Ibrutinib/Rituximab Induction Followed by R-HCVAD in Front-Line Treatment of Patients Aged 65 and Younger With Mantle Cell Lymphoma

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In the single-institution phase II WINDOW-1 trial reported in The Lancet Oncology, Michael L. Wang, MD, and colleagues found that 12 cycles of induction ibrutinib/rituximab produced objective response in nearly all patients aged ≤ 65 years with mantle cell lymphoma, allowing a reduction in cycles of consolidation R-HCVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone).

As stated by the investigators, “Induction with ibrutinib and rituximab provides an opportunity to minimize chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight.”

Michael L. Wang, MD

Michael L. Wang, MD

Study Details

In the study, 131 patients enrolled at The University of Texas MD Anderson Cancer Center between June 2015 and December 2018 received 12 cycles of ibrutinib/rituximab induction (part A), consisting of ibrutinib at 560 mg daily and rituximab at 375 mg/m² weekly for the first 4 weeks and then on day 1 of cycles 3 to 12 in 28-day cycles. As soon as patients achieved a complete response in part A, they received four cycles of R-HCVAD alternating with methotrexate/cytarabine (part B) and were observed.

Patients without a complete response after part A received two cycles in part B; those with a complete response were given two more cycles (for a total of four cycles). Patients without a complete response also received two more cycles and reassessment; if they achieved a complete response after four cycles, they then received a total of eight cycles. Patients without a complete response received two cycles with reassessment, up to a total of eight cycles.

Patients with stable disease or progression during R-HCVAD were taken off the study. The primary outcome measure was overall response rate after part A.


Patients received a median of seven cycles (interquartile range [IQR] = 5–9 cycles) in part A and four cycles (IQR = 4–4 cycles) in part B.

In part A, objective response was achieved in 129 (98%, 95% confidence interval [CI] = 95%–100%) of 131 patients, including complete response in 114 (87%, 95% CI = 80%–92%). The median time to complete response in part A alone was 5 months (IQR = 4–7 months).

A total of 118 patients (90%) were evaluable for response in part B. The best overall response rate after part B on intent-to-treat analysis was 90% (95% CI = 84%–95%), with complete response in 89% (95% CI = 83%–94%). A total of 107 patients (91%) received four or more cycles and 13 (11%) received less than four cycles.

Among the 118 evaluable patients, 117 (99%) had a complete response. Of these, 107 (91%) had achieved a complete response during part A; among the 15 patients who had a partial response in part A, 10 (66%) achieved a complete response in part B, 1 (7%) had a partial response, and 4 (27%) were not evaluable. At the last on-study follow-up assessment, 112 (85%) of 131 patients were in sustained complete response and 3 were in partial response.

After a median follow-up of 42 months (IQR = 30–54 months), median duration of response was not reached. Median progression-free survival was not reached, with a 3-year rate of 79% (95% CI = 70%–85%). Median overall survival was not reached, with a 3-year rate of 95% (95% CI = 89%–98%).


  • Ibrutinib/rituximab induction therapy produced objective response in 98% of patients.
  • Complete response was achieved in 87% of patients, permitting fewer cycles of R-HCVAD consolidation.

Adverse Events

The most common grade 3 or 4 adverse events were lymphocytopenia (14%), skin rash (12%), thrombocytopenia (9%), infections (8%), and fatigue (8%) in part A, and lymphocytopenia (73%), leukocytopenia (32%), thrombocytopenia (30%), and neutropenia (20%) in part B. Five (4%) patients had atrial fibrillation or flutter in part A (all grade 1 or 2). No patients discontinued therapy due to adverse events in part A; four patients discontinued treatment in part B due to serious adverse events. One on-study death was observed and was not considered related to treatment.

The investigators concluded, “Induction with ibrutinib/rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimization of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton’s tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma.”

Dr. Wang, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Pharmacyclics and Janssen. For full disclosures of the study authors, visit

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