Initial Therapy of Advanced-stage Hodgkin’s Lymphoma

In 2003, the German Hodgkin Study Group (GHSG) reported the long-term results of a large randomized trial comparing three different regimens for the treatment of Stage IIb-IVb HL. The best outcomes were achieved with a dose-increased BEACOPP regimen, which resulted in a five-year survival of 91%. In the escalated BEACOPP (BE) regimen the dose of etoposide was increased from 100 to 200 mg per square meter of body surface area and the dose of cyclophosphamide was increased from 650 to 1200 mg per square meter of body surface area. The goal is to administer eight cycles of therapy. This regimen has become “the new standard” for treating advanced HL.”

At ASCO 2009, researchers compared eight cycles of BE to four cycles of BE plus four cycles of unescalated or baseline BEACOPP (BB) The purpose of this study was to determine if toxicity could be lowered without affecting other outcomes. Patients were also randomized to receive or not receive radiation therapy to bulky disease sites. A total of 1571 patients were included in this trial and the median follow-up was 78 months. The following summarizes the main findings of this trial:

• Anemia occurred in 65% of patients receiving BE and 51% of patients receiving BB.
• Thrombocytopenia occurred in 65% of patients receiving BE and 51% of patients receiving BB.
• Disease progression occurred in 6.6% of patients in the BE group and 8.5% in the BB group.
• There were 72 deaths in the BE group and 84 in the BB group.
• There were 15 deaths from HL in the BE group and 24 in the BB group.
• Deaths from secondary malignancies occurred in 22 patients in the BE group and 13 in the BB group.
• OS at five years was 91% for the entire group with an improvement in 1.8% in the BE group.
• Freedom from treatment failure was 85.5% for the entire group with an improvement of 2.3% for the BE regimen.
• There were no statistically significant differences in any outcome parameters.
• There were no differences between the radiation therapy or no-radiation therapy groups.

These authors concluded that “The adoption of 4BE+4BB as a new standard in the future GHSG will depend on a refined analysis of the total data set.”

Salvage Regimens for HL

The optimal treatment for patients with HL who have failed chemotherapy is high-dose therapy with autologous or allogeneic stem cell support. The results of high-dose therapy with stem cell support are improved if patients respond to salvage chemotherapy. Thus, the better the salvage chemotherapy, the more likely a patient will be cured with an autologous transplant. For patients who fail autologous transplant there is also a need for effective palliative chemotherapy.

Rituximab, Gemcitabine, Ifosfamide and Oxaliplatin 

Rituximab is effective in patients with relapsed lymphocyte-predominant HL that express CD20. Gemcitabine is active in salvage regimens for patients with recurrent HL. Researchers affiliated with Leukemia Group B have presented the results of a Phase I-II clinical trial suggesting that a regimen of gemcitabine, vinorelbine, and liposomal doxorubicin (GND) was an effective salvage therapy for patients with HL who had failed chemotherapy or an autologous transplant. Researchers from Hammersmith Hospital in England have also reported the effectiveness of a regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) for patients with relapsed or refractory HD. There are limited data on the use of oxaliplatin in patients with HL. In one study from France, gemcitabine was combined with oxaliplatin for the treatment of patients with recurrent HL. The overall response rate to gemcitabine and oxaliplatin or gemcitabine and vinorelbine was 20% with 10% having a CR.

At ASCO 2009, researchers from Italy have reported that the combination of gemcitabine and oxaliplatin provides effective salvage therapy prior to autologous stem cell transplant in patients with recurrent HL. There were 21 patients in this study; two had PR’s and 16 had CRs for an ORR of 76%. Four of six patients who had failed autologous transplantation had CRs. At 42 months the failure-free survival was 57%. Patients who had an autologous stem cell transplant had disease-free survival of 79% compared to 41% for those deemed unfit for high-dose therapy. These data suggest that this is a highly effective salvage regimen that allows stem cell collection for most patients.

Ifosfamide, Gemcitabine and Vinorelbine

At ASCO 2009, researchers from Italy presented data on 121 patients with relapsed/refractory HL who were treated with four cycles of ifosfamide, gemcitabine and vinorelbine (IGEV). Seventy-eight patients received single (n=59) or tandem (n=19) transplants following remission induction. The overall response rate to induction chemotherapy was 75% with a CR rate of 46%. This study found that achieving a CR was the most important favorable factor for ultimate outcome of treatment. This article emphasized the goal of increasing the CR rate prior to transplantation.

Anti-CD30 Monoclonal Antibody XmAb2513 

Anti-CD30 (a cell surface antigen expressed on Reed-Sternberg cells) monoclonal antibody XmAb2513 is a second-generation humanized monoclonal antibody directed against the cell surface receptor CD30 with potential immunotherapeutic activity. Anti-CD30 monoclonal antibody XmAb2513 specifically binds to the CD30 antigen, which may result in a cytotoxic T lymphocyte (CTL) response against CD30-expressing tumor cells. CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed on activated lymphocytes transiently and is constitutively expressed in hematologic malignancies including Hodgkin’s disease and some T-cell non-Hodgkin’s lymphomas.

At ASCO 2009 researchers from several US medical centers presented data from a Phase I study of XmAb2513 in patients with HL and anaplastic large cell lymphoma. In this study, MTD was not reached and responses were observed.

Anti-CD30 Monoclonal Antibody-Drug Conjugate (ADC): SGN-35

SGN-35 is comprised of an anti-CD30 monoclonal antibody attached to monomethyl auristatin E (MMAE), a synthetic drug payload; the two are attached by an enzyme cleavable linker. SGN-35 releases MMAE upon internalization into cells expressing CD-30. A previous dose-escalation trial was carried out in patients with relapsed or refractory HL or systemic anaplastic large cell lymphoma. Fifty-four percent of patients treated at the higher doses had an objective response with a 32% CR rate. These data were presented at the 2008 International Conference on Malignant Lymphoma in Lugano, Switzerland.

The current study evaluated a more frequent weekly dosing of SGN-35 weekly for three weeks every 28 days for a maximum of 12 cycles. Nine of 22 patients with refractory or relapsed HL and four of five with anaplastic large cell lymphoma responded. Treatment-related toxicity was described as non-significant.

Summary

Large clinical trials continue to fine tune therapy for up-front treatment of HL to decrease long-term side effects. For the first time there appears to be beginning progress in the development of monoclonal antibodies that may have activity in HL.
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