted between baseline serum rituximab level and absorbed radiation dose to the spleen or liver.

Table 6. Baseline Rituximab Serum Level versus Absorbed Radiation Dose to Lung: Kruskal-Wallis Analysis
Baseline rituximab level (μg/mL)No. of patientsLung dose (cGy)
MedianRange
  1. cGy: centigrays.

None4163.61141.94–194.40
Low (< 10)19204.80153.60–527.20
High (≥ 10)3245.10185.60–265.78
Unknown1172.70172.70–172.70
P value0.047

Discussion

The dosimetry results of this trial are similar to those observed in other trials of Zevalin RIT for NHL,1, 2 suggesting that 90Y-Zevalin biodistribution and dosimetry are unaffected by prior therapy with rituximab. Figure 4 summarizes dosimetry results from four clinical trials of Zevalin RIT. All patients had relapsed or refractory NHL. The four studies were as follows: the current Phase III study of patients with rituximab-refractory follicular NHL (n = 27, 0.4 mCi/kg); a Phase I/II dose escalation study of patients with low-grade, intermediate-grade, or mantle cell NHL (n = 50, 0.2–0.4 mCi/kg);8 a Phase III randomized controlled trial involving patients with low-grade, follicular, or transformed NHL (n = 72, 0.4 mCi/kg);13 and a Phase II reduced dose study of patients with low-grade, follicular, or transformed NHL and mild thrombocytopenia (n = 30, 0.3 mCi/kg).14 With the exception of the current study, all patients were rituximab-naïve.

Figure 4.

Comparison of rituximab-refractory patient dosimetry results with those from other Zevalin trials.

The ORR in the Phase I/II dose escalation trial was 67% for all patients (low-grade, intermediate-grade, and mantle cell NHL) and 82% for those with low-grade NHL.8 The ORR to 90Y-Zevalin in the Phase III randomized controlled study was 80%,13 while an ORR of 74% has been observed in the current Phase III study of rituximab-refractory patients.15 These promising results were achieved with a safe dosimetric profile: all estimated red marrow doses were below the protocol-defined limit of 3.0 Gy, and normal organ (uninvolved with NHL) doses were below the limit of 20 Gy.

In 21 of the 27 rituximab-refractory patients in this study, the spleen received the highest absorbed radiation dose to an organ, while the liver received the highest estimated dose in the remaining 6 patients. The absorbed radiation dose estimates to the liver remained well within a safe range, and no hepatic dysfunction or toxicity (as measured by shift table analysis for bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase) was detected. Patients with higher baseline serum rituximab levels (from prior rituximab immunotherapy) had significantly higher pulmonary dose estimates, but all lung doses were well below lung tolerance and no lung toxicity was noted.

The pattern of normal organ doses is similar to results reported in other studies of radioimmunotherapy for NHL in which 90Y was used as the radionuclide. DeNardo et al. administered 90Y-2IT-BAD-Lym-1, a murine IgG2 monoclonal antibody, to patients with advanced NHL.16 Juweid et al. reported on 90Y-humanized LL2, a murine anti-CD22 monoclonal antibody, for patients with recurrent NHL.17 In both of these trials and in this Phase III study of rituximab-refractory patients, absorbed radiation doses were highest to the spleen or liver. In all three studies, absorbed radiation doses to these two organs fell within a close range. The median or mean dose was 22–36 centigrays (cGy)/mCi to the spleen and 13–23 cGy/mCi to the liver.

The only toxicity of note in this trial was transient and reversible hematologic suppression,15 which did not correlate with estimated absorbed radiation dose to red marrow or the total body. One possible explanation for the lack of correlation is that the blood-based method of bone marrow dosimetry used here does not account for targeting of the radiopharmaceutical to NHL within the marrow. Targeting of marrow NHL results in secondary irradiation of red marrow and subsequent myelosuppression. Patients with follicular NHL often have bone marrow infiltration by tumor cells; 37% of patients in this study had biopsy evidence of bone marrow involvement. Another possible explanation for the lack of correlation is that dosimetry methods do not account for variably decreased bone marrow reserve in patients whose marrow has been damaged by prior chemotherapy and external beam radiation. Patients in this trial had received a median of 4 prior NHL therapies (range, 1–9).15

Pretreatment dosimetry plays an important role in many RIT applications. It is particularly important in early trials to determine the biodistribution of the radiopharmaceutical, confirm tumor uptake, and establish a data base of estimated normal organ doses. In the myeloablative setting, dosimetry provides a basis for determining dose-limiting critical organ toxicity. Dosimetry also provides a means of individualized patient dosing, which is important for agents that exhibit significant variability in biodistribution or urinary excretion, such as iodine-131.18, 19 However, the dosimetry process results in added resource utilization, treatment costs, and patient inconvenience. Furthermore, as demonstrated in the current study, estimated absorbed radiation doses do not always correlate with safety or efficacy parameters. In addition, with 90Y-Zevalin, total-body clearance by urinary excretion over the 7-day interval following administration is minimal (3.2–8.5%).2 Thus individualized dosing based on dosimetry is unnecessary. Based on these factors, our experience supports the prospect that dosimetry can be safely eliminated with Zevalin RIT for relapsed or refractory NHL, just as pharmacokinetic assessments are not routinely required with most chemotherapy agents.

In summary, absorbed radiation dose assessments performed on 27 patients indicated that normal organ doses were acceptable and consistent with those observed in other Zevalin trials, and that dosimetry did not correlate with either toxicity or disease response.

Acknowledgements

This multicenter clinical trial could not have been completed without the expert participation of many principal investigators. The authors thank the following investigators for their participation in the trial: Nancy Bartlett, Kirkman Baxter, Vincent Caggiano, A. Cahid Civelek, P. Duffy Cutler, Myron Czuczman, Walter Drane, William Dunn, Christos Emmanouilides, Louis Fehrenbacher, Ian Flinn, Leo Gordon, Michael Haseman, John Hilton, Nalini Janakiraman, Judith Joyce, Robin Joyce, Kastytis Karvelis, Michael Katin, Randolph Knific, Brian Kraviski, John Lister, James Lynch, Jr., Ruby Meredith, Daniel Navarro, Anthony Parker, William Porter, Henry Royal, Fred Saleh, Mansoor Saleh, Aldo N. Serafini, Barry Skikne, William Spies, and James Welsh.

Ancillary