Treatment Side Effects

Both Y-90-ibritumomab tiuxetan and I-131-tositumomab have comparable side effect profiles when given at the FDA-approved nonmyeloablative doses. In the series by Dr. Witzig, summarizing the safety of Y-90-ibritumomab tiuxetan in a series of 349 patients treated with this approach, 80% of the patients were noted to have had at least one adverse event. Patients experienced additional toxi-cities such as chills, fever, or flushing 21%, 13%, or 5% of the time, respectively (16). Many of these events were related to the unlabeled rituximab infusion, which is known to cause such reactions. The most important toxicity however is the hematologic toxicity. Unlike traditional chemotherapy, the hematologic nadir of platelets and neutrophils typically occurs six to eight weeks after therapy. In this series of 349 patients, 129 (37%) experienced grade I or II thrombocytopenia, whereas 63% experienced grade III or IV cytopenia. In addition, 40% of patients experienced grade I or II neutropenia, whereas 60% of the patients experienced grade III or IV neutropenia. Infection or fever associated

Table 4 Selected Trials Evaluating Myeloablative Anti-CD20 Radioimmunotherapy for Relapsed B-cell NHL

Drug

Isotope

Radiation dosea (Gy)

Chemotherapy

Phase

N

CR/PR

Follow-up

Reference

1F5, tositumomab

1-131

15-37.5

No

I

13

77%/15%

Median OS > 26 months

(13)

Tositumomab

1-131

25-31

No

II

21

76%/10%

2-year OS/PFS = 93%/62%

(21)

Tositumomab

1-131

20-27

VP-16, CY

I/II

52

77%/10%

2-year OS/PFS = 83%/68%

(22)

Rituximab

1-131

< 27

No

II

7

86%/14%

5 of 6 in CR at 25 months

(23)

Ibritumomab

Y-90

< 10

VP-16, CY

I

18

100%/0%

1-year OS and DFS = 92%

(24)

aDose to highest critical normal organ.

Abbreviations'. CR, complete remission; DFS, disease free survival; 1-131, iodine-131; OS, overall survival; PFS, progressive free survival; Y-90, yttrium-90.

aDose to highest critical normal organ.

Abbreviations'. CR, complete remission; DFS, disease free survival; 1-131, iodine-131; OS, overall survival; PFS, progressive free survival; Y-90, yttrium-90.

with neutropenia occurred in 29% of the patients, resulting in 7% of the patients requiring hospitalization. Increased hematologic toxicity was found to be associated with a higher percentage of bone marrow involvement at study entry, and prior fludarabine therapy.

Similar toxicity profiles have been observed for I-131-tositumomab. Dr. Kaminsky reported in the pivotal trial of I-131-tositumomab, that 42% of the patients experienced infusional toxicity during the dosimetry infusion, as compared with 24% during the therapeutic dose. These toxicities were predominantly in the grade I—II category, with only 2% of the patients having grade III or IV toxicity (17). One explanation for the lower rates of infusional toxicity with Bexxar may be the lack of a chimeric monoclonal antibody such as rituximab, that is used as predosing for Zevalin® therapy and can more actively fix complement. As with yttrium-based RIT, the dose-limiting toxicity was hematologic, with a median time to nadir of approximately 35 to 45 days following therapy. Eighteen percent of patients experienced grade IV neutropenia, and 22% experienced grade IV thrombocytopenia. Finally, 1 of 56 evaluable patients developed hypothyroidism, 8.3 months after therapy. In summary, the acute toxicities associated with nonablative anti-CD20 RIT are rather mild as compared with traditional chemotherapeutic agents, with some degree of infusional toxicities and delayed cytopenias, most of which do not result in infections, bleeding, or hospitalization.

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