To BeEAM or to R-BEAM prior to ASCT in B-cell lymphomas?

On 23 February 2018, two studies independently investigated the efficacy and safety of modified carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning prior to autologous stem cell transplantation (ASCT), in B-cell lymphoma patients. One study by Sylvain P. Chantepie from the Caen University Hospital, Normandy, France, and colleagues, published ahead of print in the American Journal of Hematology, results on the safety of replacing carmustine with bendamustine in BEAM (BeEAM). The second study, by Jad Chahoud from the MD Anderson Cancer Center, Houston TX, and colleagues, reported the efficacy and safety of combining rituximab with BEAM (R-BEAM), in the journal of Clinical Cancer Research.

BEAM conditioning is one of the most commonly used regimens for either non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) patients, undergoing ASCT, as it presents with acceptable safety and efficacy. Nevertheless, a big percentage of patients relapse after ASCT, as seen in approximately 50-60% of patients with diffuse large B-cell lymphoma (DLBCL). The BeEAM study retrospectively evaluated  the safety of bendamustine-based BEAM conditioning prior to ASCT, in a large cohort of relapsed B-cell lymphoma patients (NHL and HL) from LYSA centers. Their primary endpoint was safety. The R-BEAM study, investigated retrospectively the possible advantage of R-BEAM prior and after ASCT, in relapsed DLBCL patients (NHL) enrolled on three consecutive phase II clinical trials (NCT00591630, NCT01538472). The primary endpoints for this study included disease-free survival (DFS), overall survival (OS) and toxicity.

Patient characteristics

BeEAM study

• N = 474 patients with ≥ 1 pre-transplant chemotherapy line
  • n = 302 (63.7%) had received prior platinum-based chemotherapy
  • Median prior line of chemotherapy (range): 2 (1–9)
  • n = 272 (57.4%) were transplanted after 2 lines of chemotherapy
• Aged ≥ 16, median age (range): 56 (17–72)
  • Diffuse large B-cell lymphoma (DLBCL), n = 43.5%
  • Mantle cell lymphoma (MCL), n = 16.5%
  • Hodgkin lymphoma (HL), n = 15.2%
  • Follicular lymphoma (FL), n = 12.2%
  • Peripheral T-cell lymphoma (PTCL), n = 7.6%
• Prior chronic renal failure history in 5.9% of the patients

R-BEAM study

• N = 113 patients with CD20-positive DLBCL persistent or relapsed chemosensitive disease
• Aged: 19.6–69.7 years

Study designs

BeEAM study

• BeEAM dosing:
• Bendamustine median dose (range): 196 (51–250) mg/m²/day on -7D and -6D
  • Median duration of bendamustine perfusion (range): 60 min (30–143)
  • n = 145 (31%) patients received 100–160 mg/m²/day bendamustine
  • n = 325 (69%) patients received > 160 mg/m²/day bendamustine
  • n = 4 (8%) patients received < 100 mg/m²/day on D 1–2
• Etoposide dose: 200 mg/m²/day
  • Two-hour infusions twice/day from -5D to -2D (in 92.4% of the patients)
• Cytarabine median dose (range): 395 (99–505) mg/m²/day
  • Two-hour bolus twice/day at > 250 mg/m²/day from –5D to –2D (in 58.2% of the patients)
• Melphalan median dose (range): 140 (0–154) mg/m² at –1D,
  • Dose reduction due to renal failure in 7.9% patients

R-BEAM study

• Rituximab dosing:
  • Rituximab first dose: 375 mg/m² the day before chemo-mobilization (ifosfamide [ 3.33 g/m² daily for 3 days] and etoposide [150mg/m² twice per day, or bid, for 3 days] in most patients)
  • Rituximab second dose: 1000 mg/m² 7 days after dose 1 and on D1 and D8 after ASCT
• BEAM dosing:
  • Carmustine: 300 mg/m² by 1h IV infusion on -6D
  • Etoposide: 200 mg/m² IV on -5D till -2D (total of 8 doses)
  • Cytarabine: 200 mg/m² IV on -5D till -2D (total of 8 doses)
  • Melphalan: 140 mg/m² IV on -1D
• ASCT:
  
  • Autologous grafts: peripheral-blood progenitors (n = 111, 98%)
    • Median number of CD34-positive cells infused: 5.5 x 10⁶/kg

Key results

BeEAM safety

• Most common toxicities:
  • Mucositis, gastroenteritis, colitis, skin toxicity, hepatic toxicity, pneumonitis, cardiac rhythm disorders, opportunistic infection and human herpesvirus 6 reactivation
• Intensive care management: 10%
• Toxic death: 3.3%
• Non-relapse mortality (NRM): 3.3%
• Acute renal failure (ARF): 27.9% (n = 132; grade ≥ 2; 12.3%)
• Univariate analysis revealed:
  • Colitis (P = 0.0017), skin toxicities (P = 0.0267), pneumonitis (P = 0.0003), cardiac arrhythmia (P ≤ 0.0001), intensive care admission (P ≤ 0.0001), need for a blood/platelet transfusion (P ≤ 0.0001), hospital stay duration (P ≤ 0.0001) and death (P ≤ 0.0001) more frequent in patients with post-conditioning renal failure
• Prognostic factors for ARF (multivariate analysis):
  • Pre-transplant chronic renal failure
  • Bendamustine dose > 160 mg/m²
  • Age > 55 years
• NRM-associated factors (multivariate analysis):
  • Pre-transplant chronic renal failure (P = 0.02)
  • Lower volume of hyperhydration (P = 0.044)
  • Time of hyperhydration onset (P = 0.016)
  • Etoposide dose (P = 0.0003)

R-BEAM safety & efficacy

• Median follow-up: 11.8 years (group A) and 4.8 years (group C)
• 5-year DFS rate: 62% (95% CI [0.50–0.73])
• 5-year OS rate: 73% (95% CI [0.62–0.83])
• Similar OS (P = 0.52) and DFS (P = 0.64) for patients with transformed DLBCL or mediastinal DLBCL, or DLBCL with a germinal centre B cell-like (GCB) or a non-GCB immunophenotype
• Similar DFS (P = 0.82) and OS (P = 0.65) for patients receiving R-BEAM with or without the radioimmunoconjugate, yttrium-90 ibritumomab tiuxetan (⁹⁰YIT)
• Prognostic DFS factors (univariate analysis):
  • Elevated LDH
  • IPI score > 0 prior chemo-mobilization
  • Number of prior chemotherapy regimens
  • PET positivity
• Prognostic OS factors (univariate analysis), worst OS associated with:
  • Serum beta₂-microglobulin level > 2 mg/L
  • IPI score > 0 prior chemo-mobilization
  • Prior chemotherapy regimens > 3
  • PET positivity at time of enrolment
• Safety:
• Death in n = 28 (24.8%) patients
• Most common causes of death:
  • Relapse or progression: n = 23
  • NRM: n = 5
• 5-year rate of secondary hematologic malignancies: 6.2 %
• Four additional patients developed secondary solid-organ malignancies with a cumulative incidence of 3.5%
• No significant difference in the rate of secondary malignancies in patients receiving R-BEAM with or without ⁹⁰YIT

The results from the above studies suggest: (a) that bendamustine-based BEAM treatment prior to ASCT presents with a high rate of ARF (28% all grades) and a 3.3% of BeEAM-associated toxic deaths, in relapsed B-cell lymphoma patients, whereas (b) the addition of rituximab in BEAM (R-BEAM) prior and after ASCT, produces high survival rates and is well-tolerated by relapsed DLBCL patients. Moreover, the addition of the ⁹⁰YIT radioimmunoconjugate to R-BEAM conditioning did not confer any additional treatment benefits.