Mitchell R. Smith, MD, PhD, associate cancer center director for clinical investigations, chief, Division of Oncology and Blood Disorders, GW Cancer Center, clinical professor of medicine, GW School of Medicine and Health Sciences, discusses the patient population of the phase 2 of theECOG-ACRIN E1411 trial (NCT01415752) in mantle cell lymphoma (MCL).

The ECOG-ACRIN E1411 trial randomized patients with untreated MCL to the combination of bendamustine and rituximab (Rituxan; BR) followed by rituximab consolidation, BR plus bortezomib (Velcade; BVR) followed by rituximab consolidation, BR followed by lenalidomide (Revlimid) and rituximab (R2) consolidation, or BVR followed by R2.

Historically, clinical trials evaluating intensive frontline regimens excluded older patients with MCL because patients often received autologous stem cell transplant as consolidation, Smith says. In the ECOG-ACRIN E1411 trial, patients of all ages were eligible for enrollment, Smith explains. 

Thirteen percent of patients enrolled were under 60 years old, which translated to a median patient age of 67 years, Smith says. These patients had previously untreated MCL and adequate organ function, Smith adds. However, patients with low blood counts were eligible for enrollment because MCL can cause low counts, Smith explains. 

No other significant exclusion criteria were included in the trial; however, patients with known disease in the central nervous system were ineligible for enrollment, Smith adds. In turn, the study evaluated the utility of induction and consolidation therapy in a broad patient population, concludes.

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Mitchell R. Smith, MD, PhD, discusses the patient population of the phase 2 ECOG-ACRIN E1411 trial in mantle cell lymphoma. 

Dr. Smith on the Patient Population of the ECOG-ACRIN E1411 Trial in MCL 

Mitchell R. Smith, MD, PhD, associate cancer center director for clinical investigations, chief, Division of Oncology and Blood Disorders, GW Cancer Center, clinical professor of medicine, GW School of Medicine and Health Sciences, discusses the rationale for the phase 2 ECOG-ACRIN E1411 trial (NCT01415752) in mantle cell lymphoma (MCL).

Findings from the ECOG-ACRIN E1411 trial, which were presented during the 2021 ASCO Annual Meeting, failed to demonstrate an improvement in overall response rate, complete response rate, or median progression-free survival with the addition of bortezomib (Velcade) to standard, frontline bendamustine plus rituximab (Rituxan; BVR) vs bendamustine/rituximab (BR) alone in older patients with MCL.

Older patients with MCL receive less aggressive chemotherapy compared with younger patients, says Smith. Typically, older patients receive BR followed by rituximab maintenance, Smith adds.

The study, which was conceptualized about 10 years ago, aimed to evaluate whether BR and/or rituximab maintenance therapy could be improved upon, Smith says. The 4-arm study randomized patients to BR followed by rituximab maintenance, BVR followed by rituximab maintenance, BR followed by maintenance with rituximab and lenalidomide (Revlimid), or BVR followed by maintenance with rituximab and lenalidomide, concludes Smith.

Mitchell R. Smith, MD, PhD, discusses the rationale for the phase 2 ECOG-ACRIN E1411 trial in mantle cell lymphoma.


Dr. Smith on the Rationale of the ECOG-ACRIN E1411 Trial in MCL 

Mitchell R. Smith, MD, PhD, associate cancer center director for clinical investigations, chief, Division of Oncology and Blood Disorders, GW Cancer Center, clinical professor of medicine, GW School of Medicine and Health Sciences, discusses the results of the phase 2 ECOG-ACRIN E1411 trial (NCT01415752) in mantle cell lymphoma (MCL).

Findings from the study, which were presented during the 

, failed to demonstrate an improvement in overall response rate, complete response rate, or median progression-free survival with the addition of bortezomib (Velcade) to standard, frontline bendamustine plus rituximab (Rituxan; BR) vs BR alone in older patients with MCL.

The median PFS was 5.9 years with BR plus bortezomib vs 5.4 years with BR alone, which indicated that BR alone performed better than expected in this study, Smith says. Additionally, this lessened the potential that the addition of bortezomib would yield positive results, Smith explains. Overall, these findings support BR plus rituximab maintenance therapy as a standard induction therapy for patients with MCL, concludes Smith.

Mitchell R. Smith, MD, PhD, discusses the results of the phase 2 ECOG-ACRIN E1411 trial in mantle cell lymphoma. 



Dr. Smith on the Results of the ECOG-ACRIN E1411 Trial in MCL 

Mitchell R. Smith, MD, PhD, division director, Cancer and Blood Disorders, and professor of medicine, GW Cancer Center, discusses the rationale behind the trial looking at the fixed duration of the ibrutinib (Imbruvica) and venetoclax (Venclexta) combination in chronic lymphocytic leukemia (CLL).

Preclinical data showed there was synergy between ibrutinib and venetoclax, which makes sense, according to Smith, because ibrutinib blocks site signaling and venetoclax promotes cell death. Ibrutinib and venetoclax are opposites in terms of proliferation and lack of apoptosis, adds Smith.

Although there was some apprehension regarding the ibrutinib/venetoclax combination, data from the early studies looked promising enough, specifically the depth of response, to warrant formal examination, explains Smith. In chronic myeloid leukemia (CML), TKI treatment can be stopped, but only in certain patients who reach minimal residual disease negativity for a few years. Even then, stopping TKI treatment must be done very carefully, says Smith. In CML, there was evidence to suggest that TKI treatment could be stopped during pregnancy and that the response would be regained. Therefore, researchers began to consider that TKIs and small molecule inhibitors may be different than chemotherapy in the treatment of patients with CLL, concludes Smith.

Mitchell R. Smith, MD, PhD, discusses the rationale behind the trial looking at the fixed duration of the ibrutinib and venetoclax combination in chronic lymphocytic leukemia.

Dr. Smith on the Rationale Behind the Fixed Duration Trial for Ibrutinib/Venetoclax in CLL

Mitchell R. Smith, MD, PhD, division director, Cancer and Blood Disorders, and professor of medicine, GW Cancer Center, discusses the use of PI3K inhibitors in chronic lymphocytic leukemia (CLL).

PI3K inhibitors have become an important drug class in CLL, despite their reputation for having significant associated toxicities, says Smith. Idelalisib (Zydelig) was the first PI3K inhibitor to receive regulatory approval in 2014. In 2018, duvelisib (Copiktra) was also approved for the treatment of patients with relapsed/refractory disease. Duvelisib targets PI3K-delta and -gamma with a slightly different mechanism of action than idelalisib, explains Smith.

Umbralisib (TGR-1202) is another PI3K-delta inhibitor that also inhibits an enzyme called casein kinase-1ε. As opposed to earlier-generation PI3K inhibitors, umbralisib appears to be well tolerated. Copanlisib (Aliqopa) is another PI3K inhibitor that selectively inhibits p110-alpha and delta. Now that several active PI3K inhibitors have emerged in the space, the challenge will be determining which inhibitors to combine with other agents to optimize outcomes, concludes Smith.

Dr. Smith on PI3K Inhibitors in CLL

Mitchell R. Smith, MD, PhD, division director, Cancer & Blood Disorders, and professor of medicine, GW Cancer Center, discusses frontline treatment considerations in patients with chronic lymphocytic leukemia (CLL).

Fludarabine/cyclophosphamide/rituximab (Rituxan; FCR), bendamustine/rituximab, and ibrutinib (Imbruvica) monotherapy are all indicated for use in patients with newly diagnosed CLL. Therefore, the treatment decision has to be made on an individualized basis. For example, young, fit patients with 

mutations may do better on FCR than on ibrutinib, says Smith. Data have shown that this subpopulation of patients can reach 10 years without progression after 6 months of FCR.

Considering cost, adverse events, and toxicity, BR could also be used as frontline therapy. If after several years, patients relapse, they can turn to ibrutinib—either alone or in combination. There is no known optimal therapy because there are no head-to-head data, says Smith.

However, a lot of work is being done on resistant clones and ways to detect them early, which could potentially inform subsequent treatment decisions. The goal is to be able to personalize these treatments and come up with the best strategy for each patient, says Smith. In the future, that could include following patients and monitoring their blood to see if the clones have the mutation that makes PI3K upregulate and makes BTK resistant to ibrutinib. These are all strategies that are on the horizon, concludes Smith.

Mitchell R. Smith, MD, PhD, discusses frontline treatment considerations in patients with chronic lymphocytic leukemia.

Dr. Smith on Frontline Treatment Considerations in CLL

Mitchell R. Smith, MD, PhD, professor of medicine, George Washington University, associate center director for clinical investigations, Division of Hematology and Oncology, GW Cancer Center, discusses the use of venetoclax (Venclexta) versus ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL). 

Venetoclax differs from ibrutinib in that it kills cancer cells rather than ceasing cell growth, explains Smith. Moreover, deeper responses have been reported with the BCL-2 inhibitor, leading to higher rates of minimal residual disease negativity (MRD), and potentially, treatment discontinuation. 

If patients achieve MRD negativity after receiving venetoclax as a single agent, in combination with ibrutinib, or a CD20 inhibitor, they could potentially discontinue treatment, says Smith. Those trials are planned, and investigators are eager to see what the results will be. Early data suggest that a significant number of patients who achieve MRD negativity can stop treatment for a period of time rather than remaining on ibrutinib indefinitely, Smith says. 

This may open the door to time-limited therapy, concludes Smith. 

Mitchell R. Smith, MD, PhD, discusses the use of venetoclax versus ibrutinib in patients with chronic lymphocytic leukemia. 

Dr. Smith on Using Venetoclax Versus Ibrutinib in CLL

Mitchell R. Smith, MD, PhD, professor of medicine, George Washington University, associate center director for clinical investigations, Division of Hematology and Oncology, GW Cancer Center, discusses the potential advantage of lenalidomide (Revlimid) in chronic lymphocytic leukemia (CLL).

Lenalidomide has gained traction in multiple myeloma and low-grade lymphoma. However, the drug first demonstrated activity in CLL, says Smith. 

In 2018, results of the randomized phase II Alliance CALGB 10404 trial demonstrated a 2-year progression-free survival benefit of 72% with the addition of lenalidomide to fludarabine and rituximab (Rituxan; FR) versus 64% with FR alone. Notably, 6 months of consolidative treatment with lenalidomide alone demonstrated a progression-free survival and overall survival benefit in the trial, says Smith. Utilization of this drug as either maintenance therapy or as an immune modulator could yield significant benefit in CLL, Smith concludes. 

Mitchell R. Smith, MD, PhD, discusses the potential advantage of lenalidomide in chronic lymphocytic leukemia.

Dr. Smith on Utilizing Lenalidomide in CLL

Mitchell R. Smith, MD, PhD, professor of medicine, George Washington University, associate center director for clinical investigations, Division of Hematology and Oncology, GW Cancer Center, discusses two randomized phase III trials investigating the benefit of ibrutinib (Imbruvica)-based therapies in patients with chronic lymphocytic leukemia (CLL).

The phase III ECOG E1912 trial accrued 529 previously untreated patients under the age of 70 and randomized them to receive the combination of ibrutinib and rituximab (Rituxan) or standard fludarabine, cyclophosphamide, and rituximab (FCR).

In the phase III ALLIANCE A041202 trial, investigators tested ibrutinib with or without rituximab versus the combination of bendamustine and rituximab. There were 547 patients in the trial, and patients had a median age of 71.

In both trials, a progression-free survival (PFS) benefit was reported with the use of ibrutinib. In ECOG E1912, a 65% reduction in the risk of disease progression or death was reported with ibrutinib compared with FCR. In the ALLIANCE study, a 63% reduction in the risk of disease progression or death was reported with ibrutinib.

Notably, no significant benefit was seen with the addition of rituximab in the ALLIANCE trial; therefore, single-agent ibrutinib is recommended, Smith concludes.

Mitchell R. Smith, MD, PhD, discusses two randomized phase III trials investigating the benefit of ibrutinib-based therapies in patients with chronic lymphocytic leukemia.

Dr. Smith on Ibrutinib-Based Therapies in CLL

Mitchell R. Smith, MD, PhD, professor of medicine, George Washington University, associate center director for clinical investigations, Division of Hematology and Oncology, GW Cancer Center, discusses emerging therapeutic approaches in indolent lymphoma.

Indolent lymphoma is an incurable cancer and is often treated by the “watch and wait” approach, says Smith.

Although immunotherapy has not shown considerable efficacy in indolent lymphoma, CAR T-cell therapy and antibody-drug conjugates are cause for excitement. Smith also highlights radioimmunotherapy, an area that he says has been overlooked but should be further explored. According to Smith, combination therapy is on the horizon. For example, drugs that inhibit B-cell proliferation combined with venetoclax (Venclexta), which promotes apoptosis, also have potential.

Moving forward, the field will have to learn how to integrate currenttreatment paradigms with these new agents. This may shed light on the optimal time to stop treatment in this patient population which remains an unanswered question in the field, says Smith.

Mitchell R. Smith, MD, PhD

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