Update on the rational use of tositumomab and iodine-131 tositumomab radioimmunotherapy for the treatment of non-Hodgkin’s lymphoma

Figures & data

Table 1 Characteristics of type I and type II anti-CD20 antibodies as determined by preclinical experiments

	Type I antibodies	Type II antibodies
Examples	Rituximab	Tositumomab
Redistribute CD20 into Triton X-100 insoluble lipid rafts	+	–
Homotypic adhesion	+	+++
Induction of apoptosis	+	+++
Complement-dependent cytotoxicity	+	–
B-cell depletion in transgenic mice models	+	+++

Figure 1 Theoretical reasons for variations in clearance which leads to individualized dosing of ¹³¹I activity for each patient.

Table 2 Summary of major published trials of ¹³¹I-Tositumomab for relapsed, refractory, or transformed low-grade B-cell non-Hodgkin’s lymphoma (NHL)

Study design	N	OR (%)	CR (%)	PFS (TTP) [MDR] (months)
Phase I/II single center trial; prior stem cell transplant allowed; includes 17 patients with de novo intermediate/high-grade NHL; no prior RTX^Citation25	59	71	34	12 for all responders
Phase II multicenter nonrandomized trial; at least one prior anthracycline or anthracenedione based chemotherapy regimen with disease progression within 1 year; no prior RTX^Citation19	47	57	32	5.3 [9.9]
Phase III multicenter nonrandomized trial; at least two prior chemotherapy regimens with either no response or relapse within 6 months of completing their last regimen; no prior RTX^Citation26	60	65	20	8.4 for all responders [6.5]
Phase II open label single arm trial; only 1 or 2 previous chemotherapy regimens; no prior RTX^Citation20	41	76	49	0.8 years [1.3 years]
Multicenter randomized trial comparing ^131I-TST to unlabeled TST; no prior RTX^Citation13	78	55	33	(6.3) [not reached]
Mutlicenter phase II trial; failure after prior RTX^Citation31	40	65	38	10.4 [24.5]

Abbreviations: OR, overall response; CR, complete response; PFS, progression-free survival; TTP, median time to progression for all patients in study; MDR, median duration of response in responders; RTX, rituximab; ¹³¹I-TST, ¹³¹I tositumomab.

Table 3 Results of autologous stem cell transplant protocols involving ¹³¹I tositumomab in non-Hodgkin’s lymphoma

Center	N	Histology	Chemo	^131I-TST	OR	CR	Outcome
Washington^Citation37	29	66% LG, 34% iG	None	27 Gy to lung or kidney	86%	79%	4-year PFS 42%
Washington^Citation38	52	65% FL G1–2, 8% FL G3 12% MC, 16% DLBCL	CE	25 Gy to lung or kidney	87%a	77%a	2-year PFS 68%
Washington^Citation40	16	MC	CE	25 Gy to lung or kidney	82%b	73%b	3-year PFS 61%
Nebraska^Citation42	23	61% DLBCL, 17% FL G3, 22% MC	BEAM	75 cGy total body	65%	57%	3-year EFS 39%
Washington^Citation41	24	38% DLBCL, 33% MC, 25% FL, 4% MZ	None	25–27 Gy to lung or kidney	67%	54%	3-year PFS 51%

a Excludes 18 patients with no measurable disease after the mobilization regimen;

b Excludes 5 patients with no measurable disease after the mobilization regimen.

Abbreviations: ¹³¹I-TST, ¹³¹I tositumomab; OR, overall response; CR, complete response; LG, low grade; IG, intermediate grade; PFS, progression-free survival; FL, follicular lymphoma; G, grade; MC, mantle cell lymphoma; DLBCL, diffuse large B cell lymphoma; CE, cyclophosphamide and etoposide; BEAM, carmustine, etoposide, cytarabine, melphalan; EFS, event-free survival; MZ, marginal zone lymphoma.

Figure 2 Comparison of progression-free survival (PFS) of 90 patients with bulky stage II to stage IV follicular non-Hodgkin’s lymphoma treated with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by tositumomab I-131 (radioimmunotherapy [RIT]) with the PFS of 356 similar patients treated on previous Southwest Oncology Group studies of CHOP without anti-CD20 antibodies (historical CHOP). Five-year estimates of PFS for each regimen are shown. Reprinted with permission from Press OW, Unger JM, Braziel RM, et al. Phase II Trial of CHOP chemotherapy followed by tositumomab/iodine-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group Protocol SW9911. J Clin Oncol. 2006;24(25):4143–4149.⁴³ Copyright © 2006 American Society of Clinical Oncology.

Figure 3 Comparison of the overall survival (OS) of 90 patients with stage II to IV follicular non-Hodgkin’s lymphoma treated with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by tositumomab I-131 (radioimmunotherapy [RIT]) on the current trial (S9911) with the OS of 356 similar patients treated on previous studies with CHOP without anti-CD20 antibodies (historical CHOP). Five-year estimates of OS for each regimen are shown. Reprinted with permission from Press OW, Unger JM, Braziel RM, et al. Phase II Trial of CHOP chemotherapy followed by tositumomab/iodine-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group Protocol SW9911. J Clin Oncol. 2006;24(25):4143–4149.⁴³ Copyright © 2006 American Society of Clinical Oncology.

Table 4 Phase II studies investigating the use of ¹³¹I tositumomab in the initial management of low grade B-cell NHL

Center	Patients	Regimen	CR after chemo	CR after ^131I-TST	5-yr PFS
Michigan^Citation27	76 stage III–IV	^131I-TST	N/A	75%	59%
Iowa, Michigan, Cornell^Citation45	30 bulky stage II–IV	CVP × 6 + ^131I-TST	50%	80%
Cornell^Citation44	35 stage III–IV	Fludarabine × 3 + ^131I-TST	9%	86%
SWOG S9911^Citation43	90 bulky stage II–IV	CHOP × 6 + ^131I-TST	39%	69%	67%

Abbreviations: CR, complete response; PFS, progression-free survival; ¹³¹I-TST, ¹³¹I tositumomab; CVP, cyclophosphamide, vincristine, prednisone; CHOP, cyclophosphamide, hydroxydaunomycin (doxorubicin or adriamycin), oncovin (vincristine), and prednisone.

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