Genetic Aberration Affects Response to Bortezomib in AL Amyloidosis

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The t(11;14) translocation was associated with poorer response rates and shorter overall survival in with bortezomib-based regimens.
The t(11;14) translocation was associated with poorer response rates and shorter overall survival in with bortezomib-based regimens.

Bortezomib-based regimens are less effective in patients with systemic light chain (AL) amyloidosis who have the t(11;14) translocation, according to a study just published in the Journal of Clinical Oncology.1

Researchers at University Hospital Heidelberg in Germany, analyzed a consecutive series of 133 patients with AL amyloidosis who received bortezomib as first-line therapy, either in combination with dexamethasone (BD group, 101 patients) or in combination with cyclophosphamide and dexamethasone (BCD group, 32 patients).

Bortezomib was offered as first-line therapy because this high-risk patient group required rapid lowering of amyloidogenic light chains. Patients had severe cardiac and/or renal damage as a result of their disease and were not eligible for high-dose chemotherapy or stem-cell transplantation.

Cytogenetic aberrations were identified by interphase fluorescence in situ hybridization (iFISH).

Marked Difference in Outcomes

After median follow-up of 24 months, median hematologic event-free survival in the BD group was 4.7 months (95% CI, 3.7 to 7.0 months). Median hematologic event-free survival was significantly shorter, however, in patients with the t(11;14) translocation (3.4 vs. 8.8 months, P=0.002).

Patients with the high-risk aberrations t(4:14), t(14;16), and deletion 17p13 had longer hematologic event-free survival than patients without these aberrations (10.3 months vs. 3.9 months), although the difference was not statistically significant.

Presence of t(11;14) also predicted shorter median overall survival (OS) in the BD group (8.7 vs. 40.7 months; P=0.05). Median OS was longer in patients with high-risk genetic aberrations than in patients without them.

In addition, patients in the BD group with t(11;14) achieved partial remission only half as often as patients without it (23% vs. 47%; P=0.02). By contrast, patients with high risk genetic aberrations were markedly more likely to achieve partial remission than patients without them (67% vs. 26%; P=0.008).

Multivariable analysis confirmed that t(11;14) is an independent risk factor for AL amyloidosis patients on the BD regimen.

Presence of t(11;14) also predicted worse outcomes in the BCD group, who were somewhat younger and healthier, with better renal function, than the BD group. t(11;14)-positive patients in the BCD group had a 24% remission rate and median hematologic event-free survival of 4.0 months, whereas t(11;14)-negative patients had an 80% partial remission rate and did not reach median hematologic event-free survival. Neither cohort reached median OS.

The study authors considered the finding that t(11;14) is associated with poorer prognosis in bortezomib-treated patients somewhat surprising, because their previous research had shown this translocation to be associated with slightly improved OS in patients with AL amyloidosis treated with melphalan and dexamethasone.

Patients with t(11;14) tend to have indolent disease; thus it appears that the translocation is not itself a risk factor, but predicts poor response to bortezomib.

The study authors wrote that these results “highlight that the prognostic impact of cytogenetic markers largely depends on the administered therapy and should therefore be judged only in the context of a specific therapy.”

Reference

  1. Bochtler T, Hegenbart U, Kunz C, et al. Translocation t(11 ;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens. J Clin Oncol. March 16, 2015. [Epub ahead of print] doi: 10.1200/JCO.2014.57.4947.

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