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. 2021 Mar 22;137(25):3473–3483. doi: 10.1182/blood.2020009688

Figure 3.

Figure 3.

pERK status during treatment and clinical outcome. (A) pERK expression in HCL cells in the bone marrow are shown for 4 representative patients at screening and week 48 of ibrutinib treatment. pERK expression is shown as red cytoplasmic staining. Leukemia cells were identified by a PAX5 stain with brown nuclear staining when present. The use of both stains identifies pERK expression specifically in the leukemia cells. The presence of cytoplasmic pERK is shown with thick arrows and the absence is shown with thin arrows. Patient 2 has vHCL and had a diffuse infiltrate of leukemic cells at both screening and week 48 of treatment. The leukemia cells were negative for pERK staining at every time point tested. Patients with vHCL have previously been shown to not have pERK, and this may not be a prosurvival signal in these patients, given that vHCL and cHCL have relatively different biology. The remaining 3 patients (3, 8, and 30) all have cHCL and a durable benefit from ibrutinib with a PFS of more than 2 years, and all were continuing to receive ibrutinib at the last follow-up. They all had different changes in pERK status after starting treatment. Patient 3 had pERK in the leukemia cells at screening that was absent by week 48, patient 8 had persistent presence of pERK at all time points tested, and patient 30 had a subset of pERK-positive leukemia cells at screening and at week 48. (B) Swimmer’s plot with pERK status at screening, week 32, and week 48 for all patients for whom samples were available. Both patients with vHCL (patient 2 and patient 4) were pERK negative at every time point tested, which is consistent with what was previously described in patients with vHCL. Many patients with persistence of pERK continued to receive ibrutinib without progression for an extended period. This supports that (contrary to what was shown with vemurafenib) the presence of pERK during ibrutinib treatment may not predict a shorter PFS and argues that the mechanism of effect of ibrutinib may not involve decreasing ERK phosphorylation.