All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the Lymphoma Coalition.

The Lymphoma Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

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

Apr 16, 2020
Share:

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

  1. Campo E & Rule S. Mantle cell lymphoma: evolving management strategies. Blood. 2015 Jan 1; 125(1):48–55. DOI: 1182/blood-2014-05-521898
  2. Van’t Veer MB et al. High‐dose Ara‐C and beam with autograft rescue in R‐CHOP responsive mantle cell lymphoma patients. Br J Haematol. 2009 Jan; 144 (4):524–530. DOI: 1111/j.1365-2141.2008.07498.x
  3. Zinzani PL et al. Bortezomib as salvage treatment for heavily pretreated relapsed lymphoma patients: a multicenter retrospective study. Hematol Oncol. 2012 Oct 29; 31(4):179–182. DOI: 1002/hon.2036

Share: