Highdose Radioimmunotherapy

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In contrast to the aforementioned studies whereby the radioisotope dose was limited by marrow suppression, other investigators have evaluated the use of further escalating the dose of RIT and providing hematologic support with auto-logous hematopoetic stem cell infusions. This strategy was pioneered at the University of Washington in Seattle. These investigators used organ-specific dosimetry as it was hypothesized that specific normal organs may encounter tox-icity as doses were escalated beyond the level of myeloablation and that a mCi/ kg approach could not accurately predict the radiaton dose to normal organs (12). The initial phase I trials escalated the dose, based on the dose to the highest normal organ starting at 10 Gy and escalating through 30.75 Gy (13). This dose escalation schema established the maximally tolerated dose with autologous hematopoetic support to be approximately 27 Gy to the highest normal organ. The dose-limiting toxicity was cardiopulmonary toxicity reflecting the fact that the normal organ receiving the highest dose was typically the lung. As with the nonablative RIT, the nonhematopoietic toxicities under the maximally tolerated dose were mild to moderate with toxicities considerably less than what one would expect with traditional transplant regimens. The escalation of the radiation dose did translate into improved responses with an overall response rate of 95% and complete response rate of 84% (13). Long-term follow-up of the cohort of

Table 3 Summary of Selected Nonmyeloablative Anti-lymphoma Radioimmunoconjugates

Lymphoma type/

Table 3 Summary of Selected Nonmyeloablative Anti-lymphoma Radioimmunoconjugates

Lymphoma type/

Drug

Isotope

Target

disease setting

n

Response

References

Tositumomab

1-131

CD20

Indolent NHL/relapsed

9

67% (44% CR)

(10)

Tositumomab

1-131

chemotherapy refractory

60

65% (20% CR)

(17)

Ibritumomab

Y-90

CD20

Indolent NHL/

34

82% (26% CR)

(11)

Tiuxetan

relapsed-refractory

Ibritumomab

Y-90

CD20

Indolent NHL/

54

74% (15% CR)

(16)

Tiuxetan

rituximab-refractory

LL2

I-131/Y-90

CD22

NHL/relapsed

22

15-29%

(18)

Lym-1

Cu-67

HLA-DR

NHL/relapsed

12

58%

(19)

Anti-ferritin

Y-90

Ferritin

Hodgkin's disease/

39

51%

Abbreviations'. CR, complete remission; Cu-67, copper-67; 1-131, iodine-131; NHL, non-Hodgkin's lymphoma; Y-90, yttrium-90.

relapsed

Abbreviations'. CR, complete remission; Cu-67, copper-67; 1-131, iodine-131; NHL, non-Hodgkin's lymphoma; Y-90, yttrium-90.

these patients with follicular lymphoma estimated that 67% would be alive and 48% alive without disease progression at five years (14). Patients did, however, experience expected periods of cytopenias, which one would expect to see with autologous transplant patients in general. Another general finding was that in spite of protection of the thyroid gland with oral iodine solution over 60% of the patients eventually developed an elevated thyroid-stimulating hormone (TSH) (15). More recently, this myeloablative approach has been evaluated with alternative radioimmunoconjugates as well as in combination with high-dose chemotherapy. Selected myeloabltive anti-CD20 RIT trials are summarized in Table 4.

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