Results from the phase II HOVON 75 trial in patients with newly diagnosed mantle cell lymphoma

Rituximab and high-dose cytarabine (HD-Ara-C) induction immunotherapy, followed by autologous stem cell transplantation (auto-SCT), has significantly improved the prognosis of patients with mantle cell lymphoma (MCL).¹ Results from the HOVON 45 trial reported 4‐year progression‐free survival (PFS) rate of 44% and 4‐year overall survival (OS) rate of 66% for the three cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) followed, in responding patients, by one cycle of HD‐Ara‐C and autoSCT.² However, most patients with MCL relapse after auto-SCT. Bortezomib is a protease inhibitor approved for the treatment of relapsed/refractory MCL.³

Here, we present the results of HOVON 75 - a randomized phase II study, recently published in British Journal of Haematology. Jeanette Doorduijn and colleagues investigated the outcome of a modified chemo-immuno regimen and auto-SCT with or without maintenance therapy with bortezomib for treatment of patients with MCL.

 Study design and patient characteristics

• Eligible patients were aged 18–65 years with newly‐diagnosed MCL, Ann Arbor stage II to IV, with WHO performance status 0 to 2 and had measurable disease
• A total of 135 patients were eligible for the study and 60 of them underwent randomization following auto-SCT. Their characteristics are presented in Table 1.
• Induction therapy:
  • Three cycles of R-CHOP21 (rituximab 375 mg/m² Day 1, cyclophosphamide 750 mg/m² Day 1, doxorubicin 50 mg/m² Day 1, vincristine 1.4 mg/m² Day 1 (max 2 mg), all intravenous (IV), and prednisone 100 mg Days 1–5 orally),
  • Two cycles of HD-Ara-C (2 × 2 g/m² IV Day 1–4 [every 12 hours] in a 3‐hour saline infusion) and rituximab (375 mg/m², IV) on Day 11
  • Patients in partial (PR) or complete remission (CR) after the second cycle of HD‐Ara‐C continued with auto-SCT after carmustine, etoposide, cytarabine, melphalan (BEAM) conditioning
  • BEAM (carmustine 300 mg/m² Day −7, cytarabine 2 × 100 mg/m² Day −6 to −3, etoposide 2 × 100 mg/m² Day −6 to −3 and melphalan 140 mg/m² Day −2, IV ) was administered to patients, followed by auto-SCT (n = 115)
• Maintenance therapy:
  • Patients with a partial remission (PR) or complete remission (CR) after auto-SCT with a neutrophil count > 0.5 × 10⁹/L and platelets > 80 × 10⁹/L were randomized (1:1) to bortezomib or no further treatment
  • Bortezomib 1.3 mg/m² IV was given once every two weeks, for two years, starting between 6–12 weeks after transplantation
  • In total, 60 of 115 transplanted patients were randomized to bortezomib (n = 30) or no further treatment (n = 30)
• The primary endpoint: event-free survival (EFS)

Table 1. Patients characteristics

WHO, World Health Organization
	All patients     n = 135	Randomized patients after auto-SCT
		No further treatment, n = 30	Bortezomib maintenance, n = 30
Age (median, range)	57 (34–66)	54 (36–65)	56 (34–66)
Male sex	78%	77%	80%
WHO performance
WHO 0	105 (78%)	25 (83%)	25 (83%)
WHO 1	60 (19%)	5 (17%)	4 (13%)
WHO 2	5 (4%)	–	1 (3%)
Ann Arbor stage
II	11 (8%)	1 (3%)	3 (10%)
III	8 (6%)	2 (7%)	2 (7%)
IV	116 (86%)	27 (90%)	25 (83%)

Results

Outcomes of induction therapy

• In total, 127 patients completed all three cycles of R-CHOP and both cycles of HD-Ara-C. There were 79 (63%) patients who achieved a CR/CR unconfirmed (Cru) and 39 (31%) a PR
• In total, 115 patients underwent BEAM conditioning and autoSCT and 99 of them (86%) achieved a CR/CRu, while 15 (13%) achieved a PR. One patient was not restaged

Outcomes of maintenance therapy

• After autoSCT, 60/115 patients were analyzed for the maintenance phase (n = 30 patients received bortezomib and n = 30 no further treatment)
• With a median follow-up of 77.5 months for all patients
  • five-year EFS: 51%
  • OS: 73%
• In total 50 (37%) patients died; causes included
  • MCL: 52%
  • treatment-related: 2%
  • intercurrent disease: 10%
  • secondary malignancy: 8%
  • unknown: 8%
  • other: 20% (including seven patients who died from complications from auto-SCT)
• The median follow-up of randomised patients still alive was 71.5 months
  • 2-year EFS:
    • 83% in the bortezomib arm
    • 80% without maintenance
  • 5-year EFS:
    • 63% in the bortezomib arm
    • 60% without maintenance
  • 5-year OS: 90% both arms

Treatment course and safety

• Median duration of maintenance therapy: 21 months
• Out of 30 patients randomized to bortezomib
  • 15 continued the bortezomib therapy for the planned 24 months
  • 15 patients received bortezomib treatment for a median of 14 months (range, 0–23)
• Neurological adverse events (AEs) Grade 2 were experienced by four patients and Grade 3 by one patient; no Grade 4 neurological AEs were observed
• There were 15 patients (11%) who developed a secondary malignancy
  • six patients in the bortezomib arm
  • nine patients in the observation arm

Conclusion

This HOVON 75 trial was designed to improve the outcomes achieved in the earlier HOVON 45 trial,² and to investigate if bortezomib maintenance after auto-SCT could improve outcomes.

• The protocol used in the HOVON 45 trial was modified to include two cycles of HD-Ara-C instead of one and to proceed with it regardless of the response to R-CHOP treatment. These interventions seem worthwhile: following the modified protocol, 85% of patients could be transplanted resulting in the EFS of 51% and OS of 73% at five years, compared with 70% transplanted patients and failure-free survival of 36% and OS of 66% at four years in the HOVON 45 study
• No difference in EFS between the bortezomib maintenance arm and the patients without maintenance was observed