The impact of second-line regimens on outcomes in younger patients with MCL

Mantle cell lymphoma (MCL) remains an incurable disease. MCL accounts for 5–7% of all malignant lymphomas, and its incidence rates are increasing. Despite recent advances, patients with refractory disease or those who relapse following induction therapy have limited treatment options, and their disease is considered hard to treat. Younger patients with MCL are believed to have improved outcomes in the long term, however, systematic studies in this population are rare.

In the retrospective MANTLE-FIRST study, Carlo Visco et al. investigated outcomes in younger patients with MCL who relapsed for the first time or were refractory, to assess their second-line treatment options. They recently published their results in Leukemia.¹

Study design

• An international, multicenter, retrospective cohort study to describe the consecutive lines of therapy, and outcomes in younger patients with relapsed/refractory (R/R) MCL.
• Eligibility criteria:

• • R/R MCL after induction therapy;
  • Diagnosed between January 1, 2008 and June 30, 2018;
  • Frontline treatment with an intensive therapy consisting of rituximab and high dose (a single dose > 1 g/m²) cytarabine (see Table 1).

• Data cutoff date: July 1, 2019.
• Four groups were investigated for second-line therapy options:
  1. Ibrutinib: Patients receiving ibrutinib monotherapy.
  2. R-B: Patients receiving rituximab 375 mg/m² (Day 1) and bendamustine 90 mg/m² (Day 1–2).
  3. R-BAC: Patients receiving rituximab 375 mg/m² (Day 1), bendamustine 70 mg/m2 (Day 1–2), and cytarabine 500 mg/m2 (Day 1–3).
  4. Others: Patients receiving other therapy options, consisting of R-CHOP (n = 20), R-DHAP (n = 19), and bortezomib- (n = 17), lenalidomide- (n = 7), temsirolimus- (n = 5), gemcitabine- or fludarabine-based (n = 13) therapies.
• Progression of disease (PD) was defined as early if the disease had progressed within 24 months since MCL initial diagnosis, as compared to late PD (> 24 months).
• Outcomes of interest included overall survival (OS-2), and progression-free survival (PFS-2), overall response rate (ORR), complete response (CR), and disease progression.

Patients

The total number of patients with R/R MCL was 261, with a median age of 58 years (range, 19–70) and more than half (59%) of patients younger than 60 years. Almost half (49%) of patients had early PD, and 36% had a high MCL International Prognostic Index (MIPI) score. Baseline characteristics of the patients are provided in Table 1.

Table 1. Patient characteristics among treatment groups¹

allo-SCT, allogeneic stem cell transplantation; auto-SCT, autologous stem cell transplantation; B, bendamustine; BAC, bendamustine + cytarabine; CHOP, cyclophosphamide + doxorubicin + vincristine + prednisone; DHAP, dexamethasone + high dose cytarabine + cisplatin; HDS, high dose sequential therapy; HyperCVAD, cyclophosphamide + vincristine + doxorubicin + dexamethasone; MA, methotrexate + cytarabine; PD, progression of disease; R, rituximab.
Characteristics, n (%)	Study population (N = 261)	R-BAC (n = 76)	R-B (n = 54)	Ibrutinib (n =50)	Others (n = 81)
Blastoid or pleomorphic disease	59 (24)	17 (24)	13 (25)	20 (20)	19 (27)
Early PD Late PD	127 (49) 134 (51)	31 (41) 45 (59)	22 (41) 32 (59)	27 (54) 23 (46)	47 (58) 34 (42)
Refractory	37 (14)	10 (13)	5 (9)	8 (16)	14 (17)
Frontline treatment
R-HyperCVAD/MA R-CHOP/R-DHAP + auto-SCT Nordic regimen/R-HDS	64 (24) 85 (33) 112 (43)	30 (39) 16 (22) 30 (39)	7 (13) 22 (41) 25 (46)	3 (6) 23 (46) 24 (48)	24 (30) 24 (30) 33 (40)
Further transplantation in subsequent remission, n (%)
Auto-SCT Allo-SCT	18 (7) 59 (23)	(6) (27)	(7) (16)	(2) (29)	(10) (22)

Results

ORR to second-line therapies was 59% in all patients, and the highest ORRs were achieved with R-BAC (73%), compared to the lowest ORR with Others (37%). Overall CR rate was 44%, while age- and early/late PD-adjusted CR rates were highest with R-BAC (63%), followed by R-B (43%; odds ratio [OR], 0.43; 95% CI, 0.20–0.93; p = 0.033), ibrutinib (38%; OR, 0.36; 95% CI, 0.16–0.81; p = 0.013), and Others (30%; OR, 0.27; 95% CI, 0.13–0.56; p < 0.0001). While patients with early PD had similar CR rates with ibrutinib (31%) and R-BAC (32%), CR in patients with late PD was highest with R-BAC (85%).

Median OS-2 and PFS-2 for the whole study population were 36 and 13 months, respectively. Patients receiving other regimens (the ‘Others’ group) had a shorter median OS-2 (22.3 months; 95% CI, 13.3–37.8) compared with other second-line options. Treatment with Others was associated with a significantly shorter OS-2 versus ibrutinib (HR, 2.07; 95% CI, 1.14–3.74; p = 0.016). PFS-2 for the respective treatment groups is outlined in Table 2.

Table 2. PFS-2 among study groups¹

B, bendamustine; BAC, bendamustine + cytarabine; PFS, progression-free survival; R, rituximab. PFS-2 was defined as time until lymphoma relapse or progression after second-line therapy, or death due to any cause.
Outcome	Study population (N = 261)	R-BAC (n = 76)	R-B (n = 54)	Ibrutinib (n =50)	Others (n = 81)
Median PFS-2, months	13	25	13	24	7

Early PD was another factor that had a negative impact on both OS and PFS (see Table 3).

Survival curves demonstrated that patients with early PD were at higher risk of death and disease progression compared with those who experienced late progression (see Table 3).

• In patients with early PD, ibrutinib therapy led to a favorable OS-2 of 29.7 months (CI, 15.7–not reached).
• Patients who progressed late benefited most from ibrutinib and R-BAC, with median OS-2 not reached at the time of cutoff.
• When censoring patients at the time of allo-SCT, the impact of second-line treatments and PD status remained the same for OS-2 and PFS-2.

Survival data among study groups by timepoint of disease progression are presented in Table 3.

Table 3. OS-2 and PFS-2 by time of disease progression and second-line therapy option¹

B, bendamustine; BAC, bendamustine + cytarabine; CI, confidence interval; NR, not reached; OS, overall survival; PD, progression of disease; PFS, progression-free survival; R, rituximab. OS-2 was defined as time until death due to any cause, censored at last contact in patients surviving the follow-up period. PFS-2 was defined as time until lymphoma relapse or progression after second-line therapy, or death due to any cause.
	Median OS-2, months (95% CI)		Median PFS-2, months (95% CI)
	Early PD	Late PD	Early PD	Late PD
R-BAC	10.3 (7.7–22.1) p = 0.02	NR (34.1–NR)	6.5 (3.8–18.9)	52.4 (24.7–NR)
R-B	11.9 (5.3–28.7) p = 0.02	73.5 (46.2–NR)	5.5 (1.9–9.6)	31.7 (12.6–NR)
Ibrutinib	29.7 (15.7–NR)	NR (28.1–NR)	9.9 (4.9–NR)	44.9 (18.9–NR)
Others	12.8 (6.9–16.6) p = 0.02	40.7 (22.3–76.3)	5.5 (2.7–9.0)	12.5 (5.49–26.3)

Patients who were refractory to frontline induction therapy had a median PFS-2 of 3.5 months (95% CI, 2.1–9.3), and a median OS-2 of 7.9 months (95% CI, 4.4–15.7). Ibrutinib was associated with better survival outcomes in these patients (OS-2, 15.7 months; PFS-2, 9.3 months), however, the difference was not statistically significant.

Conclusion

The MANTLE-FIRST study appears to demonstrate that ibrutinib and R-BAC as second-line therapy in younger patients with MCL yield the best survival outcomes, while ORRs were best with R-BAC. This study also confirmed early PD as an independent variable influencing outcome.  In terms of PFS-2 and OS-2, the study concluded that ibrutinib therapy was significantly associated with better OS and PFS in patients with early PD, while ibrutinib, R-B, and R-BAC were equally effective in patients with late PD. However, the authors suggest that further evaluation of best treatment options is needed in patients with late PD.

Limitations of this study include the lack of central pathologic review and the use of different allo-SCT guidelines due to the multi-center design. The selection bias that may have arisen from the retrospective study design was another limitation.