 Risk stratification, in my opinion, is 1 of the most critical things in the art of treating a patient with a lymphoma. In my opinion, everybody is different. Everybody’s tumor is different. In some cases, in almost all cases, each patient’s tumor, in each part of the body of that patient, is also different. So risk stratification lies in the heart of the therapy.

When we do clinical trials, we usually use 1 or 2 therapies to treat many patients. Patients are all labeled with the same diagnosis—let’s say mantle cell lymphoma—but the disease is different in each patient and among all patients. Therefore, when we treat all these different patients with 1 or 2 therapies, outcomes vary. Some patients with low-risk factors get overtreated. Some patients with high-risk factors get undertreated. Usually, those in the middle get the right therapy. But every cohort—low risk, moderate risk, high risk—could be further risk stratified. So risk stratification is 1 of the most important things used to treat mantle cell lymphoma in daily practice. That is my opinion.

For mantle cell lymphoma, high-risk features include a 

 percentage of over 30%. People with over 50% have an even worse prognosis, and we also have patients who have complex karyotype. This means they have chromosomal abnormalities excluding the 11;14 translocation. There are 3 or more chromosomal abnormalities we call the complex karyotype.

Also, in mantle cell lymphoma morphology, a blastoid or pleomorphic variant puts a person as higher risk. In summary, 

, pleomorphic or blastoid karyotype, or complex karyotype are all high-risk features.

This is only the beginning of what I’m describing. Actually, how to risk stratify is even more complicated. There’s the MIPI [Mantle Cell Lymphoma International Prognostic Index] score. There are additional chain mutations. There is bulky tumor load. There’s also relapse within 24 months. Those are all data-driven risk factors. That’s why it’s very complicated to treat a mantle cell lymphoma patient.

A patient who has had 3 prior therapies has automatically transformed into a very complex high-risk mantle cell lymphoma patient. Those people who were treated with 3 prior therapies, including a BTK [Bruton tyrosine kinase] inhibitor, have only about 6 to 10 months’ delay. The risk stratification is complicated, but their high-risk factors continue to grow with more genetic testing and more data from trials and daily practice.

The MIPI score considers a patient’s age, performance status, LDH [lactate dehydrogenase], and WBC [white blood cell] count. MIPI is a very important prognostic factor. One of the main reasons why MIPI is so reliable is because it considers age and performance status in addition to other laboratory parameters.

In Sweden it was published that age and performance status affected overall survival. MIPI is very important, especially when the patient is newly diagnosed. When MIPI is combined with the Ki-67, that’s even more reliable. It’s able to categorize the survival of the mantle cell lymphoma patient very nicely.

However, most of the time clinicians don’t calculate the MIPI score. If you treat mantle cell lymphoma, you already automatically and intuitively categorize the patient based on different risk factors. When you calculate them in a MIPI score—your clinical mutations are consistent with the MIPI. I think MIPI is very useful. Especially as we publish papers and data, MIPI is very important to see, to gauge whether a patient is actually part of a low-risk population, a moderate-risk population, or a high-risk population. In my opinion, MIPI is very useful.

Risk Stratification of Mantle Cell Lymphoma

 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 

, 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.

Novel Therapies for Mantle Cell Lymphoma

 The natural history of mantle cell lymphoma is the same as the natural history of lymphoma and myeloma overall and the same as other hematologic malignancies. What is the natural history of mantle cell lymphoma? It is a repeated cycle of remission-relapse, remission-relapse, and this can keep repeating for 5, 10, 20 cycles. Unfortunately, with each repeated cycle of relapse, the efficacy drops further. The more you treat them, the more resistant they become. At the end, efficacy drops to 0 because the resistance is almost 100%. Then we lose the patient to mantle cell lymphoma.

Neither chemotherapy or chemotherapy-free therapy can cure high-risk patients. You can put them into a remission for a period of time, but inevitably they will relapse. Every time they relapse you put them into another remission using chemotherapy, or a chemotherapy-free therapy, or targeted therapies, or a combination, or new trials, but they will relapse again.

What is our approach? Before CAR [chimeric antigen receptor] T-cell therapy, we did not really have any effective means. We used allogeneic transplantation. We were able to put some of the patients into a long-term remission but at a heavy price of mortality. The patient may not even survive the allogeneic transplant. Also, the allogeneic transplantation was not readily available to the majority of patients. Then we actually started treating the patients with CAR T-cell therapies. I’m very excited for Tecartus [brexucabtagene autoleucel] and that the CD19 Kite Pharma ZUMA-2 protocol data were used for FDA approval for relapsed mantle cell lymphoma.

This clinical trial particularly includes all-risk patients. Many patients have 

 mutations, blastoid and pleomorphic variants, complex karyotype, and all that. The overall response is 87%, and the CR [complete response] rate is 62%. This is the basis of the FDA approval. Regarding adverse effects, we only saw CRS [cytokine release syndrome] toxicity. The neurotoxicity profile is very favorable. Overall, this brings hope to the high-risk patient population. Why? According to my ASH [American Society of Hematology Annual Meeting] presentation in December 2019, a big fraction of patients—approximately 50%—had 2-year follow-up data at that time. For about 40% of patients, the curves were flat. It looks as though fewer patients are relapsing. This is very encouraging. So far, the curve appears to be flat. Of course, at that time we had only 12 months of a median follow-up, with a fraction of people exceeding 24 months.

During this coming ASH in December, we’re going to present more follow-up data—more than 1-year. So please come to see our data at that conference, either in person or virtually.

KTE-X19 Treatment for R/R Mantle Cell Lymphoma

 I really think this is a milestone, regarding progress in therapy for high-risk mantle cell lymphoma. It is going to change the way we treat high-risk mantle cell lymphoma. Please remember, because of the natural history of mantle cell lymphoma, almost all patients will eventually evolve into high risk. When they were high risk in the past, they are not curable. I cannot state that a CAR [chimeric antigen receptor] T-cell therapy is already proving curable. However, there’s a hope for long-term remission because we have observed long-term remissions. We saw this for about 39% of patients in an even more refractory disease called large cell lymphoma. In the ZUMA-1 clinical trial, after 3 or 4 years of follow-up, the curve still remains relatively flat, with over 30% of patients enjoying long-term remissions.

My feeling is that we probably will do a little better than we have in large cell lymphoma, but I cannot guarantee this. I can see that some of the patients already enjoy long-term remissions. Whether this is a curable modality or not totally depends on the test of time. We cannot claim cure, but we are cautiously optimistic, especially me. CAR T-cell therapy is changing the way we treat high-risk mantle cell lymphoma. Because all patients eventually become high risk, CAR T therapy will totally change the landscape of mantle cell lymphoma.

The most exciting part of the data is the overall response rate—87%—and the CR [complete response] rate—62%. After a median 1-year follow-up, overall survival has not been reached. The duration of remission has not been reached. The CRS [cytokine release syndrome] grade 3 or 4 toxicities are about 15%. Only 1 patient actually has a grade 5 CRS event. The majority of patients did very well. And the neurotoxicity, grade 3 or 4, is also around 15%. This is very comparable with other Kite Pharma ZUMA studies in large cell lymphoma and other lymphomas.

I really think these are very encouraging data. I’m looking forward to sharing the longer-term follow-up data with you during ASH [American Society of Hematology Annual Meeting] 2020.

Implications of ZUMA-2 in R/R Mantle Cell Lymphoma

 We did publish data about the pharmacokinetics and pharmacodynamics so far because of 2 factors: the nature of the therapy and, potentially, sample size. So far, the CAR [chimeric antigen receptor] T-cell therapy Tecartus [brexucabtagene autoleucel] has ignored all the worst prognostic factors. That means it demonstrated the same amount of response rate and duration response in low-risk and high-risk patients.

The skew toward CD8 could be a factor with prior ibrutinib. It’s a very small sample observation, and we need more time and more samples to validify this potential scientific finding.

This trial is designed to enroll only patients pretreated with a BTK [Bruton tyrosine kinase] inhibitor. Eighty percent of the patients are refractory to prior BTK therapy. About 10% of people are intolerant to BTK therapy. So the majority of the patients relapse after BTK therapy. They are refractory to BTK therapy. Based on data, we see an 87% overall response rate. The CR [complete response] rate applies to those people treated with a prior BTK therapy because that’s the nature of the study.

The most frequent toxicities include cytopenias. All the adverse events reported in the clinical trial are regardless of their relationships to starting therapy because, as I explained before, this population in this clinical trial, ZUMA-2, is a population being treated with later-line CAR T therapy. The median of patients were treated with prior, other therapies, including chemotherapies, and could induce cytopenias. Cytopenia, neutropenia, anemia, thrombocytopenia are most common.

The most common adverse events related to CAR T-cell therapy are hypotension, hypoxemia, fever, and infections. These are adequately addressed in the clinical trial, except for in the few patients who actually had a severe adverse effect. However, the majority of patients did very well. Their median time to CRS [cytokine release syndrome] and peak median time is very quick, about 1 to 2 days. Neurotoxicity usually started at day 5 to day 7, with a peak at about day 10 or day 14. This is totally consistent with other CAR T-cell products. So the benefit and the risk ratio are very favorable.

The other ongoing clinical trial is the Juno Therapeutics CAR T-cell clinical trial with a CD19. The difference between the 2 products is that the Kite Pharma product used the costimulatory molecule CD28, versus 4-1BB utilized by the Juno product. There are some comments floating around about 4-1BB being less toxic than CD28, but we cannot definitively answer that question unless there is a head-to-head comparison. Because of the population difference, and because many factors are not identical, we could not compare, directly, the toxicities between the 2 different trials. I’m not able to definitively answer that question because of the lack of the data. However, people have generally felt that they are very good trials in mantle cell lymphoma.

KTE-X19 for R/R MCL: Treatment Considerations

 I really think MRD [minimal residual disease] is 1 of the most exciting areas in hematologic malignancies, probably in the whole field of oncology. MRD in mantle cell lymphoma is evolving very fast. Not only can we measure the minimal residual disease, but we can also achieve deep, profound molecular remission. Not only that, but we are also able to use the MRD methodology to track clonal evolution. If the patient appears to be relapsing, we can actually catch the relapse at the molecular stage. We can actually use therapies to strike the relapse, to treat the relapse, to attack the relapse—whatever word you want to use—to get rid of the clonal evolution at the molecular stage.

When the patient has a big tumor, it’s very hard to eradicate the whole tumor. But when the patient has a small tumor, we can much more easily eradicate the tumor. But imagine eradicating the evolution of the emerging clones before they can form a tumor mass. That is much easier. We don’t need much therapy. We can track them with MRD, whether they disappeared or reappeared. This will be the next stage of therapy in the next era.

In summary, mantle cell lymphoma therapy has evolved from the use of chemotherapy to the use of chemotherapy-free therapies to a cellular therapy era. But after cellular therapy, we’re going to reach the next therapy, which is the precision medicine era in mantle cell lymphoma. MRD is just 1 of the molecular-type tools we can use to strike relapses early.

We could also use biological and mechanistical studies to track the clonal evolution, especially the single-cell technologies, including single-cell RNA, DNA, proteomics, and to decipher not only the evolution of the tumor cells but also the CAR T cells and, very importantly, the tumor microenvironment. When we reach that age, we can actually find out the clonal evolution of the driver-resistant clones. We know exactly what pathway is upregulated in that driver-relapsed clone, and we can knock it out with precision medicine.

That’s the next era, after the current cellular therapy era. I’m very, very excited. My colleagues and I are in collaboration with many respected colleagues in the field. We think we could cure a population of mantle cell lymphoma within our careers using all the therapies I described above. I am particularly excited that what’s happening in the laboratory and what’s happening in clinical trials are getting closer and closer. In the future, in the near future, laboratories and clinics are not going to be separated anymore. Because to cure diseases such as mantle cell lymphoma, we need the 2 to work together. And we need precision medicine to happen.

MRD Assessment in Mantle Cell Lymphoma

 The therapies for mantle cell lymphoma have evolved, but unmet clinical needs have also evolved. We relied on chemotherapy. When the patients became chemotherapy resistant, what did we do? We used to use chemotherapy-free therapies. The urgent need was a strategy to address the chemotherapy-resistant patient population. Then we found a targeted therapy, chemotherapy-free therapies. Then we found that some patients continued to relapse after chemotherapy and chemotherapy-free therapy.

The urgent unmet clinical need was a way to help manage these high-risk patients who are resistant to chemotherapy or chemotherapy-free therapies. So we are using cell therapies. We’re using cell therapies to combat the high-risk patient after chemotherapy and chemotherapy-free therapy.

Now we see that the majority of patients treated with a CAR [chimeric antigen receptor] T-cell therapy will eventually relapse. The urgent unmet clinical need is a strategy to manage those patients who relapsed after chemotherapy, chemotherapy-free therapy, and CAR T-cell therapy. You can see that the unmet clinical needs evolved with advances in therapies.

In my opinion, precision medicine will answer the unmet clinical needs after chemotherapy-free therapy, chemotherapy, and CAR T-cell therapies. The reality is evolving, and the future is also evolving. That’s the nature of the nature.