Bendamustine plus ofatumumab for naïve, elderly patients with DLBCL: Results from a phase II trial

On 9 May 2019, Ian Flinn from the Sarah Cannon Research Institute, Nashville, TN, USA, and colleagues, published diffuse large B-cell lymphoma (DLBCL) phase II clinical trial results (NCT01626352) in The Oncologist.¹ This trial investigated the efficacy of bendamustine and ofatumumab in elderly patients with newly-diagnosed DLBCL, who were not good candidates for standard chemotherapy regimens.

The current standard of care for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Nevertheless, old age has been associated with worse outcomes following R-CHOP in patients with DLBCL². Bendamustine in combination with rituximab has shown a more tolerable safety profile in elderly patients than R-CHOP³. The anti-CD20 antibody ofatumumab, is also well-tolerated in this population and mediates B-cell lysis.⁴ Therefore, this trial sought to examine whether bendamustine plus ofatumumab could be an effective and well tolerated regimen for naïve and elderly DLBCL patients.

The primary endpoint of this single-arm trial was complete response (CR) rate. Secondary endpoints included, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.

Study design & baseline characteristics

• N = 21 enrolled patients with DLBCL, aged ≥ 70 years
• Median patient age (range): 83 (73−88) years
• Male patients: 42.9% (n = 9)
• Dosing (21-day treatment cycles):
  • Bendamustine: 90 mg/m² intravenously (IV) on Days 1 and 2 of cycles 1−6
  • Ofatumumab: 1000 mg IV on Days 1 and 8 of cycle 1 and on Day 1 of cycles 2−6
• Modified Ann Arbor disease stage at diagnosis:
  • Stage III: 66.7% (n = 14)
  • Stage IV: 33.3% (n = 7)
• Patient race:
  • White: 95.2% (n = 20)
  • American indian/Alaskan native: 4.8% (n = 1)
• Median β2-microglobin levels (range): 3 (0−7)
• Abnormal β2-microglobin levels: 85.7% (n = 18)

Key findings

• Median follow-up (range): 9.9 (2.3−4) months

ORR, n (%)	19 (90.5%)
Complete response (CR)	7 (33.3%)
Partial response (PR)	12 (57.1%)
Stable disease (SD)	1 (4.8%)
Progressive disease (PD)	1 (4.8%)
Not evaluable	0
Median PFS (90% CI)	8.6 months (4.6−10.6)
Median OS (90% CI)	12.0 months (5.9−30.8)
Median time-to-progression (TTP; 90% CI)	10.5 months (4.5−not reached)

• 12-month OS probability: 52.4% (90% CI, 33.4−3)
• 12-month PFS probability: 31.7% (90% CI, 15.9−8)
• 12-month TTP probability: 40.1% (90% CI, 19.1−4)
• Patients who completed treatment: 57.1% (n = 12)
• Reasons for treatment discontinuation:
  • PD: 14.3% (n = 3)
  • Concurrent illness: 9.5% (n = 2)
  • Death: 9.5% (n = 2; one treatment-related bowel sepsis and one from unknown cause)
  • Patient request: 4.8% (n = 1)
  • Non-compliance: 4.8% (n = 1)
• The study was discontinued early on due to low patient accrual

Safety

• Hematological Grade ≥ 3 adverse events (AEs) that occurred:
  • Thrombocytopenia: 14% (n= 3)
  • Neutropenia: 10% (n= 2)
  • Leukopenia: 5% (n = 1)
  • Anemia: 5% (n = 1)
  • Lymphopenia: 5% (n = 1)
• Non-hematological Grade ≥ 3 AEs observed:
  • Vomiting: 10% (n = 2)
  • Diarrhea: 5% (n = 1)
  • Necrosis: 5% (n = 1)
  • Hypomagnesemia: 5% (n = 1)
  • Hyperuricemia: 5% (n = 1)
  • Sepsis: 5% (n = 1)
  • Anorexia: 5% (n = 1)
  • Fatigue: 5% (n = 1)
  • Pneumonia: 5% (n = 1)
  • Hypocalcemia: 5% (n = 1)
  • Hypokalemia: 5% (n = 1)
  • Tumor lysis syndrome: 5% (n = 1)
• Patient deaths at follow-up: 66.7% (n = 14)
  • Reasons of death:
    • Due to AE: 4.8% (n = 1; bowel necrosis)
    • Due to disease: 28.6% (n = 6)
    • Due to concurrent illness: 4.8% (n = 1)
    • Due to unknown causes: 28.6% (n = 6)

Conclusions

The results of this small phase II trial showed that the combination of ofatumumab and bendamustine was well tolerated and led to modest response rates in elderly, newly-diagnosed patients with DLBCL. The degree of efficacy may appear modest when compared to standard of care, but maybe of benefit to those intolerant to R-CHOP.