HL

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
References
  1. Garcia-Sanz R. et al. Brentuximab Vedotin and ESHAP is Highly Effective as Second-Line Therapy for Hodgkin Lymphoma Patients (Long-Term Results of a Trial by the Spanish GELTAMO Group). Ann Oncol. 2019 Jan 18. DOI: 10.1093/annonc/mdz009 [Epub ahead of print].
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