Abstract
BackgroundThe mechanisms responsible for chemoresistance in patients with refractory classical Hodgkin lymphoma (CHL) are unknown. ATP-binding cassette (ABC) transporters confer multidrug resistance in various cancers and ABCC1 overexpression has been shown to contribute to drug resistance in the CHL cell line, KMH2.FindingsWe analyzed for expression of five ABC transporters ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2 using immunohistochemistry in 103 pre-treatment tumor specimens obtained from patients with CHL. All patients received first-line standard chemotherapy with doxorubicin (Adriamycin®), bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens. ABCC1 was expressed in Hodgkin and Reed-Sternberg (HRS) cells in 16 of 82 cases (19.5%) and ABCG2 was expressed by HRS cells in 25 of 77 cases (32.5%). All tumors were negative for ABCB1, ABCC2 and ABCC3. ABCC1 expression was associated with refractory disease (p = 0.01) and was marginally associated with poorer failure-free survival (p = 0.06). Multivariate analysis after adjusting for hemoglobin and albumin levels and age showed that patients with CHL with HRS cells positive for ABCC1 had a higher risk of not responding to treatment (HR = 2.84, 95%, CI: 1.12-7.19 p = 0.028).ConclusionsExpression of ABCC1 by HRS cells in CHL patients predicts a higher risk of treatment failure and is marginally associated with poorer failure-free survival using standard frontline chemotherapy regimens.
Highlights
The mechanisms responsible for chemoresistance in patients with refractory classical Hodgkin lymphoma (CHL) are unknown
Expression of ABCC1 by Hodgkin and Reed-Sternberg (HRS) cells in CHL patients predicts a higher risk of treatment failure and is marginally associated with poorer failure-free survival using standard frontline chemotherapy regimens
ABCG2 and ABCC1 were expressed by HRS cells in a subset of CHL tumors (Figure 1)
Summary
The mechanisms responsible for chemoresistance in patients with refractory classical Hodgkin lymphoma (CHL) are unknown. ATP-binding cassette (ABC) transporters confer multidrug resistance in various cancers and ABCC1 overexpression has been shown to contribute to drug resistance in the CHL cell line, KMH2. Classical Hodgkin lymphoma (CHL) is largely a curable disease using the widely accepted current standard firstline chemotherapy regimen of doxorubicin (AdriamycinW), bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens, with or without consolidation radiotherapy [1]. ABC transporters play a role in multidrug resistance (MDR) in multiple tumor types by using ATP as an energy source to actively expel drug substrates from the tumor cell cytoplasm into the extracellular space [12]. Expression of ABC transporters has been shown to correlate with response to therapy and prognosis in several hematological malignancies including acute myeloid leukemia and diffuse large B-cell lymphoma [13,14,15]. The clinical impact of ABC transporters in CHL has not been reported, several drugs used to treat CHL are known substrates of various ABC transporters [11,16], including doxorubicin (a substrate for ABCB1, ABCC1, ABCC2, ABCC3, ABCG2), vinblastine (a substrate for ABCB1 and ABCC1) and vincristine (a substrate for ABCC1)
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