Novel Therapies for Mantle Cell Lymphoma

Michael Wang, MD: There is a new standard for first-line therapy in mantle cell lymphoma. First, it is a rare lymphoma. It is very hard to collect enough cases to do a phase 3 trial. This is happening now, but in the past, phase 3 trial data were almost nonexistent in the frontline setting for mantle cell lymphoma. However, we do have very strong phase 2 clinical trial data.

For patients who are younger than 65 years old, we used to use very intensive therapy. We used hyper–CVAD [cyclophosphamide, vincristine, doxorubicin hydrochloride, dexamethasone] chemotherapy—6 to 8 cycles—or we used induction therapy, including araC [cytarabine], followed by autologous stem cell transplantation after high-dose chemotherapy.

There are many other data out there, but those 2 options are represented by the best clinical data for patients with newly diagnosed mantle cell lymphoma who are younger than 65 years old. The survival in each clinical trial exceeded 10 years. If you have a very deadly mantle cell lymphoma case, you can tell the patient that if they are in the median they are going to survive more than 10 years. Those are fantastic data, right?

For the younger population, however, we realized that if you treat them with such intensive chemotherapy, they often have secondary malignancies. Many years after the therapy, another form of cancer would arise because of the prior intensive chemotherapy. This is in addition to the acute toxicities. Those therapies have been around for 15, 20, or even more years. These are intensive chemotherapies.

Intensive chemotherapy was at the peak of its usage. When I started as a fellow, a study about hyper–CVAD [cyclophosphamide, vincristine, doxorubicin hydrochloride, dexamethasone] therapy was published in the Journal of Clinical Oncology, with me as a coauthor. I was able to witness the suffering of all those patients who have secondary malignancies, who are so weak after such intensive therapy. Throughout my career, I have put forth effort for many years to try to replace chemotherapy with chemotherapy-free therapies. Gradually, methodically, reasonably, and step by step but chemotherapy-free therapies.

For example, the Window-1 trial utilizes chemotherapy-free therapy upfront. We have had such great results. The response rate before chemotherapy was 100%, and the overall response with a CR [complete response] rate was about 92%. A lot of colleagues from academic settings are using this therapy because it’s already in the NCCN [National Comprehensive Cancer Network] Guidelines. If you look at the NCCN Guidelines, you can actually use ibrutinib-rituximab to reduce the number of chemotherapy cycles you have to use in young patients.

On top of the Window-1 therapy trial, and we are hoping to publish on this in 2020 with robust MRD [minimal residual disease] data, we also had a Window II clinical trial that further enhanced chemotherapy-free therapy with ibrutinib-rituximab before chemotherapy, adding the BCL2 inhibitor venetoclax.

The Window II trial is even more exciting. If Window-1 has achieved the CR rate of 92% before chemotherapy, by adding venetoclax we might have an even higher CR rate. After that, there will be 3 categories in the low-risk-patient population.

Now, coming back to risk stratification, very importantly, no chemotherapy is needed to treat low-risk patients. Only maintenance therapy with 3 drugs for up 2 years is recommended. For the high-risk group of patients, after the Window II frontline 3-agent chemotherapy-free therapy regimen, they would receive 4 cycles of chemotherapy because of their risk status. However, many patients fall between the high-risk and low-risk groups. We call this cohort the moderate-risk cohort, and we use only 2 cycles of chemotherapy.

You can see we are moving away from 8 cycles of chemotherapy to a mixture of chemotherapy-free therapy and totally chemotherapy-free therapy as a result of the Window-1 and Window II trials. We’re moving away from chemotherapy in the younger patient population.

In the older population, we have migrated from R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] to R-bendamustine [rituximab- bendamustine] therapy based on the StiL study performed by German investigators under the leadership of Dr Mathias Rummel. That progress has, in my opinion, evolved into R2 [lenalidomide, rituximab] therapy. What is R2? R2 is Revlimid [lenalidomide] with rituximab. This was initially developed by me at The University of Texas MD Anderson Cancer Center. It look 7 years to do this trial. There was good success. In the relapsed setting, we saw a 57% overall response rate.

Then my good friend and colleague, an excellent scholar from Cornell University, published on R2 [lenalidomide, rituximab] in the frontline setting for mantle cell lymphoma. This is also with the same guidelines in the older population, with an R2 [lenalidomide, rituximab] therapy, and the data is wonderful.

A lot of people are using R2 [lenalidomide, rituximab] therapy instead of chemotherapy, either with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or R-bendamustine [rituximab-bendamustine]. In my opinion, the newest therapy for older patients is Rituxan-ibrutinib. I have conducted this trial. We reported on this at the 15th International Conference on Malignant Lymphoma meeting in Lugano, Switzerland, and we’re getting ready to publish these data. We have submitted another abstract for ASH [the American Society of Hematology Annual Meeting]. In this older population, the response rate is almost 100%. With rituximab-ibrutinib, the CR rate is very high. I think this will challenge R2 [lenalidomide, rituximab]. We do need to pay attention to some cardiac adverse events, and we are going to show you the whole data at ASH.

As you can see, in the older population we are also evolving from chemotherapy to chemotherapy-free therapies. In the future, we would entertain more populations by studying acalabrutinib with rituximab. Another clinical trial will be done at MD Anderson Cancer Center.

Other trials include AVR, which is acalabrutinib, venetoclax, and rituximab. We’re also studying zanubrutinib with rituximab versus chemotherapy in a phase 3 clinical trial. As you can see, the whole field is moving away from chemotherapy to chemotherapy-free therapies, in the older population as well as the young population.

Transcript edited for clarity.