Pentostatin, cyclophosphamide, and rituximab combination for advanced-stage iNHL

On 28 February 2019, Tamer Khashab from the University of Texas MD Anderson Cancer Center, Texas, USA, and colleagues, published in the British Journal of Haematology updated results from a prospective phase II trial that investigated the efficacy of pentostatin, cyclophosphamide, and rituximab (PCR) combination in naïve patients with advanced-stage indolent non-Hodgkin lymphoma (iNHL).

In the primary analysis of this phase II trial (NCT00496873), PCR was well tolerated and led to strong responses in previously-untreated iNHL patients. In this study, the follow-up results after a median of 108 months are reported. The primary endpoints of this study were progression-free survival (PFS) and overall survival (OS). The main secondary endpoint was the long-term safety profile of PCR in this patient population.

Study design

• N = 83 previously-untreated iNHL patients, with disease stage III−IV or bulky disease stage II, and with Eastern Cooperative Oncology Group (ECOG) performance status 0−2 with the following diagnoses:
  • Follicular lymphoma (FL): 43.4% of patients
  • Small lymphocytic lymphoma (SLL): 38.5% of patients
  • Marginal zone lymphoma (MZL): 18.1% of patients
• Most patients had Ann Arbor stage IV lymphoma (78.3%) and bone marrow (BM) involvement (63.9%)
• Median patient age (range): 59 (34−84) years
• Dosing (PCR; six 21-day cycles [three additional cycles if complete response was not reached]):
  • Pentostatin: 4 mg/m²
  • Cyclophosphamide: 600 mg/m²
  • Rituximab: 375 mg/m²
• Clinical responses were assessed based on the Cheson criteria at baseline and after cycles 3, 6, and if needed 9. After treatment completion, responses were evaluated every three months in the first year, every six months in the second year and annually thereafter

Key results

• Total patient cohort (n = 83)
  • Overall response rate (ORR): 92%
  • CR: 71% (n = 59)
  • Unconfirmed CR (CRu): 15.7% (n = 13)
  • Partial response (PR): 5% (n = 4)
  • CR/CRu were not significantly different among FL, MZL and SLL patient cohorts
• FL patients (n = 36)
  • CR: 97%
  • 10-year OS rate: 94% (95% CI, 0.86−1.0)
  • Patients remaining in remission: 75% (n = 25)
• SLL patients
  • CR: 83.9%
  • 10-year OS rate: 39% (95% CI, 0.20−0.75)
  • Patients remaining in remission: 21.9% (n = 7)
• MZL patients
  • CR: 100%
  • 10-year OS rate: 66% (95% CI, 0.46−0.95)
  • Patients remaining in remission: 53.3% (n = 8)
• After a median follow-up of 108 months (range, 22−128):
  • 5-year PFS: 64% (95% CI, 0.54−0.75)
  • 10-year PFS: 42% (95% CI, 0.27−0.65)
• 10-year PFS based on histological subtype:
  • For FL: 71%
  • For SLL: 15%
  • For MZL: 67%
  • Comparison: P = 0.0014
• 10-year PFS for patients with BM involvement was 72% versus those without BM involvement, 29% (P = 0.0173)
• Better PFS was significantly associated with:
  • Lower pre-treatment β2M levels (< 2.2 mg/l versus ≥2 mg/l; P = 0.0017)
  • Female sex (P = 0.0439)
• At the end of the analysis:
  • Median OS: not reached
  • 5-year OS for all patients: 87%
  • 10-year OS for all patients: 64%
• 10-year OS based on histological subtype:
  • For FL: 94%
  • For SLL: 39%
  • For MZL: 66%
  • Comparison: P = 0.0017
• Better OS was associated with:
  • Lower pre-treatment β2M levels (< 2.2 mg/l versus ≥2 mg/l; P = 0.0079)
  • Age < 60 years at enrolment

Long-term safety

• Acute adverse events leading to toxic death occurred in two patients
• By year 10:
  • Twenty-one patients died (25.3%) from:
    • Acute disease progression: n = 2
    • Infection: n = 4
    • Multi-organ failure: n = 1
    • Unknown causes: n = 10
  • At a median of 30 months after PCR treatment 18 second malignancies (21.7%) were recorded:
    • Five patients developed non-melanoma skin cancer
    • One patient developed melanoma
    • Two patients developed myelodysplastic syndrome
    • Four patients transformed to diffuse large B-cell lymphoma

Conclusions

• PCR in previously-untreated aggressive stage iNHL patients resulted in clinically significant 5-year remission rated (PFS: 69%; OS: 87%)
• 10-year PFS and OS rates validate the long-term efficacy of PCR in this patient population
• Long-term toxicities of PCR were observed in 21.7% patients through second malignancies and in two patients (2.4%) as myelodysplastic syndrome