Ibrutinib–rituximab combinations for frontline use in MCL

The treatment landscape for patients with mantle cell lymphoma (MCL) has progressed significantly in recent years with the emergence of targeted agents.^1,2 There are a number of studies underway evaluating novel treatment combinations in both the frontline and relapsed/refractory setting, working towards a personalized treatment approach.¹

Ibrutinib and rituximab are among the targeted agents used to treat MCL and are being investigated as a frontline combination, with the hope to limit patient exposure to chemotherapy.² The Lymphoma Hub is happy to provide a summary of the data from two phase II studies investigating ibrutinib–rituximab combination regimens for the treatment of patients with MCL.

IMCL-2015¹

Study design

Patients with indolent presentations of MCL often demonstrate favorable survival, without the need for intensive chemotherapy. Personalized, chemotherapy-free regimens may be of particular benefit in the frontline indolent MCL setting.

The single-arm IMCL-2015 study (NCT02682641) enrolled patients aged ≥18 years with treatment-naïve, asymptomatic, indolent MCL (confirmed using World Health Organization diagnostic criteria) from across 12 centers. Patients had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, and those with blastoid presentation and/or Ki-67 >30% were ineligible for enrolment. The study evaluated frontline rituximab plus ibrutinib and employed a measurable residual disease (MRD)-directed approach to limit treatment duration.

Patients received treatment in 28-day cycles as follows:

• Rituximab (weekly intravenous [IV] dose of 375 mg/m²)
  • Cycle 1: Days 1, 8, 15, and 22
  • Cycles 3, 5, 7, and 9: Day 1
• Ibrutinib: 560 mg/day orally for 2 years if sustained MRD negativity is achieved, or until progression or intolerable toxicity.

Primary endpoint: Complete response (CR) in the intention-to-treat population following 12 cycles of treatment

Secondary endpoints: Overall response rate (ORR), rate of undetectable MRD (uMRD), progression-free survival (PFS), duration of response, overall survival (OS), safety, and tolerability

Results

• A total of 50 patients were enrolled (Figure 1, Table 1)

C12, Cycle 12; C24, Cycle 24; MRD, minimal residual disease.
*Adapted from Giné, et al.¹

 
Table 1. Baseline characteristics of patients enrolled in the IMCL-2015 study*

BM, bone marrow; cMCL, conventional MCL molecular subtype; ECOG, Eastern Cooperative Oncology Group; MCL, mantle cell lymphoma; MIPI, Mantle Cell Lymphoma International Prognostic Index; nnMCL, non-nodal MCL molecular subtype; PB, peripheral blood. *Data from Giné, et al.1 †49  evaluable patients.
Characteristic (% unless stated otherwise)	Patients (N = 50)
Median age, years (range)	65 (40–85)
Sex
Male	66
Female	44
BM involvement	88
PB involvement by flow cytometry†	90
MIPI risk
Low	24
Intermediate	38
High	38
TP53 alterations, n (%)	6/41 (15)
Del 17p/LOH, n	5
TP53 mutation, n	6
L-MCL-16
nnMCL	55
cMCL	45

Efficacy

• Following 12 cycles of the ibrutinib–rituximab regimen
  • ORR across all patients was 84%, with a CR of 80% (Figure 2). uMRD in peripheral blood (PB) and bone marrow (BM) was achieved by 93% and 70% of patients with a complete response, respectively.
  • uMRD in PB and BM was achieved by 87% and 65% of 46 evaluable patients, respectively.

cMCL, conventional MCL molecular subtype; CR, complete response; mut, mutation; nnMCL, non-nodal MCL; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; WT, wildtype.
*Data from Giné, et al.¹

• Sustained uMRD was achieved in 69% of patients who reached treatment Cycle 24 (Figure 1), and ibrutinib was discontinued. uMRD persisted in 19 patients at the latest data collection.
• The estimated 36-month PFS was 93% (95% confidence interval [CI], 86–100).
• EFS and OS at 36 months were 76% (95% CI, 64–89) and 92% (95% CI, 84–100), respectively, with six patients dying on study to date (MCL progression, n = 4; pancreatic adenocarcinoma, n = 1; SARS-CoV-2 infection, n = 1).
• PFS and OS were significantly influenced by MIPI and TP53 mutational status.

• Patients with TP53-mutated MCL had significantly lower median PFS compared with TP53^wt cases (38.5 months vs not reached, respectively; p = 0.0001) and OS (38.5 months vs not reached, respectively; p = 0.0002).

Safety

• The most commonly observed treatment-related adverse events are shown in Table 2.
• Ibrutinib discontinuation due to AEs was reported in six patients.

Table 2. Treatment-related adverse events observed in ≥20% of patients in the IMCL-2015 study*

*Data from Giné, et al.1
AE, %	All grades	Grade 3	Grade 4
Hematologic
Thrombocytopenia	14	0	2
Neutropenia	36	16	6
Nonhematologic
Diarrhea	38	2	0
Fatigue	32	2	0
Upper respiratory infection	24	0	0
Nausea	22	0	0
Hypertension	20	2	0

IMCL-2015 study conclusions

In patients with indolent MCL, frontline ibrutinib plus rituximab demonstrated encouraging CR and uMRD rates, meeting the study’s primary endpoint. The presence of TP53 mutations was associated with poor outcomes. The trial utilized an MRD-guided treatment approach to identify avoidable treatment cycles and further optimize personalized care in the setting.

WINDOW-1²

Study design

Although induction with intensive chemotherapy can induce favorable and durable responses in patients with MCL, AEs and the risk of second cancers remain significant drawbacks. WINDOW-1 (NCT02427620) is a single-arm, single-center study evaluating the safety and efficacy of chemotherapy-free induction with ibrutinib–rituximab (part A) followed by shortened consolidation with alternating R-HCVAD (rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and methotrexate–cytarabine (part B; Figure 3).

WINDOW-1 enrolled patients aged ≤65 years with treatment-naïve MCL, an ECOG PS of ≤2, serum bilirubin <1.5 mg/dL, and creatinine clearance ≥30 mL/min.

Primary endpoint: ORR following part A

Secondary endpoints: PFS, OS, CR, duration of response, and toxicities following part A and part B

CR, complete response; HSCT, hematopoietic stem cell transplantation; IV, intravenous; PD, progressive disease; PO, by mouth; PR, partial response; R-HCVAD, rituximab + hyper-fractionated cyclophosphamide + vincristine + doxorubicin + dexamethasone; SD, stable disease.
*Data from Wang, et al.^2
†Once every 12 h for six doses.
^‡24-hour infusion.
^§200 mg/m² IV for 2 h, then 800 mg/m² IV for 22 h.
^¶Four doses.
^#12 h post-methotrexate.
^**24–36 h post-cytarabine 

Results

• A total of 131 patients were enrolled in the WINDOW-1 study (Figure 4, Table 3).
• The median number of treatment cycles received by patients in part A and part B were seven and four, respectively, with 11 patients not continuing to part B.

*Adapted from Wang, et al.² 

Table 3. Baseline characteristics of patients enrolled in the WINDOW-1 study*

BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; GI, gastrointestinal; MIPI, Mantle Cell Lymphoma International Prognostic Index. *Data from Wang, et al.2
Characteristic (% unless stated otherwise)	Patients (N = 131)
Age, years (range)	56 (49–60)
Sex
Male	79
Female	21
ECOG
0–1	99
2	<1
Bulky disease	9
BM involvement	88
GI involvement	86
Simplified MIPI
Low risk	80
Intermediate risk	12
High risk	8
Biological MIPI
Low risk	31
Intermediate risk	33
High risk	36
Cytomorphology
Classic	88
Blastoid/pleomorphic	12
SOX-11
Positive	89
Negative	11
Ki-67 percentage
<30%	45
≥30%	44
Unavailable	11
TP53
Positive	32
Negative	68

Efficacy

• Patient responses across part A and part B of the WINDOW-1 study are shown in Figure 5.
• ORR was not influenced by Ki-67 percentage, disease risk, or MCL cytomorphology. Despite comparable OS rates between patients with/without TP53 aberrations, the presence of TP53 abnormalities significantly reduced CR rates.
• At the 42-month follow-up
  • 24 patients progressed and six patients died due to disease progression (n = 5) and an unknown reason (n = 1);
  • median PFS and OS were not reached; and
  • 3-year PFS and OS were 79% (95% CI 70–85) and 95% (89–98), respectively.
• Patients with high-risk MCL, including Ki-67 ≥50%, blastoid or pleomorphic MCL, complex karyotype, and high-risk MIPI demonstrate a significantly increased risk of disease progression. OS rates were comparable between patients with high- and low-risk disease, with the exception of patients with complex karyotypes, who exhibited inferior OS.
• BM MRD negativity by flow cytometry was observed in 65% of patients.

MRD, measurable residual disease; PET-CT, positron emission tomography-computed tomography.
*Data from Wang, et al.^2
†All patients had baseline imaging; 30 had CT scans, and 101 had PET–CT scans.  

Safety

• The most commonly observed Grade 3–4 AEs are shown in Table 4.
• In part A, dose reductions occurred in 33% of patients, but no patients discontinued treatment as a result of AEs.
• In part B, Grade 3–4 AEs resulted in chemotherapy dose reductions in 22% of patients, and four patients discontinued treatment due to serious AEs.
• There was one death during study, which was not attributed to the study drugs.

Table 4. Common Grade 3–4 AEs observed in the WINDOW-1 study*

AE, adverse event. *Data from Wang, et al.2 †118 patients received Part B chemotherapy.
AE, %	Part A (n = 131)		Part B (n = 131†)
	Grade 3	Grade 4	Grade 3	Grade 4
Hematologic
Anemia	4	—	17	—
Lymphocytopenia	9	5	23	50
Leukocytopenia	2	—	10	22
Thrombocytopenia	9	—	6	24
Neutropenia	4	2	5	14
Nonhematologic
Skin rash	12	—	3	—
Infection	8	—	4	—
Fatigue	8	—	19	—
Elevated liver enzymes	4	—	9	2
Myalgia	6	—	9	—

WINDOW-1 conclusions

In the WINDOW-1 study, ibrutinib–rituximab induction with subsequent alternating R-HCVAD and methotrexate–cytarabine consolidation demonstrated impressive ORR and CR rates in young patients with treatment-naïve MCL. Induction alone resulted in an ORR of 98%, and outcomes did not differ significantly between patients who received at least four cycles of chemotherapy and those not completing part B. Median OS and PFS were not reached at the 42-month follow-up.

Data from the study demonstrate the feasibility, efficacy, and favorable toxicity profile of chemotherapy-free induction followed by reduced-exposure consolidation in the frontline MCL setting; however, the authors note that the transition from chemotherapy to chemotherapy-free regimens should be approached with caution.