Novel antivirals for HCV-associated lymphomas

In this issue of Blood, Arcaini et al have identified that patients with indolent B-cell non-Hodgkin lymphomas (NHLs) associated with chronic hepatitis C virus (HCV) infection, particularly those with marginal zone lymphomas (MZLs), can achieve both virologic and lymphoma responses when treated with highly effective, novel HCV eradication therapy.¹ 

A strong association between HCV and certain NHLs, including a possible etiologic link, had been previously reported in studies showing that effective eradication of HCV with traditional interferon (IFN)–based therapy was strongly associated with NHL regression in most patients.^2-5  However, IFN-based therapies are long and toxic, and achieve sustained HCV eradication in about 60% to 80% patients.^2,3 

Over the last decade, several novel direct-acting antivirals (DAAs) against HCV have been developed. These agents target structural and nonstructural proteins involved in HCV RNA replication and virus assembly inside infected hepatocytes. DAAs can be given alone or in combination with IFN/ribavirin or other DAAs that inhibit additional regions of the HCV genome, in order to reduce the emergence of resistant variants. DAA-containing regimens are highly effective, as measured by sustained virologic responses in as high as 90% of treated patients. In addition to greater efficacy, these regimens are significantly less toxic than traditional IFN-containing regimens.^6-8  Therefore, it makes sense to investigate whether the use of DAAs in the treatment of HCV-associated B-cell NHL may improve lymphoma response rates and outcomes with less toxicity.

In the present study, Arcaini and colleagues assembled a cohort of 46 patients with indolent B-cell NHL and simultaneous hepatitis C infection who were treated with DAAs at various centers in Europe and 1 center in the United States. Antiviral therapy was given with the goal of eradicating the hepatitis C infection while simultaneously attempting to treat the lymphoma. Because the study was not prospective, patients received different types of DAA-based regimens, most commonly including sofosbuvir.

As anticipated, DAA induced sustained virologic responses at 12 weeks in all but 1 patient, with very little reported toxicity. With a median follow-up of only 8 months (range, 2-30 months), and a median duration of DAAs of 12 weeks (range, 6-24 weeks), all patients received the entire intended course of antiviral therapy with the exception of 1 patient with advanced cirrhosis who had NHL progression on DAAs.

In terms of lymphoma responses, ∼2 of 3 patients responded to DAAs. One of the most interesting findings of this study is that 11 of 12 complete responses occurred in patients with MZL, whereas there were no responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. This suggests that the biology of the NHL and its interaction with chronic HCV infection play an important role in lymphomagenesis and therapeutics. It also cautions that effective HCV eradication may not necessarily treat non-MZL histologies, and that these patients may still require standard therapies such as chemoimmunotherapy. However, there were only 9 patients with non-MZL histologies, and this observation will require further prospective investigation.

In the entire study cohort, 12 patients had received prior IFN-based HCV therapy, and 10 patients had received prior systemic therapy for indolent NHL. Neither of these factors was associated with a lack of response to DAAs, strengthening the idea that cessation of chronic HCV antigenic stimulation is the key biologic event leading to lymphoma regression. This important assumption has therapeutic implications: HCV therapy appears to be effective as lymphoma therapy whether it is used in the first line or relapsed settings. HCV therapy makes most sense in patients with indolent NHL who do not have an immediate need for systemic therapy, and who can safely wait several weeks for the immunologic effects of DAAs to take place. At the same time, HCV therapy may also be equally appropriate following standard chemoimmunotherapy for advanced, symptomatic NHL.

Within the short length of follow-up, 6 patients experienced lymphoma progression (1 during DAA, 5 after DAA), all with MZL. It is possible that their lymphomas progressed because the initial virologic response was not sustained; however, this information is not available. It is also possible that successful HCV eradication did not sufficiently reverse the complex immunologic processes that gave rise to the NHL, particularly in the patients whose MZL progressed within 3 months of DAAs. The latter hypothesis is consistent with the observation that in other NHLs associated with chronic infections such as gastric and ocular adnexal MZL, eradication of the putative microorganism does not consistently eradicate the lymphoma.

Although the data presented by Arcaini and colleagues advance our understanding of the relationship between HCV infection, HCV therapy, and B-cell NHL, there are a number of outstanding issues. First, longer follow-up is required to determine whether sustained virologic responses and their ensuing sustained lymphoma responses will translate into favorable long-term outcomes for these patients. Second, prospective studies involving homogeneous treatments and assessments, together with biologic correlates, are necessary to identify the most effective strategy for the subgroup of patients most likely to benefit. Third, pharmacoeconomic analyses should be built into these studies because DAA-based therapy is expected to incur a significant economic burden for the payer, public or private, responsible for the cost of HCV therapy. However, this may turn out to be a cost-effective investment in the long run if these 2 chronic diseases are simultaneously successfully managed and even possibly cured.