New frontiers for brentuximab vedotin for lymphomas

Targeting of the potent anti-tubulin agent, monomethyl auristatin E (MMAE), directly to CD30 positive tumor cells using brentuximb vedotin (BV) has recently proven to be quite effective for patients with relapsed and refractory (rel/ref) Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). Before the entry of BV, these patients had very limited treatment options at their disposal, and the introduction of BV has undoubtedly prolonged many lives. However, the full extent of its impact on HL and ALCL still remains to be determined. Clinical trials evaluating BV in the front-line setting in HL and ALCL are under way and may lead to dramatic changes in our treatment strategies for these malignancies.

Following its success in HL and ALCL, the logical next step was to determine which other patient categories might benefit from BV. Other non-Hodgkin lymphomas are known to express CD30 at varying rates, but whether this would translate into sensitivity to BV was still unknown. It was also unclear at this point what constitutes CD30 positivity and what percentage of CD30 positive cells is required to regard a tumor as positive or whether there was a particular cut-off sufficient for BV activity. Ongoing studies are beginning to provide an answer to these questions, although some of the answers given may not be what we would have expected. Considerable single-agent activity has been reported for BV in other CD30 positive B cell lymphomas and systemic T cell lymphomas, as well as mycosis fungoides (MF) (Table I) [1–3]. Contrary to what we may have predicted, in each of these analyses, the level of CD30 expression did not correlate with response to BV, and in fact, responses were even observed among patients determined by immunohistochemical (IHC) staining to have no CD30 expression in their tumors. The reason for this is as yet not known; however, it is possible that a very low level of CD30 expression is indeed sufficient for BV efficacy due to the action of free MMAE on neighboring CD30-negative cells at the time of its release from dying CD30-positive cells within tumors. Furthermore, standard IHC may not be sensitive enough to detect very low levels of CD30 expression. Among patients with MF treated with BV, Krathen and colleagues were able to detect CD30 expression using quantitative image analysis on biopsies from 12 patients that were initially deemed negative by routine IHC. Even with this more sophisticated technique for evaluating CD30 expression, though, no correlation between CD30 expression and sensitivity to BV was found [3]. While these findings clearly raise questions regarding mechanisms of resistance to BV and the issues of biomarkers of sensitivity beyond CD30, they also illustrate the potentially broad utility of BV in lymphoma.

Table I. Activity of brentuximab vedotin in other non-Hodgkin lymphomas.

Diagnosis	n	CD30 expression level	Response
Mycosis fungoides [3]	19	< 10% (n = 7)	ORR: 68%
		10–50% (n = 10)
		> 50% (n = 2)
Diffuse large B-cell lymphoma [1]	43	Variable (ranging from 0 to 100% expression)	ORR: 40%; CR: 16%
Other B cell lymphomas [1]	18	Variable (ranging from 0 to 100% expression)	ORR: 22%
GZL	6		2 PR
PMBL	6		1 CR
FL	3		0
PTLD	3		1 CR
PTCL-NOS [2]	21	77% positive*, 18% negative	ORR: 33%; CR: 14%
AITL [2]	13	69% positive*, 15% negative	ORR: 54%; CR: 38%

GZL, gray zone lymphoma; PMBL, primary mediastinal large B-cell lymphoma; FL, follicular lymphoma; PTLD, post-transplant lymphoproliferative disorder; PTCL-NOS, peripheral T cell lymphoma, not otherwise specified; AITL, angioimmunoblastic T cell lymphoma; ORR, overall response rate; CR, complete response; PR, partial response.

*Defined as any detectable CD30 positivity by immunohistochemistry.

In the case report presented in this issue of Leukemia and Lymphoma, Hill and colleagues describe a 62-year-old woman with relapsed CD30-positive post-transplant lymphoproliferative disorder (PTLD) who achieved a complete response to BV [4]. This patient was diagnosed with diffuse large B-cell lymphoma (DLBCL) involving the small bowel 16 years after undergoing heart transplant for rheumatic heart disease. Following an attempt to reduce immunosuppressive medications, she achieved a complete response after receiving six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), only to relapse 4 months later. She was then treated with the R-ICE (R, ifosfamide, carboplatin, etoposide) regimen, which was complicated by neutropenic fever leading to renal failure. She subsequently developed disease recurrence confirmed by biopsy showing DLBCL in the terminal ileum associated with CD30 expression in a subpopulation of large cells by IHC. Without any standard treatment options available, the authors chose to treat with BV, hoping that the presence of CD30 positivity would confer sensitivity to this targeted agent. Without literature to guide dosing in renal insufficiency, they decided to administer the standard dose for BV, 1.8 mg/kg every 21 days. As described in the case report, BV proved to be effective and well tolerated for this individual, although she potentially experienced more neuropathy than would have been expected.

The success of BV in treating this individual highlights its potential in patients with organ dysfunction. The recently completed pharmacology study of BV in patients with renal insufficiency (NCT01026415) evaluated a reduced dose of BV, 1.2 mg/kg, and showed prolonged MMAE exposure in patients with severe renal impairment (creatinine clearance < 30 mL/min) [5]. This led to a recent update of the package insert recommending the reduced dose of 1.2 mg/kg for patients with renal impairment. This case also highlights the importance of investigating the therapeutic role of BV in other lymphomas. The post-transplant lymphoprolifertive disorders (PTLDs) represent a logical new frontier for BV treatment, given that many express CD30 [6]. Currently, there are very few reports of patients with PTLD treated with BV; three patients with PTLD were included in the CD30 positive B cell lymphoma study, one achieving a complete response. In this respect the role of BV in PTLD will be better clarified in the ongoing phase I/II study evaluating BV plus rituximab in untreated CD30 positive or Epstein–Barr virus (EBV) positive lymphomas (NCT01805037). Hopefully, through this and other ongoing studies we will learn more about the mechanisms of resistance to BV and additional markers of sensitivity beyond CD30.

Potential conflict of interest

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