Activation of NF-kB is a possible mechanism of drug resistance in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Bortezomib is a proteasome inhibitor that inhibits NF-kB activation and has promising activity in some lymphoma subtypes. We hypothesized that bortezomib may be active in ABC DLBCL and enhance the efficacy of chemotherapy. The effect of bortezomib on NF-kB and other pathways in serial tumor samples will be examined by microarray and correlated with outcome. The study employs a sequential treatment design. Patients first receive bortezomib alone (Part A), unless they require chemotherapy due to disease, and then cross over to DA-EPOCH-bortezomib (Part B) if they do not achieve a CR. In Part A, the dose of bortezomib is 1.3 mg/m2 IV d 1, 4, 8, 11 q21days. In Part B, bortezomib is escalated over 4 dose levels, in an accelerated design, of 0.5, 1, 1.5 and 1.7 mg/m2 on d 1,4 with DA-EPOCH, q21days. Of 32 patients enrolled, there are 16 on Part A and 26 on Part B. Patient characteristics include median age (range) 54 (19–76); stage III/IV 29 (91%); median 4 (1–8) prior regimens and; 25 (83%) refractory to the last therapy. Part A response in 15 (1 TE) patients includes 1 PR, 3 SD and 11 (73%) PD. Toxicity over 35 cycles includes 2 (6%) grade 3 neutropenia; 2 and 3 grade 3/4 thrombocytopenia, respectively; and 3 grade 3 GI toxicities. Part B response in 25 (1 TE) patients includes 2 (8%) CR, 4 (16%) PR, and 20 (80%) NR. Twenty-three patients enrolled at bortezomib 1.7 mg/m2 (max dose). Toxicity over 58 cycles includes 31 (53%) grade 4 neutropenia; 13 (22%) grade 4 thrombocytopenia and; 12 (21%) fever/neutropenia. Transfusions were required with red cells on 22 (38%) and platelets on 18 (31%) cycles. Other toxicity included grade ≥ 3 sensory neurotoxicity in 2 (8%) patients and grade ≥ 2 GI toxicity on 32 (55%) cycles. Comparison of hematological toxicities of DA-EPOCH-bortezomib with fixed dose EPOCH in relapsed patients (

JCO
18
:
3633
,
2000
) was similar with fever/neutropenia 21% vs. 18%; grade 4 neutropenia 53% vs. 48% and; grade 3/4 thrombocytopenia 51% vs. 27%, respectively. GI toxicity appears higher with ≥ grade 2 on 55% vs. 14% of cycles. Neurotoxicity ≥ grade 2 was 8% vs. 22%, but patients on the present study received fewer cycles of treatment. Bortezomib alone is ineffective in relapsed/refractory DLBCL. Bortezomib can be safely combined with combination chemotherapy but does not appear to increase the efficacy of DA-EPOCH chemotherapy in relapsed/refractory DLBCL. However, compared to our previous study of EPOCH alone, most patients on the current study entered with chemotherapy-refractory disease. Results of microarray profiling are pending. Accrual continues.

Topics:
b-lymphocytes, bortezomib, chemotherapy regimen, epoch protocol, lymphoma, toxic effect, diffuse large b-cell lymphoma, neutropenia, nf-kappa b, thrombocytopenia

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2005, The American Society of Hematology
2004
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