Brentuximab vedotin: the science of common sense

An estimated 15–30% of patients will experience either primary refractory or a relapse of Hodgkin lymphoma (HL) despite modern therapy [1]. A second chance at cure can be achieved using non-cross-resistant second-line therapy followed by high-dose therapy and autologous stem cell transplant [2]. Several studies have demonstrated that tumor chemosensitivity predicts better treatment outcome after stem cell transplant, with the best outcome observed in patients who achieve a positron emission tomography- negative response [3]. In general, patients who do not respond to second-line therapy are considered not ideal candidates for stem cell transplant, and typically are offered subsequent treatments. Novel therapies to improve response rates and the quality of remissions in patients with relapsed and refractory HL would increase the pool of transplant-eligible patients, and therefore the chances of cure.

Brentuximab vedotin is an anti-CD30 drug–antibody conjugate that delivers a potent tubulin-disrupting agent to the malignant Hodgkin and Reed–Sternberg (HRS) cells of HL. The initial phase I clinical trial examined the safety and efficacy of brentuximab vedotin in heavily pretreated patients [4]. In a follow-up phase II study that led to the approval of brentuximab vedotin by the United States Food and Drug Administration (FDA), 102 patients with relapsed HL were treated. All patients were required to have prior stem cell transplant. The overall response rate was 75%, with 34% of patients achieving complete remissions [5]. Based on these impressive results, the FDA granted approval to patients with HL who had relapsed post-stem cell transplant. In addition, the FDA extended the approved indication to include patients who are transplant-ineligible and were refractory to two prior combination chemotherapy regimens [6]. This extended label indication was based more on common sense than on actual data. Given the high response rate and excellent safety profile in the post-transplant setting, it is logical to predict that brentuximab vedotin would be at least as effective in the pre-transplant setting.

In this edition of Leukemia and Lymphoma, Sasse and colleagues expand the limited literature on transplant-naive or transplant ineligible relapsed/refractory patients with HL who have received brentuximab vedotin [7]. In total, 14 patents were treated with brentuximab vedotin in a named program at the FDA-approved dosing and schedule. Congruent with the prior phase II study, brentuximab vedotin performed well, with an overall response rate of 71% (9/14) and a complete response rate of 36% (5/14). Importantly, brentuximab vedotin allowed 56% (5/9) of patients felt to be transplant-eligible to undergo transplant. At the time of publication four are alive. Brentuximab vedotin also afforded tolerable palliative treatment, as noted by no dose reductions due to toxicity in the transplant-ineligible cohort. Other groups have also reported small numbers of patients treated in similar situations, and their results remain encouraging (Table I).

Table I. Brentuximab vedotin in transplant-naive relapsed/refractory Hodgkin lymphoma.

Authors	Number*	Refractory^†	Transplant-ineligible	ORR	CR rate	Proceeded to transplant
Sasse et al. [7]	14	11	5	71%	36%	56%
Forero-Torres et al. [9]	20	13	7	30%	10%	23%
Gibb et al. [10]	18	UNK	UNK	72%	17%	22%^‡
Chen et al. [11]	8	6	UNK	88%	50%	75%

ORR, overall response rate; CR, complete responses; UNK, unknown.

*Includes only patients with Hodgkin lymphoma with evaluable response.

^†Refractory to at least one therapy.

^‡May include patients considered transplant-ineligible.

The safety and efficacy of brentuximab vedotin in combination with front-line and second-line regimens are currently being investigated in prospective trials. In a phase I trial, brentuximab vedotin combined with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was associated with significant pulmonary toxicity [8]. This was an unexpected toxicity and could be prevented by omitting bleomycin. Therefore, despite the excellent safety profile of single-agent brentuximab vedotin, clinicians should avoid the temptation of adding brentuximab vedotin to commonly used regimens outside of clinical trials.

The most understudied population at this point is the transplant-ineligible cohort. In this setting, the best dose and schedule, and ideal number of doses of brentuximab vedotin, remain undetermined. Likewise, several other questions in the relapsed/refractory setting remain. Is there a difference in transplant outcome in patients achieving remission after conventional chemotherapy compared with brentuximab vedotin? Is there an impact on the ability to collect stem cells or for stem cell engraftment after brentuximab vedotin? Should brentuximab vedotin be given as a single agent or in combination in the pre-transplant setting? Should the role of stem cell transplant be re-examined in the brentuximab vedotin era, similar to what has been done in non-Hodgkin lymphoma in the rituximab era? Logically, the answers to these questions can only be obtained from prospective clinical trials, some of which are being conducted.

With the introduction of brentuximab vedotin, the first new agent to be approved for patients with HL in more than 30 years, a new era has begun for the thousands of young men and women who have relapsed and refractory non-curable HL. The study reported by Sasse et al. has provided valuable information to fill a knowledge gap, and they are to be congratulated for taking this initiative. For many, these clinical responses provided hope for a second chance at cure. While it is tempting to speculate that further development of brentuximab vedotin is likely to improve the cure rate of HL, it is now important to be steadfast in collecting data from prospective clinical trials to scientifically validate common-sense approaches.

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