The impact of early relapse on outcome in patients with mantle cell lymphoma (MCL)

In aggressive and indolent non-Hodgkin lymphoma, time to progression of disease (POD) following frontline treatment is a prognostic factor for patient outcome.¹ Carlo Visco and colleagues recently published data showing that, in patients with mantle cell lymphoma (MCL) treated with intensive frontline regimens, progression within 24 months of diagnosis is associated with increased mortality, and progression beyond 24 months leads to prolonged survival.² However, within the field of MCL, there remain unanswered questions:¹

1. Is early POD following less intensive treatment prognostic for outcome?
2. Does the type of salvage therapy used to treat very early POD impact outcome?

To address these unanswered questions, David A. Bond, The Ohio State University Hospital, Columbus, US, and colleagues conducted a retrospective analysis to evaluate the impact of early relapse on patient outcome in MCL. The data were presented during the 61^st American Society of Hematology  Meeting & Exposition, Orlando, US.¹

Study design and patient characteristics¹

Patients with MCL, treated at 12 North American medical centers between 2000–2017 were retrospectively identified (n= 1,168). In total, 711 patients were excluded from the analysis due to a lack of progression following frontline therapy, or a lack of follow-up data. The remaining patients (n= 457) who experienced relapse were split into three groups based on time to first relapse and treatment intensity*:

1. Primary refractory (PRF): progression of disease during induction, or within six months of induction (n= 65)
2. POD24: progression between six and 24 months post-treatment (n= 153)
3. POD> 24: disease progression > 24 months following treatment (n= 239)

* Intensive treatment was defined as high-dose cytarabine-containing induction and/or autologous stem cell transplant (ASCT) in first complete remission (CR1)

Patients in the early relapse groups (PRF and POD24) were generally older (p< 0.001), with a higher frequency of known baseline risk factors including: presence of B symptoms (p< 0.001), a higher MCL International Prognostic Index (MIPI) score (p= 0.001), blastoid morphology (p< 0.001), a Ki67 > 30% (p< 0.001) and a complex karyotype (p= 0.001).

Results¹

Median follow-up was 2.6 years in surviving patients. Patients who experienced early relapse (PRF and POD24) had a lower secondary median progression-free survival (PFS2) and overall survival (OS) compared to patients with POD> 24 (Table 1). In patients treated with intensive treatment, patients relapsing in < 24 months following induction had a poorer OS. However, OS was improved in patients with POD24 (and POD> 24) following a less intensive frontline treatment. PRF patients had the poorest outcomes.

Table 1. Patient outcomes by POD status

CI, confidence interval; NR, not reached; OS, overall survival; PFS2, secondary progression-free survival; POD, progression of disease; PRF, primary refractory

 

PRF

POD24

POD> 24

p value

Median PFS2 from first relapse, years (95% CI)

1 (0.4–1.3)

1 (0.8–1.4)

2.3 (1.8–3.2)

< 0.0001

OS from first relapse, years (95% CI)

1.3 (0.9–2.4)

3 (2–6.8)

8 (6.2–NR)

< 0.0001

Patients treated with intensive frontline treatment

OS from first relapse, years (95% CI)

0.9 (0.4–3)

2 (1.1–3.4)

9.5 (4.8–NR)

< 0.0001

Patients treated with less-intensive frontline treatment

OS from first relapse, years (95% CI)

2 (0.9–4.5)

6.8 (3.1–9.7)

10.5 (5.8–NR)

< 0.0001

Univariable analysis¹

Univariable analysis identified factors associated with mortality (Table 2) which included POD status. Patients in the PRF and POD24 groups had an increased risk of mortality compared with the POD> 24 group.

Table 2. Factors significantly associated with survival in univariable analysis

CI, confidence interval; HR; hazard ratio, MIPI, MCL International Prognostic Index; POD24, progression of disease within 24 months; PRF, primary refractory

Factor

Risk of mortality

HR

95% CI

p value

PRF status

Increased

3.77

2.47–5.77

< 0.001

POD24 status

Increased

2.12

1.53–2.94

0.002

B symptoms

Increased

1.42

1.02–1.96

0.036

High MIPI score

Increased

2.47

1.40–4.36

0.003

Blastoid morphology

Increased

1.93

1.28–2.91

0.002

Complex karyotype

Increased

2.21

1.12–4.36

0.022

Rituximab maintenance

Reduced

0.57

0.37–0.87

0.010

Multivariable analysis (n= 192)¹

Study investigators conducted multivariable analysis to analyze whether the increased risk in early relapse was present, irrespective of baseline MIPI score and maintenance rituximab. A high MIPI score remained associated with increased risk of death (HR= 2.40; 95% CI, 1.28–4.50, p= 0.006) and maintenance rituximab was still associated with a reduced risk of death (HR= 0.29; 95% CI, 0.14–0.58, p< 0.001).

Significantly, early relapse remained a prognostic factor for poor OS:

• PRF: HR= 5.58 (95% CI, 2.68–11.61, p< 0.001)
• POD24: HR= 2.46 (95% CI, 1.34–4.52, p= 0.004)

Outcome by second-line treatment in patients with PRF (n= 22)¹

Given that patients with PRF had the highest risk of early death, their subsequent outcomes were compared by type of second-line treatment. Second-line treatment was lenalidomide and/or bortezomib, chemo-immunotherapy (CIT) or BTK inhibitor (BTKi) (Table 3).

Type of second-line treatment was significant in PRF patients (p= 0.036), with BTKi treatment providing the longest median PFS2. OS was unaffected by second-line treatment (p= 0.546).

Table 3. PFS2 by second-line treatment in patients with PRF disease

BTKi, BTK inhibitor; CIT, chemo-immunotherapy; CI, confidence interval; PFS2, second progression-free survival; PRF, primary refractory

Second-line treatment

Median PFS2, years

95% CI

BTKi

1.2

0.5–2.3

CIT

0.5

0.2–2.3

Lenalidomide and/or bortezomib

0.3

0.1–0.6

Conclusion¹

In this analysis of patients with MCL, a short duration of first remission was associated with an increased risk of death, irrespective of frontline therapy intensity. In patients receiving a less intensive frontline treatment, early mortality was lower in patients who relapsed between six and 24 months following frontline treatment. In patients who relapse very early, BTKi therapy may initially control the disease, but these responses are not durable and novel therapeutic approaches, such as chimeric antigen receptor (CAR) T-cell therapy, are required.