Preetesh Jain, MD, PhD, discusses data from the following study:

Ibrutinib plus rituximab and venetoclax followed by risk-stratified observation or short-course R-hyper-CVAD [rituximab, cyclophosphamide, vincristine, doxorubicin hydrochloride, dexamethasone]–methotrexate in young patients with previously untreated mantle cell lymphoma: phase 2 WINDOW-2 clinical trial. (

The objective of this study is to report results in young patients with previously untreated mantle cell lymphoma treated with IRV [ibrutinib, rituximab, venetoclax] followed by observation or short-course R-hyper-CVAD–methotrexate.

IRV is a chemotherapy-free combination option.

50 patients were enrolled to receive IR [ibrutinib, rituximab] induction for an initial 4 cycles, restaging at cycle 4, then IRV for up to 8 cycles. Patients were then risk-stratified (high, moderate, or low) to receive R-hyper-CVAD–methotrexate consolidation or observation, followed by 2 years of IRV maintenance.

Safety and efficacy outcomes were assessed in the population:

Overall response rate (ORR) was assessed at 96% with a complete response in 92% before consolidation.

Best ORR after consolidation in medium- and high-risk patients was 96%.

The median number of cycles of IRV to reach best response was 8.

Grade 3/4 toxicities with initial IRV were 3% mucositis and 10% each with myelosuppression, fatigue, myalgia, and rashes.

Grade 3 atrial flutter developed in 1 patient with initial IRV, while none had bleeding or bruising.

Among 35 patients who received consolidation, grade 3/4 toxicities were 46% neutropenia, 30% anemia, and 40% thrombocytopenia.

IRV induced unprecedented efficacy before chemotherapy consolidation.

Thirteen patients (26%) came off study: 5 for adverse events, 3 for on-study deaths, 2 for patient choice, 2 lost to follow-up, and 1 for disease progression.

Overall, 5 patients died (3 on trial and 2 off, 1 from progressive disease and another from COVID-19).

WINDOW-2 suggests that patients with low-risk mantle cell lymphoma may not need chemotherapy, but further follow-up is warranted.

Further studies on predictors of response, minimal residual disease, and clonal evolution are ongoing.

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Expert perspectives on the phase II clinical trial assessing IRV triplet therapy in young patients with previously untreated mantle cell lymphoma to help minimize chemotherapy exposure. 

Rapid Readouts: Ibrutinib Plus Rituximab and Venetoclax Followed by Risk-Stratified Chemoimmunotherapy in Young Patients With Previously Untreated MCL 

Preetesh Jain, MD, PhD, clinical fellow in medical oncology at The University of Texas MD Anderson Cancer Center, discusses the efficacy of ibrutinib (Imbruvica) plus rituximab (Rituxan) in mantle cell lymphoma (MCL).

Findings from a phase 2 clinical trial (NCT01880567), which were presented during the 2020 ASH Annual Meeting and Exposition, demonstrated a best overall response rate of 96%, comprising a 66% complete response rate, with ibrutinib/rituximab in previously untreated, older patients with MCL. Additionally, the minimal residual disease–negativity rate at best response was 87%.

Notably, the median age was 71 years (range, 65-84), and some patients had clinically controlled comorbidities that made them ineligible for transplant, Jain explains. 

Patients with a low Ki-67 score of less than 30% appeared to derive additional benefit from ibrutinib/rituximab compared with patients whose Ki-67 score was 30% to 50%, Jain says. However, the differences in progression-free survival and overall survival were not statistically significant between these groups, Jain concludes.

Preetesh Jain, MD, PhD, discusses the efficacy of ibrutinib plus rituximab in mantle cell lymphoma.  



Dr. Jain on the Efficacy of Ibrutinib/Rituximab in MCL 

Preetesh Jain, MD, PhD, clinical fellow in medical oncology at The University of Texas MD Anderson Cancer Center, discusses the rationale to evaluate ibrutinib (Imbruvica) in combination with rituximab (Rituxan) in mantle cell lymphoma (MCL).

During the 2020 ASH Annual Meeting & Exposition, findings from a phase 2 clinical trial (NCT01880567) were presented, demonstrating high rates of clinical efficacy with the combination of ibrutinib and rituximab in transplant-ineligible, elderly patients with non-blastoid histology. 

The rationale for this study was to determine whether a chemotherapy-free regimen would have utility in this patient population, says Jain. Currently, the field of MCL is shifting toward incorporating chemotherapy-free options due to the short- and long-term toxicities of chemotherapy, such as secondary malignancy, high infection risk, and myelosuppression.

The promise of a chemotherapy-free regimen, as well as the encouraging responses demonstrated with ibrutinib/rituximab, provided a basis to evaluate the combination among older patients with treatment-naïve, low-risk MCL, concludes Jain.

Preetesh Jain, MD, PhD, discusses the rationale to evaluate ibrutinib in combination with rituximab in mantle cell lymphoma.  



Dr. Jain on the Rationale to Evaluate Ibrutinib/Rituximab in MCL 

Preetesh Jain, MD, PhD, clinical fellow in medical oncology at The University of Texas MD Anderson Cancer Center, discusses research efforts examining resistance patterns with venetoclax (Venclexta) in mantle cell lymphoma (MCL).

The findings from a small prospective study indicated that venetoclax-based therapy was highly effective in patients with high-risk MCL and acquired resistance to the agent was predominantly associated with non–BCL-2 mutations. These findings need further validation in a larger cohort of prospectively collected samples, says Jain. Similar types of analyses in other ongoing trials with venetoclax and ibrutinib (Imbruvica) in the frontline setting are also being conducted to understand the pattern of resistance to the agent in less heavily pretreated patients.

To do this, pretreatment samples will need to be collected and studied. In the phase 1 study, the pretreatment samples had been previously treated with other agents, such as ibrutinib or chemotherapy, making the pretreatment clonal evolution data not indicative of what an untreated sample would look like.

Even in patients with poor-risk MCL, the response rate with venetoclax was very impressive. These findings are very provocative, according to Jain, even though it was a retrospective study that had enrolled a small number of patients with limited samples available for whole-exome sequencing. These are preliminary findings, which will potentially lead to studying this particular pattern of resistance in a larger number of samples, concludes Jain.

Preetesh Jain, MD, PhD, discusses research efforts examining resistance patterns with venetoclax in mantle cell lymphoma.

Dr. Jain on Future Research Efforts Examining Venetoclax Resistance Patterns in MCL

Preetesh Jain, MD, PhD, clinical fellow in medical oncology at The University of Texas MD Anderson Cancer Center, discusses the activity of venetoclax (Venclexta) in mantle cell lymphoma (MCL).

In a single-center phase 1 study, investigators evaluated the activity of venetoclax in patients with MCL. In the trial, investigators reached a dose of 800 mg. 

The highest complete remission rate of 21% was reported in the cohort of patients with MCL, says Jain. These data speak to the activity of venetoclax in MCL, despite the fact that these patients had not progressed on a BTK inhibitor, concludes Jain.

Preetesh Jain, MD, PhD, discusses the activity of venetoclax (Venclexta) in mantle cell lymphoma (MCL).

Dr. Jain on the Activity of Venetoclax in MCL

Preetesh Jain, MD, PhD, clinical fellow in medical oncology at The University of Texas MD Anderson Cancer Center, discusses the next steps for a study examining the efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL).

In chronic lymphocytic leukemia (CLL), it is known that BCL-2—based mutations are very significant, says Jain. However, in this study, only 17% of patients had a BCL-2 mutation, suggesting that the pattern of resistance with venetoclax in MCL is distinct from CLL. These findings need further validation in a larger cohort of prospectively collected samples.

Investigators are going to conduct similar types of studies and other ongoing trials with venetoclax (Venclexta) and ibrutinib (Imbruvica) in the frontline setting to understand the pattern of resistance in less heavily pretreated patients. To do this, they will have to look at pretreatment samples, Jain adds. In this study, the pretreatment samples had been collected from patients who had previously been treated with some other agents, such as ibrutinib or chemotherapy. As such, their pretreatment clonal evolution findings were not depictive of what an untreated sample would look like.

Even in poor-risk MCL, the response rate with venetoclax was very impressive, says Jain. These data are very provocative, even though it is a retrospective study with a small number of patients and samples available for whole-exome sequencing. These preliminary findings will lead investigators to study this particular pattern of resistance in a larger number of samples, concludes Jain.

Preetesh Jain, MD, PhD, discusses the next steps for a study examining the efficacy of venetoclax in high risk relapsed mantle cell lymphoma.

Dr. Jain on Next Steps for Venetoclax in Relapsed MCL

Preetesh Jain, MD, PhD, clinical fellow in medical oncology at The University of Texas MD Anderson Cancer Center, discusses response and resistance to venetoclax (Venclexta) in relapsed/refractory mantle cell lymphoma (MCL).

Investigators at The University of Texas MD Anderson Cancer Center conducted a prospective study of 24 patients who received venetoclax-based salvage therapy. These patients were heavily pretreated, having received a median of 5 prior lines of therapy. A few patients had also relapsed after CAR T-cell therapy, says Jain. However, the overall response rate was 50%, suggesting that venetoclax works well in patients with highly refractory disease that has progressed on a BTK inhibitor.

However, patients did progress after receiving venetoclax. These patients have a poor survival of around 6 to 7 months, says Jain. Investigators found a pattern of clonal evolution and increased frequency in histone modifier mutations, such as 

, which has never been identified in MCL before, says Jain.

Preetesh Jain, MD, PhD, discusses response and resistance to venetoclax (Venclexta) in relapsed/refractory mantle cell lymphoma (MCL).

Preetesh Jain, MD, PhD

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