Bortezomib consolidation or maintenance after immunochemotherapy and transplant in patients with MCL

Immunochemotherapy followed by autologous hematopoietic stem cell transplant (auto-HSCT) improves the median progression-free survival (PFS) of patients with mantle cell lymphoma (MCL). However, all regimens evaluated so far have been associated with late disease recurrences. In the randomized, phase II trial CALGB (Alliance) 50403, Lawrence D. Kaplan and colleagues investigated whether the addition of bortezomib following high-dose cytarabine-etoposide-rituximab (EAR) stem cell mobilization, high-dose cyclophosphamide-carmustine-etoposide (CBV) autografting, and post-transplant rituximab, could further improve outcomes in patients with MCL. The efficacy and safety results of the study were published in the American Journal of Hematology.¹

Study design

Patient eligibility

• Aged 18–69 years
• Previously untreated MCL
• Co-expression of CD20 or CD19 and CD5
• Absence of CD23
• Cyclin D1, t(11;14), or a BCL1/IgH rearrangement

Treatment

• Induction: two cycles of rituximab 375mg/m² (Day 1), methotrexate 300mg/m² (Day 2), cyclophosphamide 2000mg/m², vincristine 2mg cap and doxorubicin 50mg/m² (Day 3), and prednisone 100mg/m² (Day 3–7) (RM-CHOP)
• Stem cell mobilization: patients who achieved complete or partial response (CR/PR) and had ≤ 15% MCL involvement of bone marrow after induction received one cycle of high-dose EAR four weeks after induction
  • Patients with MCL involvement > 15% underwent a third cycle of RM-CHOP induction and had their bone marrow re-evaluated; patients with persistent involvement > 15% were removed from the study
• Filgrastim 10μg/kg/day starting from Day 14 of EAR followed by leukapheresis 
• CBV was administered > 4 weeks after stem cell collection, followed by auto-HSCT
• Rituximab 375mg/m² was administered twice weekly from 6 weeks after transplant
• Patients with CR/unconfirmed CR (CRu)/PR at Day 90 post-transplant confirmed by computed tomography (CT) and bone marrow biopsy were randomized to post-transplant bortezomib therapy:
  • Consolidation (BC): four three-week cycles of bortezomib, 1.3 mg/m² on Days 1, 4, 8 and 11
  • Maintenance (BM): eight-week cycles of bortezomib at 1.5mg/m² on Days 1, 8, 15, and 22 for 18 months

Response evaluation

• Bone marrow samples were collected after induction but prior to stem cell mobilization, at Day 90 post-transplant, and one-year post-transplant for analysis of measurable residual disease (MRD)
• CT scans were conducted after induction therapy and at Day 90 post-transplant; then repeated every 6 months for 2 years from randomization
• Follow-up clinical evaluations were performed ≤ 2 months for 2 years, then every 6 months for 3 years, then annually for a maximum of 10 years from study entry

Correlative studies

• Gene expression-based tests on formalin-fixed paraffin-embedded biopsies were used to assess the mantle cell ‘proliferation signature’ together with immunohistochemistry for Ki67 and SOX11

Endpoints

• Primary: PFS from randomization
• Secondary: toxicity, response rate, and overall survival (OS)

Results

Patient characteristics

• In total, 151 patients were enrolled from October 2006 to June 2010; 147 initiated the treatment and were included in toxicity and outcome analyses
  • 118 patients underwent auto-HSCT:
    • Ten patients withdrew before randomization due to progression/lack of response and 18 due to adverse events (AEs), including 2 treatment-related deaths
  • 102 patients were randomized to post-transplant bortezomib:
    • 52 patients to BM
    • 50 patients to BC
• Median age was 59 years (29–69)
• Majority of patients were male (78%), had bone marrow involvement (81%), and stage IV disease (85%)
• Mantle Cell International Prognostic Index (MIPI) risk was low in 52% of patients, intermediate in 31% and high in 17%
• Ki67 was ≥ 30% in 17% of patients (15/86)

Safety

• A similar percentage of patients completed BC and BM (66% and 65%, respectively)
• More patients experienced Grade 4 hematological events in the BC group compared to the BM group. AEs are described in Table 1

Table 1. Adverse events

AEs, adverse events; BC, bortezomib consolidation; BM, bortezomib maintenance; NE, not established
AEs	BC group (n= 50)	BM group (n= 52)	P value
Grade 4 hematologic events, %	42	31	NE
Non-hematologic events, % Grade 3 Grade 4 Grade 5	42 6 2	38.5 8 0	NE NE NE
Common adverse events, % Neutropenia (Grade ≥ 3) Thrombocytopenia (Grade ≥ 3) Peripheral sensory neuropathy (Grade ≥ 2) Fatigue (Grade ≥ 2)	54 32 44 40	42 17 25 31	0.32 0.11 0.06 0.41
Withdrawal due to AEs, %	28	13	0.09

 

Efficacy

Response to treatment and treatment outcomes by arm

• Median follow-up was 8.5 years
• The primary endpoint was met by both arms
• Median PFS from randomization was higher in patients in the BM group vs the BC group
  • not reached (NR) (95% CI, 8.5–NR) vs 8.2 (95% CI, 6.6–NR) years, respectively
• Median OS was also increased with the maintenance
  • NR (95% CI, NR–NR) vs 8.9 (95% CI, 7.2–NR) years, respectively
• Best responses by treatment group are presented in Table 2

Table 2. Best response to bortezomib consolidation and maintenance before and after randomization

BC, bortezomib consolidation; BM, bortezomib maintenance; CR, complete response; CRu, complete response unconfirmed; NA, not assessed; PR, partial response; SD, stable disease
	BC (n= 50)		BM (n= 52)
Randomization	Before	After	Before	After
Best response, % CR CRu PR SD NA	38 10 48 2 2	70 8 20 0 2	38.5 21.2 34.6 5.8 0	59.6 21.2 17.3 1.9 0

 

Outcomes in all patients

• The median follow-up of all 147 treated patients was 7.1 years (0.2–11)
• Median PFS from study registration was 7.1 years (95% CI, 4.4–9.1)
  • The 8-year PFS was:
  • In all patients: 43.6% (95% CI, 35.6–53.3)
  • In patients with low risk MIPI: 52.0% (95% CI, 41.1–66.0)
  • In patients with intermediate risk MIPI: 37.5% (95% CI, 25.3–55.4)
  • In patients with high risk MIPI: 28.2% (95% CI, 13.7–57.9)
• Median OS from study registration was 9.9 years (95% CI, 8.5–NR)
  • The 8-year OS was 60.0% (95% CI, 52.2–68.9)

Outcome comparison between CALGB 50403 and 59909

• Baseline patient characteristics for patients enrolled on CALGB 50403 and 59090 were similar, except for a higher number of patients with high (> 30%) Ki67 in the 59090 study
• PFS and OS in this study (N= 118) were improved compared to the CALGB 59090 (N= 66)
  • Median PFS was 8.5 years (95% CI, 6.8–NR) vs 5 years (95% CI, 3.3–NR)
    • HR 0.54 (95% CI, 0.35–0.86); p= 0.008
  • Median OS was NR (95% CI, 9.1–NA) years vs NR (95% CI, 5.5–NR) years
    • HR 0.57 (95% CI, 0.33–0.98); p= 0.04

Correlative studies

• In total, bone marrow MRD results were collected from 42 patients post-induction
• MRD negative status after induction immunochemotherapy (n= 17) was associated with significantly longer PFS (8-year PFS was 80%; HR 0.22; 95% CI, 0.06–0.77; p= 0.009) and OS (8-year OS was 86%; HR 0.22; 95% CI, 0.05–1.02; p= 0.034) compared with MRD positive status (n= 25, 8-year PFS was 43% and 8-year OS was 64%)
• There was no association between staining for SOX11 and PFS (n= 84, HR 1.00; 95% CI, 0.99–1.01)
• High Ki67 (≥ 30%) was associated with lower OS (HR 1.97; 95% CI, 1.01–3.84) and PFS (HR 1.35; 95% CI, 0.74–2.46)
• Analysis of proliferation signature in baseline tumor samples (n= 61) showed that compared to patients with standard risk (n= 18) patients with high risk disease (n= 11) had inferior PFS (HR 2.59; 95% CI, 1.14–5.89)
  • PFS of patients with low risk (n= 32) was similar to those with standard risk (HR 1.29; 95% CI, 0.60–2.78)
• Adjusting for baseline MIPI risk categories or Ki67 % attenuated the associations of proliferation signature with PFS (standard risk: HR 1.43; 95% CI, 0.62–3.29; high risk: HR 2.11, 95% CI ,0.86–5.19 and standard risk: HR 1.15; 95% CI, 0.48–2.79; high risk: HR 1.84; 95% CI, 0.70–4.83)

Conclusion

The study results demonstrate improved outcomes with the use of bortezomib after transplantation in both conditioning and maintenance settings, especially in patients who achieved MRD negativity after induction. Patients in this study had significantly longer PFS than those on the GALGB 59090 study, strengthening the evidence of BC or BM benefit after auto-HSCT. Both treatment schedules were tolerable. However, the authors of the study draw attention to the considerable toxicity in particular, fatigue and peripheral neuropathies, which for many patients may have already been present as a result of prior therapy and transplant, can significantly affect quality of life.