Brentuximab vedotin in heavily treated <scp>H</scp>odgkin and anaplastic large‐cell lymphoma, a single centre study on 45 patients (2014)

The prognosis of patients with Hodgkin lymphoma (HL) relapsing after autologous stem-cell transplantation (ASCT) is very poor, with approximately only 20% of the patients surviving longer than 5 years (Brice, 2008). Patients with anaplastic large-cell lymphoma (ALCL) relapsing after CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like regimens have a poor prognosis, with a median progression-free survival (PFS) shorter than 1 year (Gascoyne et al, 1999). This single centre retrospective study investigated the activity of single-agent brentuximab vedotin (BV) in unselected relapsed and refractory HL and ALCL, administered as in pilot phase II trials (Pro et al, 2012; Younes et al, 2012). The primary outcomes included response rate, toxicity and progression-free survival (PFS). Patients could continue therapy until disease progression or unacceptable toxicity occurred. Response was assessed by computerized tomography (CT) scan according to the revised response criteria for malignant lymphoma (Cheson et al, 2007). A total of 25 patients also underwent positron emission tomography (PET) for response evaluation. Between June 2009 and October 2012, 45 patients (32 HL and 13 ALCL) received at least one dose of BV. The median age was 38 (range 20–71). Baseline disease characteristics and previous therapies are listed in Table 1. For patients with HL, first line chemotherapy was ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) in 25 cases followed by radiotherapy in seven cases. Twenty-eight had primary refractory disease or early relapse (<1 year after end-of-treatment). The median number of previous chemotherapy lines was 4 (range 2–8); 28 patients underwent ASCT (two times in 11 cases) and five patients received an allotransplant. Before the first dose of BV, 12 out of 32 patients suffered disease progression during the last chemotherapy, 20 had relapsed after response. Twenty-eight patients had advanced-stage disease (stage III–IV) at the initiation of BV. Eleven patients with ALCL received a CHOP-like regimen as first line chemotherapy, the remaining two received radiotherapy or single agent chemotherapy. Eleven patients were primary refractory or relapsed early. The median number of previous chemotherapy lines was 2 (range 1–6), and two cases had ASCT or allotransplant. Before the first dose of BV, seven patients suffered disease progression during chemotherapy and six had relapsed after response. All patients were stage III or IV before the first dose of BV, except one in stage I. With an ORR of 62%, the present analysis confirms previous reports on the efficacy of BV in relapsed HL and ALCL (Pro et al, 2012; Younes et al, 2012). The maximal response was complete response (CR) or unconfirmed CR (CRu) in 21 patients (47%) and partial response (PR) in seven patients (16%). In the subgroup of patients with primary refractory disease, 46% achieved complete metabolic response (Table 2). For patients with HL, ORRs were statistically different among those who had previously received ASCT (P = 0·04) and who were in CR after the most recent prior regimen (P = 0·02). Of note, other comparisons did not reach statistical significance. In the setting of relapsed/refractory HL, the pivotal study reported ORR and CR rates of 75% and 35%, respectively (Younes et al, 2012). The German Hodgkin Study Group (GHSG) has recently also reported their experience of single agent BV in 45 patients with refractory or relapsed CD30+ HL (Rothe et al, 2012). They described an ORR rate of 60% and a CR rate of 22% with patients having a higher risk profile than those included in the pivotal trial. Our study compares favourably with the GHSG report, as 88% of our patients had advanced disease (stage III/IV) at the initiation of BV compared with 33% in the GHSG report. Moreover, the present study included 88% of patients with primary refractory disease or early relapse, i.e. 30% more compared to the German experience, with an overall response rate close to 50% in this setting. Finally in the present study, 38% of the primary refractory or early relapsed patients who underwent PET-CT achieved a CR. Among the 13 patients treated for ALCL, 10 achieved a CR. With a CR rate of 77%, this present study compares favourably with the pivotal trial (Pro et al, 2012). Indeed, out of 58 patients treated, Pro et al (2012) reported a 57% CR rate. Of note, patients in the phase II study had a higher risk profile compared to our study, with 62% of patients having a primary refractory disease and 50% being refractory before BV. In the present cohort, PFS after 12 months was 18% (95% confidence interval 7–29) and the median PFS was 7 months (range 1–39) (Table 2). A favourable prognosis was observed in HL patients who reached CR after the most recent prior regimen (13 vs. 5 months, P = 0·03) and without extranodal manifestations at the initiation of BV (19 vs. 7 months, P = 0·02). Four patients with ALCL had received subsequent consolidation (ASCT n = 5 and allotransplant n = 1), but of the five HL patients with an allogeneic donor, only one was able to receive the transplant. Most patients were treated very late in their disease and had no allogeneic donor available before BV treatment, so the benefit of allotransplantation cannot be evaluated in the present series. At the time of the analysis, eight patients had died of their disease. All patients received at least one injection of BV administered at the dose of 1·8 mg/kg. The median number of cycles was 7 (range 1–16). Dose reduction was necessary for three patients, with grade 4 neutropenia and thrombocytopenia for one patient. The most frequent adverse event, grade 2 sensitive neuropathy, occurred in five patients. The other adverse events reported were: grade 2 nausea (one patient), grade 3 hepatic cytolysis rapidly reversible (one patient) and grade 2 interstitial pneumonitis (one patient) occurring after mediastinal radiotherapy. Thus, particular attention must be paid to patients who received initial mediastinal radiotherapy. Nevertheless, the patient affected by this adverse event has fully recovered. Our results on 45 patients confirm previous reports on the efficacy of BV in the setting of relapsed or refractory CD30+ lymphoma (Pro et al, 2012; Younes et al, 2012). BV is effective in this heavily pretreated group of patients even though the PFS was short because many responding patients have relapsed. HM and PB designed the research, analysed data and wrote the paper. LD, CRW, MV, PF, CB, EK, MM, CT performed research, provided patients, and collected the data.