Brentuximab vedotin followed by ABVD +/- radiotherapy in patients with previously untreated Hodgkin lymphoma: final results of a pilot phase II study.
The past few decades have seen major advances in understanding the pathobiology and clinical management of Hodgkin lymphoma (HL), making it one of the most successfully treated cancers worldwide. At present, more than 90% of patients with early-stage, and up to 80% with advanced-stage disease, are cured with current combined-modality treatment. Nevertheless, some 15% to 30% of all patients respond poorly, fail to respond, or relapse after up-front conventional therapy. These patients have little chance of achieving a durable remission. Moreover, long-term treatment-related toxicities, including second primary malignancies, have emerged as leading causes of morbidity and mortality among these, mostly young, survivors, with a devastating impact on their life expectancy. Today, maintaining or improving these outcomes, along with reducing late iatrogenic complications, represents an important challenge for patients with HL. The recent advent of the anti-CD30 antibody-drug conjugate brentuximab vedotin provides, for the first time, the opportunity to selectively target the malignant Hodgkin and Reed-Sternberg cell populations while virtually sparing normal cells. In the pivotal phase II trial, brentuximab vedotin showed remarkable clinical activity and a manageable safety profile in a subset of heavily pretreated relapsed or refractory HL patients following autologous stem cell transplant; 75% (76 of 102) of patients achieved an objective response and 94% (96 of 102) achieved some tumor reduction. Interestingly, the recent evidence that a proportion of patients responding to brentuximab vedotin still remain in remission after more than four years of follow up has raised the suggestion that they have been cured. Recently, brentuximab vedotin was combined with ABVD within either a concomitant or sequential schedule treatment. In a phase I dose-escalation study of previously untreated HL, the concomitant administration of 1.2 mg/kg brentuximab vedotin with a modified-standard treatment AVD every two weeks proved to be feasible and highly active, yielding 96% complete responses. Notably, the concomitant use of brentuximab vedotin and bleomycin was discouraged because of excessive pulmonary toxicity. Based on these promising findings, we designed a multicenter, single-arm, pilot phase II study to investigate the role of brentuximab vedotin 1.8 mg/kg for 2 cycles before starting standard treatment with 3 or 6 cycles of ABVD, depending on risk group, with or without radiotherapy (RT), in patients with newly diagnosed stage IA, IIA, and IIIA HL. The primary end point was response rate after brentuximab vedotin before starting ABVD. This was assessed by F-fluorodeoxyglucose PET (FDG/PET) scan and defined as a reduction in the now recommended Five Point scale or, if there was no change in Deauville score, as a reduction in standardized uptake value (SUV) intensity compared to maximum basal SUV. Secondary end points were: i) complete response (CR) rate at the end of the full treatment program as defined by Deauville score 1, 2 or 3; ii) 1-year progression-free survival (PFS) measured from the day treatment started to the date of progressive disease; and iii) the safety profile of brentuximab vedotin. Between April and October 2013, 12 patients were enrolled in our trial and all received the planned 2 cycles of brentuximab vedotin at the full dose of 1.8 mg/kg. Fifty-eight percent of the patients were female (n=7), while 92% (n=11) had stage II disease. Median age was 36 years (Table 1). After the 2 cycles of brentuximab vedotin, 10 patients (83%) achieved a complete metabolic response, and one achieved a partial metabolic response, resulting in an overall response rate (ORR) of 92%. One patient, with stage III disease, did not respond. Following brentuximab vedotin, 10 patients with stage II disease received 3 cycles of ABVD, and one received 4 cycles. Additional RT was delivered to 5 patients. The patient with stage III received 6 cycles of ABVD and no RT. After the full treatment program, the ORR reached 100%, with 11 complete responses and one partial response converting from disease progression. At a median follow up of 12 months, all patients were alive, with 11 still in complete remission, and one relapse. Median 1year PFS (range 7-16 months) was 92% (95%CI: 55-99). Interestingly, the overall FDG/PET concordance between local and central review process was 92%, with only one case amended from a score of 4 to a score of 2 by the central review panel. The treatment was generally well tolerated, and most common adverse events during brentuximab vedotin therapy were primarily grade 1 or 2, including nausea, vomiting, pyrexia and fatigue. The only grade 3 adverse events were transient and asymptomatic increases in liver transaminases (n=3, 25%) and gammaglutamyl transpeptidase (n=2, 17%). No grade 4 adverse events were registered. During ABVD with or without RT, grade 3 and 4 neutropenia occurred in 9 patients (75%), but toxicities were transient and resolved with granulocyte colony-stimulating factor support (Table 2). In this study, 2 cycles of brentuximab vedotin used upfront in treatment-naïve patients with newly diag-