Advertisement

Efficacy in the margins of NHL with ibrutinib

Paul M. Barr

In this issue of Blood, Noy et al report on the efficacy of single-agent ibrutinib in patients with relapsed or refractory marginal zone lymphoma (MZL). They demonstrate an overall response rate of 48% and a median progression-free survival of 14 months, establishing the Bruton tyrosine kinase (BTK) inhibitor ibrutinib as a therapeutic option for this population.1

MZLs are a group of non-Hodgkin lymphomas (NHLs) divided into nodal, extranodal, and splenic entities in the World Health Organization classification system. They are among the most indolent of the NHLs, having a median overall survival ranging from many years to more than a decade. The recognition that some MZLs rely on a continuous antigenic exposure for disease pathogenesis has led to successful treatment aimed at eliminating the oncogenic stimulus. Examples include Helicobacter pylori–directed therapy in the case of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) and antiviral therapy for hepatitis C–related cases. However, for the nodal and splenic MZLs or in cases of disseminated MALT lymphomas, cure is not typically achievable, and systemic therapy is ultimately required.

Few clinical trials have focused on MZL. Data supporting the use of systemic therapy have been based on studies enrolling several indolent NHL subtypes, of which MZL typically represents a small proportion. High response rates are observed for chemoimmunotherapy in the first-line setting.2,3 However, relapse occurs in the majority of patients. In an effort to identify novel targets and improve therapeutic options, transcriptomic analyses have been performed that identify frequent deregulation of NF-κB, JAK/STAT, NOTCH, and Toll-like receptor signaling pathways as contributors to marginal zone lymphomagenesis.4,5 Although such analyses have also identified aberrations downstream of the B-cell receptor (BCR), somatic mutations of key regulators such as CARD11, MYD88, and TNFAIP3 have been observed in only a minority of patients.6,7 Nonetheless, the role of antigenic stimulation via BCR in driving MZL proliferation suggests that investigations targeting this pathway are warranted.

With this in mind, phase 1 testing of ibrutinib demonstrated responses across lymphoma subtypes, including an objective response in 1 of 4 MZL patients enrolled.8 The accompanying article by Noy et al reports on the subsequent effort to better understand the utility of ibrutinib in this lymphoma histology. Of the 63 patients enrolled, half had extranodal MZL and the remainder were split between splenic and nodal subtypes. The patients were not as heavily pretreated when compared with patients in other studies of relapsed lymphoma, with a median of 2 prior therapies, 63% having received chemoimmunotherapy, and only 22% being refractory to their most recent therapy. Perhaps this is not surprising, given the indolent nature of the disease, favorable responses to anti-CD20 therapy, and a lack of approved targeted agents. The results demonstrate objective responses in just under half the patients and a median progression-free survival of 14 months. No difference in response rates was demonstrated by MZL subtype, number of prior regimens, or previous chemoimmunotherapy. However, the small numbers of patients in the subsets limit meaningful comparisons. Tolerability was similar to that in other ibrutinib trials with low rates of severe adverse events. The single bleeding-related fatality reminds us that caution should be exercised when administering ibrutinib with anticoagulation.

Putting these results into context, the efficacy of ibrutinib seems similar to that of other single agents evaluated in patients with relapsed MZL, including other agents that target molecules downstream of BCR. In addition, the toxicity profile of ibrutinib remains favorable in this population. Thus, the US Food and Drug Administration (FDA) has granted accelerated approval for ibrutinib in MZL patients previously treated with at least 1 prior anti-CD20–based therapy. Given the modest response rate when compared with other indications for which ibrutinib is approved, additional correlative studies that would help identify a predictive biomarker would add significantly to this work. Such efforts have been used to predict for efficacy in Waldenström macroglobulinemia and to guide ongoing studies in diffuse large B-cell lymphoma.9,10

Nonetheless, the study team should be congratulated. Their trial demonstrates the ability to investigate rare disease subtypes in multicenter collaborations. The results justify ibrutinib as the first FDA-approved therapy for this disease and form the basis for subsequent trials that combine ibrutinib with anti-CD20 monoclonal antibodies and other targeted agents.

Footnotes

  • Conflict-of-interest disclosure: P.M.B. has consulted for and received research funding from Pharmacyclics and AbbVie.

REFERENCES

  1. 1.
  2. 2.
  3. 3.
  4. 4.
  5. 5.
  6. 6.
  7. 7.
  8. 8.
  9. 9.
  10. 10.