New targeted drugs might represent a more potent treatment approach for patients with relapsed or refractory HL and might reduce systemic toxicity compared with conventional chemotherapy
Stefanie Kreissl MD
German Hodgkin Study Group,
Department I for Internal Medicine,
University Hospital Cologne, Germany
Peter Borchmann MD
Study Secretary of the German Hodgkin Study Group
Department I for Internal Medicine
University Hospital Cologne, Germany
Within past decades, Hodgkin’s lymphoma (HL) has turned from an incurable malignancy into a neoplasm with a very favourable prognosis due to refined treatment regimens, including polychemotherapy and radiotherapy. With overall survival rates of >90% at five years, minimising acute and late toxicities without compromising the tumour-specific outcome of patients is considered to be the major goal of current clinical research. However, the few patients relapsing or showing primary progressive disease still face a very poor prognosis.
Introduction to CD30
Reed-Sternberg cells express a number of transmembrane receptors that belong to the tumour necrosis factor (TNF) family, including TNF receptor 1 and 2, CD30, CD40 as well as RANK.(1,2) Among this group, CD30 is considered an ideal target for monoclonal antibody therapy, as its expression is restricted to only a small number of activated B- and T-lymphocytes in healthy individuals, whereas it is aberrantly expressed in malignant RS-cells in classical HL.(3,4)
CD30 occurs both in a membrane-bound form and in a soluble form.(5–7) Former clinical trials evaluated several naked monoclonal CD30 antibodies in patients suffering from relapsed HL. All of them revealed excellent safety profiles, but only limited anti-tumour activity, mainly due to poor antigen-binding properties, ineffective activation of effector cells or neutralisation by high levels of soluble serum CD30.(8–10)
Therefore, antibody-drug conjugate (ADC) treatment strategies were generated, with brentuximab vedotin (BV, formerly known as SGN35) to be the most recent and most effective.
BV is an ADC consisting of the chimeric anti-CD30 antibody and the synthetic cytostatic monomethyl auristatin E. After binding of the antibody to the target antigen CD30, the conjugate is internalised into the cell and the cytostatic is released enzymatically.(11) By interrupting the mitotic spindle apparatus, the cytostatic arrests the cell cycle, thus leading to apoptosis of the CD30-expressing tumour cells.(12)
BV in third-line treatment
Preclinical trials showed a promising activity of BV, both as monotherapy and in combination with conventional chemotherapy.(13) Based on these findings, a multicenter phase I dose escalation trial that included 45 patients with multiply relapsed or refractory CD30-positive haematological malignancies was conducted. The vast majority (93%) of the patients had HL, out of which 73% had already undergone autologous stem cell transplantation (SCT) or a median of three prior treatment regimens, respectively. Patients received escalating doses of BV, from 0.1mg/kg to 3.6 mg/kg, in an outpatient setting. The maximum tolerated dose was 1.8 mg/kg administered at three-week intervals. Dose-limiting toxicities were grade 4 thrombocytopenia, febrile neutropenia and hyperglycaemia.
The results demonstrated tumour regression in 36 out of 42 (86%) analysed patients and a median response duration of at least 9.7 months.(11) In the analysis restricted to the cohort receiving ≥1.8mg/kg, six of 12 (50%) patients showed a tumour response, with four of them achieving complete remission.
Another phase I trial evaluated the application of BV on a weekly schedule for three weeks followed by one week of rest in a total of 37 patients, 31 with HL. The number of patients who had previously received an auto-SCT transplantation was slightly lower (62%). Sixteen (46%) patients showed a major response, and 29% achieved complete remissions. Dose-limiting toxicities in this study were grade 3 gastrointestinal (vomiting and/or diarrhoea) and grade 4 hyperglycaemia.(14)
Following these two trials, a phase II trial was initiated with 102 classical HL patients who had developed a second relapse. Patients had to have received high-dose chemotherapy and auto-SCT in first relapse. BV was administered at 1.8 mg/kg of BV every three weeks again in an outpatient setting for up to 16 cycles. The median age of patients was 31 years (range 15–77 years). Most of the patients enrolled (71%) had developed an early relapse within the first year of auto-SCT. Of all patients evaluated, 94% showed reduction in their tumour measurements. A major tumour response could be observed in 76 of 102 patients (75%), and 34% achieved complete remissions as determined by PET/CT. The median time to response was 5.7 weeks, and time to complete remission was 12 weeks.
The median duration of complete remissions was around two years. For patients with complete response, the median overall survival was not reached at two years. Peripheral neuropathy (42%), nausea (35%) and fatigue (34%) were the leading treatment-related side effects, with grade 3 or 4 neuropathy (8%) being the most common reason for discontinuation of BV.(15) Overall, the balance of efficacy and toxicity with BV is certainly superior to conventional cytostatic compounds, as neither a comparable remission rate nor a comparable tolerability have been observed before.
1. Based on these encouraging results, BV was approved for use in Europe in November 2012 for the following indications:
2. Relapsed and/or treatment-refractory CD30+ Hodgkin lymphoma after autologous stem cell transplantation or after at least two prior therapies in cases where autologous stem cell transplantation was not possible
Relapsed and/or refractory systemic anaplastic large cell lymphoma after at least one prior chemotherapy
Since BV was approved for the indications mentioned above, it is also increasingly been used as a bridge to allogeneic SCT, which is still routinely offered to healthy, young individuals failing auto-SCT.
This approach seems to provide high response rates, accompanied by few and well-manageable toxicities. However, it is still unclear which cohort of patients benefits from allogeneic SCT after achieving CR by reinduction treatment with BV.
BV in second-line treatment
These promising data raise the question of whether BV may also be effective in second-line therapy in terms of salvage therapy before ASCT or consolidation therapy after ASCT.
Regarding the value of BV in the salvage therapy approach, either as a single agent or in combination with chemotherapy regimens, further data from randomised trials are needed.
The role of BV as consolidation therapy after ASCT is currently being evaluated in a randomised, placebo-controlled trial in 329 patients at high risk for relapsed disease (AETHERA trial, NCT01100502). The randomisation has already been completed, but results of the final analysis are still pending.
BV in first-line treatment
BV was first tested in frontline therapy in a recent phase I trial in 51 patients with advanced stage HL, combining escalating doses of BV (0.6, 0.9, 1.2 mg/kg) with six cycles of the standard BV plus doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). BV was applied every two weeks. The ABVD regimen was combined with escalating doses of BV, applied every two weeks. Excellent clinical efficacy was observed in the ABVD-BV-arm, with 21 of 22 (95%) analysed patients achieving a complete remission, but nearly 40% of the patients developed pulmonary toxicity. Two patients died due to this side effect.
After this observation, bleomycin was omitted from the ABVD regimen and AVD was then combined with a fixed dose of BV at 1.2 mg/kg. The response rate in the AVD-BV arm was still high, with 92% complete remissions at the end of therapy and no single patient developed severe pulmonary toxicity. No dose-limiting toxicities were observed in either of the two treatment arms in the first cycle. Unfortunately, the subsequent cycles were not taken into account for the assessment of safety and feasibility.(16)
Based on this phase I trial, BV is currently being tested in combination with AVD chemotherapy in a multicenter randomised phase III trial (conducted by Millennium/Takeda) as first-line treatment in patients with advanced stage classical HL in comparison to standard ABVD (NCT01712490). The results of this study will allow a more accurate assessment of the side effects that may arise by combining two tubulin-inhibitors (BV and vinblastine).
Furthermore, BV is currently being investigated in combination with two modified escalated BEACOPP-regimens in advanced stage HL patients (NCT01569204) (Table 1). Minimising acute and late toxicities without compromising the tumour-specific outcome of patients is the major goal of this therapy approach. First results of this phase II trial conducted by the German Hodgkin Study Group (GHSG) were presented at the ASH meeting in December 2013.
Conclusions
The ADC BV was the first targeted drug to become approved by regulatory agencies in more than three decades for the treatment of HL patients. In relapsed or refractory HL, BV is considered to be the most effective single agent available at the moment. Moreover, randomised clinical trials investigating BV in frontline therapy as well as pre-and post-transplant regimens are currently being performed. Results from all of these trials will broaden the knowledge on the combinability of BV with different conventional cytotoxic drugs. Hopefully, these new combinations will improve the current standard of care in the treatment of HL regarding both efficacy and tolerability.
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