Initial Hodgkin treatment of the frail elderly

In this issue of Blood,Friedberg and colleagues present results of a clinical trial that suggests a new treatment option for frail Hodgkin lymphoma (HL) patients, age 60 years and older.¹ 

It is estimated that elderly patients comprise approximately 20% of the total HL population. Although their disease is potentially curable, their outcomes, including survival, are worse than are those in younger patients. Part of this difference may be due to a different disease biology reflected in differences in presentation that could affect responsiveness to treatment. These commonly include mixed cellularity histology, advanced stage, B symptoms, and poor performance status. Mediastinal involvement and bulky nodal disease are uncommon. Poor tolerance of chemotherapy due to comorbidities and frailty is at least equally important. In clinical trials of doxorubicin, bleomycin, vinblastine, and dacarbazine, the most common initial treatment regimen for HL, dose modifications and delays and grades 3 and 4 toxicities (in approximately two-thirds of patients) including leukopenia, infection, and nausea were common, and treatment-related mortality of 5% was seen even with 4 cycles of chemotherapy.^2,3  In particular, approximately one-third of patients required discontinuation of bleomycin because of pulmonary toxicity, and bleomycin pulmonary toxicity was fatal in 5% to 14% of patients.^4,5  Treatment-related mortality was 21% with standard-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), which has precluded its further use in the elderly HL population.⁶ 

Attempts have been made to continue curative intent but reduce toxicity with alternative chemotherapy regimens. The German Hodgkin Study Group conducted a phase 2 trial of prednisone, vinblastine, doxorubicin, and gemcitabine in patients ages 60 to 75 years, 93% of whom had advanced disease. The 3-year estimates of overall survival (OS) and progression-free survival (PFS) were 66% and 58%, respectively. Grades 3 and 4 toxicities were seen in 75% of patients, although there was only 1 treatment-related death.⁷  A phase 2 trial was reported by the Scotland and Newcastle Lymphoma Group with vinblastine, cyclophosphamide, prednisolone, procarbazine, etoposide, mitoxantrone, and bleomycin in patients 60 years of age or older for 3 cycles with radiation therapy for early-stage HL and 6 cycles for advanced-stage HL.

For early-stage patients, 3-year PFS and OS were 74% and 81%, respectively, and 3-year PFS was 58% and OS 66% for those with advanced stages. The overall treatment-related mortality was 7%.⁸ 

Brentuximab vedotin (BV) is an antibody-drug conjugate with approximately twice the response rate reported for any single conventional chemotherapy agent in heavily-treated relapsed and refractory HL⁹  and has been approved by the US Food and Drug Administration for that indication. Recently, favorable results have been reported in the media for BV in combination with conventional chemotherapy as initial treatment for advanced HL, as reported at the 2017 American Society of Hematology meeting.

Friedberg and colleagues now report the results of a phase 2 trial combining BV with 1 of 2 alkylating agents, bendamustine or dacarbazine (DTIC), as an initial treatment of patients at least 60 years of age who would not be candidates for conventional chemotherapy. The initial part of this trial with BV monotherapy demonstrated an overall response rate (ORR) of 92% with a complete remission (CR) rate of 73% and median response duration of 9.1 months.¹⁰ 

The trial was then amended to test BV in combination with the 2 other agents. Most patients had stage III or IV disease, and approximately half had at least 3 comorbidities or conditions interfering with quality of life. Twenty-two patients were treated with BV (1.8 mg/kg) and DTIC (375 mg/m²) every 3 weeks for 12 cycles, followed by BV alone for at least 4 additional cycles. A second cohort of 20 additional patients received BV (1.8 mg/kg) and bendamustine (90 mg/m² on days 1 and 2) every 3 weeks for up to 6 cycles, followed by BV every 3 weeks for at least 10 cycles. The dose of bendamustine was reduced to 70 mg/m² during the trial because of excessive toxicity. The primary objective was determination of the ORR. Secondary endpoints included safety, CR rate, B symptom resolution, response duration, PFS, OS, and pharmacokinetics.

For BV and DTIC, ORR was 100% and CR rate 62%. At median follow-up time of 21.6 months, median PFS was 17.9 months. For patients achieving CR, median PFS had not been reached, and median PFS for patients achieving a partial response was 10.8 months (see figure). For BV and bendamustine the ORR was also 100% and CR rate 88%.

The BV and bendamustine cohort was terminated before the target accrual of 30 patients because of serious adverse events in 65% of the patients and 2 treatment-related deaths. In the BV and DTIC cohort, 45% experienced at least grade 3 adverse events, and 18% had serious adverse events. Peripheral sensory neuropathy was the most common toxicity (77%), which led to dose modifications in 32% of patients and treatment discontinuations in 36%. The peripheral neuropathy improved or resolved in most patients.

The result with BV and DTIC is very promising for a population of frail elderly patients who would likely otherwise receive only palliative treatment. In particular, the durable responses achieved for patients in CR are impressive. Although these are results from a small number of patients, they could provide a treatment option for this population of patients, which is extremely difficult to treat.