Transcript
Hi. I'm Mehdi Hamadani. I'm a lymphoma and transplant physician at the Medical College of Wisconsin in Milwaukee, Wisconsin. Recently, at LA, at the Great Debates and Updates in Hematologic Malignancies in March 2020, I debated the benefits and risks of various cell therapies as a salvage option in patients with relapsed/refractory mantle cell lymphoma.
My specific task was to consider the pros and cons of either an allogeneic stem cell transplant versus CAR T-cell therapies in patients with mantle cell lymphoma. During that presentation, I attempted to make a case -- that's a very important point -- that not all patients with relapsed/refractory mantle cell lymphoma cell therapies or transplant-like modalities are needed.
That's one of the key points, is we really have to do a better job of identifying patients who don't need these complicated and costly therapies as a strategy to manage disease relapse. We know that in the upfront untreated setting, there are many patients with mantle cell lymphoma who don't immediately need treatment. Just like indolent lymphomas, a subset of mantle cell lymphomas can undergo watchful waiting.
Along similar lines, there are patients with relapsed/refractory mantle cell lymphoma who at least don't immediately need therapies or patients who don't need more complicated therapies like stem cell transplant and, arguably, CAR T-cell therapies once these therapies are commercially available as a standard of care option.
In my opinion, mantle cell lymphoma patients that are not highlighted by high-risk genomic features like presence of p53 mutation, patients who don't histologically high-risk disease like blastoid morphology, patients that biologically don't have high-risk disease as measured by various prognostic systems like the MIPI score or MIPIc score, are typically patients who may not need very aggressive salvage therapies, at least, as second line of treatment option.
In addition to these patients, patients who undergo an autologous transplant in the front-line setting, if they happen to stay in remission for a long time after an autologous transplant, generally, the cutoff is around two years. Maybe if you relapse within two years, those patients typically don't do well.
If you relapse late, those patients typically do well. Patients with asymptomatic, low bulk of disease at the time of relapse may not need more intensive therapies.
In summary, patients who don't have genetically high-risk disease defined by p53 mutation or high MIPI score or patients who are either primary refractory or relapsing very early after transplant, especially the subset of patients who are relapsing with very low-bulk disease, can be managed with less intensive therapies, typically ibrutinib as a single agent, maybe in combination with CD20-directed therapies.
Further down the line, therapies like lenalidomide is an option. Proteasome inhibitors are certainly active in patients with mantle cell lymphoma. Venetoclax, while not approved, is certainly active in this disease.
We can shift our focus to patients who really need cell therapies. Those could be multiple relapsed and refractory patients who have seen several lines of prior therapies or patients who relapsed very early after an autologous transplant if you offered one in first remission, are the patients I would worry about.
Certainly, most people agree that patients with p53 mutation or blastoid morphologies are very aggressive patients. If your relapse is highlighted by these high-risk features, consideration of either an allo transplant or CAR T-cell therapies are a very valid consideration.
Allo transplant, at least in young patients who are fit, don't have a lot of comorbid medical condition, has historically been a procedure that arguably has a lot of toxicities, but it is curative for a subset of patients.
Several years ago, a patient highlighted with high-risk features at relapse or multiply relapsed/refractory patients is where most transplant physicians would consider an allo transplant with a curative intent. In the recent years, obviously, our field is dramatically changing.
We have seen a shift, at least patients with aggressive B-cell lymphoma, specifically diffuse large B-cell lymphoma, where in multiply relapsed/refractory disease or after an autologous transplant, where we used to do a lot of allo transplant, the field has completely toward cell therapies, specifically CAR T-cell therapies, for management of those patients.
Similar things will likely happen in patients with mantle cell lymphoma. Michael Wang from MD Anderson recently presented the results of the ZUMA-2 trial that he looked an X19, which is essentially a CAR T-cell therapy platform for patients with relapsed/refractory mantle cell lymphoma.
Arguably, with all the limitations of a CAR T-cell trial where you eventually look at outcomes of only patients who were fit enough to go on a CAR T-cell trial...They had disease that was favorable enough for you to get cell collected, then remained alive to get the CAR T-cell infused back to those patients.
With those limitations in mind, the data of cell therapies in mantle cell lymphomas definitely looks impressive. These results are now out in "New England Journal of Medicine" within the last one or two weeks.
X19 platform provided very high response rates in these mantle cell lymphoma patients, with response rates achieving 90 percent in at least a one-year progression and overall survival. Looks favorable.
They're roughly similar to what you get with an allo transparent at one-year standpoint but obviously with much lower risk of non-relapse mortality, which is a problem with allo transplantation. It is expected that based on these data, X19 may become a standard of care for patients with relapsed/refractory mantle cell lymphoma.
Obviously, X19 is definitely not the only platform of cell or CAR T-cell therapies. In our institution at Medical College of Wisconsin, we have been working with tandem CD19/CD20 CAR, which is led Dr. Nirav Shah, one of our lymphoma faculty and transplant faculty here.
His data in a subset of about five to seven mantle cell lymphoma looks very interesting. The response rates are high. Some of the responses are durable. Similar durable responses have been seen by other CAR constructs that are typically targeting CD19 therapies.
In the years to come, cell therapy in the form of either an autologous CAR product and maybe down the road an off-the-shelf allogeneic CAR construct may start to play a bigger role in management of relapsed/refractory mantle cell lymphoma patients.
If we summarize these thoughts again, for these relapsed/refractory mantle cell lymphoma patients it is important to figure out patients who don't really need these expensive therapies. In high-risk patients that we identified a few minutes ago, in those patients, cell therapy either in the form of CAR T-cells or allo transplant is a legitimate option.
In the near future, for patients who have seen a lot of lines of therapies, who are BTK inhibitor refractory patients, will likely go to CAR T-cell-like therapies first. It is plausible that allo transplant may be relegated to patients who have failed cell therapies, which is not good from an allo perspective.
We are already transplanting very frail, very heavily pretreated patients for allo transplant, which impacts our allo transplant outcomes. Once we start to transplant even more heavily pretreated patients who have even failed maybe one or two cell therapies, it, as a natural fact, will probably make allo transplant outcomes even more worse.
The more heavily pretreated your disease is, the higher the complication rates are with allo transplantation, but overall this is an exciting time in the management of patients with mantle cell lymphoma. Not only we now have a wealth of targeted agents available to manage these patients, but our therapy option in terms of cell therapies are also expanding.
It's certainly very good news for patients. We will hopefully see more durable responses for mantle cell lymphoma patients even in the relapsed/refractory setting.
Final word would be an unmet need in terms of patients with p53-mutated disease. It's widely expected that these patients don't benefit from whatever front-line therapy we throw at them. They typically don't benefit from high-dose therapy and autologous stem cell transplant consolidation in the front-line setting as well.
Our practice has been if we find a p53-mutated patient, we typically consider an allogeneic transplant in those patients in the upfront setting. Certainly, there is some data from the Memorial Group that shows that allo transplant can cure a subset of p53-mutated mantle cell lymphoma patients.
Whether CAR T-cell therapies would be a valid alternate for such ultra-high-risk patient remains to be seen. I thank you for your attention.
