BRESHAP as second-line therapy for R/R HL patients

On 10 January 2019, Ramon Garcia-Sanz from University Hospital Salamanca, Salamanca, SP and colleagues, published in Annals of Oncology the long-term results of a phase I-II trial performed by the Spanish GELTAMO group (NCT02243436).

In this phase I-II trial the efficacy and safety of brentuximab vedotin (BV) in combination with etoposide, solumedrol, high-dose AraC, and cisplatin (ESHAP; BRESHAP) were investigated as second line treatment for relapsed or refractory (R/R) Hodgkin lymphoma (HL) patients. The initial analysis of this trial was published in Blood (2016). The primary endpoints of this long-term follow-up analysis were overall and complete response prior autologous stem cell transplantation (ASCT), as well as maximum tolerable dose (MTD). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and time-to-tumor progression (TTP).

Study design & baseline characteristics 

• N = 66 R/R HL patients after first-line chemotherapy
• Dosing:
  • ESHAP (three 21-day cycles):
    • Etoposide: 40 mg/m² (2h intravenous infusion) on Days 1−4
    • Cisplatin: 25 mg/m² (24h infusion) on Days 1−4
    • Methylprednisolone: 250 mg per day (15 min intravenous infusion) on Days 1−4
    • Cytarabine: 2 g/m² (2h intravenous infusion) on Day 5
  • BV: was administered on Day 1 in one of three dose levels (DL1, 0.9 mg/kg; DL2, 1.2 mg/kg; DL3, 1.8 mg/kg) on Day -1. Final BV dose was 1.8 mg/kg
  • Patients responding to BRESHAP proceeded to ASCT, followed by three BV courses. The first dose was administered on Day 28 post-transplant (1.8 mg/kg) and the rest every 21 days
• Dose-limiting toxicity (DLT) was defined before transplant as any non-hematological toxicity episode of Grade ≥ 3, or any hematological toxicity episode of Grade ≥ 4 lasting for > 21 days
• Median patients age (range): 36 (18−66) years
• Sex: n = 35 females, n = 31 males
• At infusion:
  • Primary refractory patients: n = 40
  • Patients with early relapses (complete response [CR] lasting less than one year): n = 16
  • Patients with late relapses (CR lasting ≥ 1): n = 10

Key findings 

Phase II data (n = 66):

• The first three treatment cycles were administered to all patients with a median time from first to second cycle, and from second to third cycle of 21 days, respectively
• Objective response (OR) rate prior transplant (n = 60): 91% (95% CI, 84−98%)
  • CR: 70% (95% CI, 59−81%)
  • Partial response (PR): 21% (95% CI, 11−31)
  • Stable disease (SD): n = 2
  • Disease progression (PD): n = 3
  • Death prior to evaluation: n = 1
• CR was less frequently achieved in patients with PD under first-line treatment, who had bone marrow involvement or who were at disease stage IV at inclusion
• Four months post ASCT, responses were seen:
  • CR: n = 49 patients
  • PR: n = 6 patients
  • PD: n = 10 patients
  • Death prior to evaluation: n = 1
• At a median follow-up of 27 months:
  • Patients with PD: n = 16
  • Death without PD: n = 3
  • PFS: 71% (95% CI, 65−77%)
• 30-month TTF: 74% (95% CI, 68−80%)
• Projected 30-month OS: 91% (95% CI, 84−98%)
• No differences in TTF or PFS were observed between DL2 and DL3 groups
• TTF was significantly influenced by:
  • Response to BRESHAP
  • Haemoglobin < 12.5 g/dL
  • Extranodal disease at inclusion
  • Bone marrow involvement at inclusion
• Stem cell mobilization was performed in n = 64 patients after the first (n = 15), second (n = 36), or third (n = 13) treatment cycle
• Six patients could not receive ASCT due to early death
• ASCT after BRESHAP was carried out in n = 60 patients (all engrafted)

Safety

• During this follow-up, 39 serious adverse events (SAEs) occurred in n = 22 patients
• The most common SAEs were:
  • Fever: n = 25 (35% neutropenic)
  • Hypomagnesemia and gastrointestinal symptoms: n = 3
• Three SAEs led to death (pneumonia, n = 1; abdominal sepsis, n= 1; pulmonary embolism, n = 1)
• All deaths were deemed as unrelated to BV protocol inclusion
• Grade 3−4 hematological AEs occurred in 28 cases (apart from ASCT):
  • Neutropenia: n = 21
  • Thrombocytopenia: n = 14
  • Anemia: n = 7
• Grade 3−4 non-hematological AEs occurred in 16 cases:
  • Non-neutropenic fever: n =13
  • Hypomagnesemia: n = 3
• Peripheral neuropathy (PNP) was never present prior to ASCT, except in one patients who developed Grade 2 PNP after BRESHAP (fourth dose was not administered). Two more patients developed PNP after ASCT
• In total, three patients discontinued BV due to PNP 

Conclusions

• BRESHAP has a tolerable profile in R/R HL patients
• BRESHAP could present an effective pre-transplant induction regimen for R/R HL patients, as it does not seem to affect transplantation success and leads to long-term remissions and OS