AETHERA

From Wiki Journal Club
Jump to navigation Jump to search

Clinical Question

In patients with relapsed or primary refractory Hodgkin's lymphoma, does Brentuximab vedotin administration after autologous stem-cell transplant improve progression-free survival over the standard of care treatment.

Bottom Line

Brentuximab vedotin increases progression-free survival from a median of 24.1 months to 42.9 months and reduces the hazard rate by 43% (n=329).

Major Points

Currently, relapsed or primary refractory Hodgkin lymphoma is treated with high-dose chemotherapy and stem cell transplant. Researchers have tried to manipulate this treatment through dose variation, radiation, and PET guided therapy to improve patient outcomes. However, all of these treatments are very toxic. After a phase 2 study showed significant success, AETHERA was conducted to test the success of Brentuximab, a CD30 antibody linked to a microtubule-disrupting drug.

The 2015 AETHERA trial used male and female patients between 18-71 years old diagnosed with Hodgkin's lymphoma who 1) had no complete remission after treatment or 2) relapsed within 12 months of treatment or 3) extranodal involvement during treatment start. They administered Brentuximab once every 3 weeks for up to 16 cycles and ran the analysis after 1 year continuing until study completion.

Guidelines

NCCN Guidelines for Hodgkin's Lymphoma (version 2.2020, adapted): https://jnccn.org/view/journals/jnccn/18/6/article-p755.xml

The following are preferred guidelines for patients <60 with relapsing or refractory Hodgkin's lymphoma:

1a) ICE (ifosfamide, carboplatin, etoposide) or DHAP (dexa, cisplatin, and high dose cytarabine)

1b) HDT/ASCR (high dose therapy + stem cell transplant)

1c) brentuximab vedotin

2) In patients >60, palliative treatment: bendamustine, brentuximab vedotin, everolimus, lenalidomide, nivolumab, or pembrolizumab.

Design

  • Multi-site, double-blind, randomized, placebo-controlled phase 3 trial
  • N=329
    • Brentuximab vedotin (n=165)
    • Placebo (n=164)
  • Setting: 78 centers in North America and Europe
  • Enrollment: April 6, 2010 to Sept 21, 2012
  • Mean follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: Progression-free survival by independent review


Population

Inclusion Criteria

  • Patients >18 with histologically confirmed classical Hodgkin's lymphoma
  • Previous high dose therapy and autologous stem cell transplant
  • complete/partial remission, or stable disease state after salvage chemotherapy with adequate organ function
  • One of the following risk factors:
  • Primary refractory HL (no complete remission)
  • Relapsed HL with remission duration <12 months
  • Extranodal involvement at the start of pre-transplant chemotherapy

Exclusion Criteria

  • Previously received brentuximab vedotin
  • Lack of written informed consent
  • Investigator decision
  • Adverse event
  • Progressive disease

Baseline Characteristics

Characteristics of experimental group vs. placebo

  • Mean age: 33 vs. 32
  • Sex (M/F): 76/89 vs. 97/67
  • Race (Asian/Black/White): 2/10/153 vs. 3/2/156 and 3 other
  • ECOG status (0/1/2): 87/77/1 vs. 97/67/0
  • Centrally confirmed HL: 159 vs. 156
  • Previous salvage therapies (1/2+): 94/71 vs. 86/78
  • >1 previous ASCT (time to dose): 5 (41 days) vs. 10 (41 days)
  • Frontline therapy (ABVD/BEACOPP/other): 119/26/20 vs. 129/20/15
  • Stem cell transplant conditioning regimen (BEAM/CBV/Other/Radiation): 106/13/46/11 vs. 96/22/46/10
  • HL status after frontline therapy (refractory/relapse <12 mo/relapse >12 mo): 99/53/13 vs. 97/54/13
  • Best therapy response after ASCT (complete remission/partial/stable dz): 61/57/47 vs. 62/56/46
  • pre-ASCT PET status (fluorodeoxyglucose +/-/unkown): 64/56/45 vs. 51/57/56
  • Extranodal involvement at pre-ASCT relapse: 54 vs. 53
  • B symptoms after frontline therapy: 47 vs. 40


Interventions

  • Randomized to intensive (targeting HbA1c <6%) or standard (HbA1c 7-7.9%) glycemic therapy

    • Then 46% were randomized to intensive (SBP <120) vs. standard (SBP <140) blood pressure therapy
    • Remaining 54% randomized to fenofibrate vs. placebo; all received statin
  • Intensive glycemic control group attended monthly visits for 4 months, then every 2 months, with additional visits and telephone calls as needed
  • Standard therapy group had glycemic control visits every 4 months

Outcomes

Comparisons are brentuximab + standard therapy vs. standard therapy.

Primary Outcomes

Progression-free survival by independent review
42.9 months (95% CI 30.4-42.9) vs. 24.1 months (95% CI 11.5-not estimable)

Secondary Outcomes

Hazard rate for progression-free survival
HR= 0.57 (95% CI .4-.81, p=0.0013)
2-year progression-free survival by independent review
63% (95% CI 55-70) vs. 51% (95% CI 43-59)

Subgroup Analysis

Subgroup analysis shows consistent HR>1 in subgroups (age, sex, ECOG status, prior Tx, salvage therapy response, lymphoma status, etc.)

Adverse Events

  • Peripheral neuropathy (67% vs. 19% in placebo)
  • Neutropenia (29% vs. 10%)

Criticisms

  • 51 of 167 patients discontinued the therapy course due to adverse reactions

Funding

Study funded by Seattle Genetics, which employs several study authors. Some authors are employees or have received payment from Takeda Pharmaceuticals International.

Further Reading


Retrieved from "http://www.wikijournalclub.org/w/index.php?title=AETHERA&oldid=41598"