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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.
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:
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
Figure 1. IMCL-2015 study profile*
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*
Characteristic (% unless stated otherwise) |
Patients |
---|---|
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 |
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. |
Figure 2. Patient outcomes following 12 cycles of ibrutinib + rituximab by molecular subtype and TP53 mutational status*
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
Table 2. Treatment-related adverse events observed in ≥20% of patients in the IMCL-2015 study*
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 |
*Data from Giné, et al.1 |
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.
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
Figure 3. WINDOW-1 treatment schema*
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
• 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.
Figure 4. WINDOW-1 study profile*
*Adapted from Wang, et al.2
Table 3. Baseline characteristics of patients enrolled in the WINDOW-1 study*
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 |
BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; GI, gastrointestinal; MIPI, Mantle Cell Lymphoma International Prognostic Index. |
Figure 5. Patient outcomes following treatment in part A and part B of the WINDOW-1 study*
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.
Table 4. Common Grade 3–4 AEs observed in the WINDOW-1 study*
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 |
— |
AE, adverse event. |
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.
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