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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
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 61st American Society of Hematology Meeting & Exposition, Orlando, US.1
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*:
* 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).
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.
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 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.
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 |
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:
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).
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 |
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.
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