Pseudo-Progression Among Patients with Follicular Lymphoma Treated with Ibrutinib in the Phase 2 DAWN Study

Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), has demonstrated robust clinical activity in various B-cell malignancies, whose mechanism of action, beside BTK signaling inhibition in B-cells may also depend partially on immune modulation as it also an inhibitor of ITK (interleukin-2-inducible T-cell kinase), a key regulator of T-cell activity. Immune-modulatory cancer therapy, such as check-point inhibitors, may result in different response patterns than traditional cytotoxic therapy, eg, resembling "tumor flare." In a recent study of single-agent ibrutinib for treatment of refractory follicular lymphoma (FL), 7 patients (pts) had documented tumor responses after initial radiological progressive disease (PD), a phenomenon termed "pseudo-progression." We describe these cases that led to a study protocol amendment.

Methods: The FLR2002 (DAWN) study was an open-label, multicenter, single-arm, phase 2 study of ibrutinib in pts with chemoimmunotherapy-refractory (ie, ≥ 2 prior lines of therapy & PD within 12 months after last dose of chemotherapy in a chemoimmunotherapy regimen) FL (NCT01779791). All pts received ibrutinib (560 mg QD) until PD or unacceptable toxicity. A protocol amendment was made to address the novel situation of delayed responses that were observed after PD to allow for continuation of ibrutinib in pts with radiological evidence of PD (any new lesion or increase by ≥ 50% of previously involved sites from nadir), but who were clinically stable/improving/exhibiting signs of tumor flare without documented PD by other methods. The primary end point was Independent Review Committee (IRC)-assessed overall response rate (ORR; complete response [CR] + partial response [PR]). T-cell subsets in peripheral blood were monitored by flow cytometry at various timepoints.

Results: The sentinel case was a pt diagnosed with grade 1 FL in 2008 and subsequently treated with 3 lines of therapy including autologous stem cell transplant. At time of enrollment, pt had stage III disease, an ECOG score: 0 and FLIPI (Follicular Lymphoma International Prognostic Index) score: 1. At Week 12, the pt was assessed as having PD. Ibrutinib was discontinued, and no other anti-cancer treatment was instituted. However, PET & CT scans performed 4 months later showed CR.

Thereafter, 2 other investigators reported similar phenomena, prompting the aforementioned protocol amendment. Investigator assessment of the pt in the sentinel case was confirmed by IRC and ibrutinib treatment was resumed. The pt remains on treatment in CR for 30 months at the time of this report.

On the basis of the protocol amendment, approximately 30 pts were approved to continue ibrutinib treatment after radiographic PD. Of these, an additional 6 pts were identified (7 in total) with IRC-confirmed "pseudo-progression" (confirmed by imaging) at a median of 22.0 (range: 11.6-59.6) weeks after starting Ibrutinib. Three of these pts (2 CR, 1 PR) maintained their response for > 1 year and 2 continue to respond. Two pts (1 CR, 1 PR) maintained responses for > 8 months, but eventually progressed. One pt maintained a PR > 1 year, but discontinued ibrutinib therapy due to an adverse event (grade 3 diarrhea). Sufficient sample was available in 2 of these 7 pts and examination of the T-cell profiles showed a strong downregulation of regulatory Tcells (Tregs) at early timepoints after initiation of therapy in both, an effect that was significant also in other responders (CR+ PR, mean decrease 17 to 12.9% CD4, p=0.02) but not in non-responders (SD+PD, 11.5 to 10.4% CD4, ns).

Conclusion: Experience from the DAWN study suggests that pts with relapsed or refractory FL treated with ibrutinib may experience initial pseudo-progression followed by robust and durable responses when continued on ibrutinib. This effect may be related to the immune-modulatory effects of ibrutinib as seen by the decrease in Tregs after start of therapy. Biomarker studies are continuing to further understand this phenomenon. Nevertheless, these and other observations have prompted a revision in response criteria that recognize specific response patterns such as these in pts treated with immune modulating agents. Therefore current and future clinical trials should consider the observed phenomenon and physicians should be aware of this pattern of response when utilizing immune-related or targeted therapies to avoid premature discontinuation of therapy.