As research and treatment options for patients with mantle cell lymphoma continue to expand, the development of risk-adapted therapies for the 3 primary subtypes—blastoid, smoldering, and classic broad-spectrum—represents a crucial next step in the field.
As research and treatment options for patients with mantle cell lymphoma (MCL) continue to expand, the development of risk-adapted therapies for the 3 primary subtypes—blastoid, smoldering, and classic broad-spectrum—represents a crucial next step in the field, according to André H. Goy, MD.
“MCL is a rare subtype of lymphoma that has the reputation to become chemotherapy resistant over time and that’s why this has been a very active field of clinical research,” Goy said. “We now have 6 drugs approved, including 3 BTK inhibitors, lenalidomide [Revlimid], bortezomib [Velcade], but also the CAR T-cell therapy brexucabtagene autoleucel [Tecartus] that has been a game changer.”
In an interview with OncLive®, Goy, physician in chief at Hackensack Meridian Health Oncology Care Transformation Service, chairman and chief physician officer of John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma and Academic Chairman Oncology at Hackensack Meridian School of Medicine at Seton Hall University, and professor of medicine at Georgetown University, discussed his recent presentation on unresolved questions that remain in MCL from the 4th Annual Precision Medicine Symposium: An Illustrated Tumor Board.
Starting with a relapsed/refractory setting—because that’s where most of the progress has been done—an unresolved question is how we [approached] treatment decisions. There’s no consensus on how we treat frontline MCL, and I think that it’s time to really look at 2 things. First, there’s a disconnect between what we think the outcome of a patient with MCL [will be] based on clinical trials where you see that with the contribution of rituximab [Rituxan] high-dose AraC [cytarabine] and stem cell transplant, the [median] PFS [progression-free survival] has been in excess of 7 or 8 years in the frontline setting and clearly improving outcomes.
All of this has changed the field of MCL with a median OS [overall survival] now that is in excess of 10 to 12 years in some of these clinical trials, particularly [among] younger patients. [In patients] younger than 65 [years] we often use high-dose therapy, such as hyper-CVAD [modified hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone], with or without transplant.
There’s a lot of interest in retrospective [and] prospective real-world large studies, looking at novel biological therapies, particularly has improved the survival in the relapsed setting. That’s important, but [data are also showing] that in the frontline setting close to half of younger patients, and more than half of the patients [overall], still just get BR treatment and sometimes get BR or R-CHOP.
There’s a disconnect in a regimen that I use in clinical trials and the real world and when you look at the median time to next therapy both in younger and older patients is approximately 2 years; there is clearly a need for improvement. If you look at the large real-world setting—[information obtained from] databases from 15 years ago vs more recently—you can see that the outcome improvement has been mostly in the younger patients, not really in the older patients with a median OS [overall survival] in a real-world data more in the range of 3 to 5 years. Clearly there’s a disconnect.
The second thing that is important to remember is that there’s been great progress in understanding the diversity or biological presentation of MCL [with more clarity of] several subtypes. One subtype that is clearly a different disease with a different gene expression profile that is called the indolent MCL that is cyclin D–negative, different gene expression profile, and clinically presents with a high white [blood cell] count and splenomegaly. [Additionally, there is] very little if any adenopathy, patients are genetically stable, disease is often very mutated, and they can be monitored for years. Over time some cases case can become more complex, cytogenetically speaking, [and] TP53 mutations would affect the type of treatment you pick, but that doesn’t make [it] progress any faster.
There are 3 presentations [of MCL]. [There is] the very aggressive presentation—blastomere pleomorphic—[categorized as having] high proliferative index by Ki-67 [expression] that is 50% up to 90%. These patients have complex karyotype, TP53 mutation, MYC rearrangement, and a number of other abnormalities that make them very high risk. Outcomes are worse [for those who] have blastomere and TP53 mutation; the median OS, regardless of the dose intensity, is 1.6 to 1.8 years, very short. Even if this patient achieved a complete response [CR], they relapse very quickly.
On the other end of this category, you have the lower-risk MCL that some [individuals] refer to as smoldering MCL. These are patients who have routine discovery of lymphadenopathy on imaging or colonoscopy, and they have low-bulk disease with low risk factors. These patients can be monitored, the median time to stop therapy is usually 1 to 3 years.
Then in the middle, [there are] the rest of the patients who have MCL who can, to varying degree, harbor TP53 abnormalities, genetic features of high-risk features, and also variable Ki-67 [expression], almost like a spectrum of disease.
[There is] great variety [among] genetic features for high-risk [disease] such as the high proliferative index, complex karyotype, TP53, MYC, and a number of other somatic mutations. That’s becoming something that we have now accessible in a routine practice with next-generation sequencing [NGS], it’s is important to take into consideration.
That brings us to how do we manage [MCL]? There’s a disconnect with the real-world and clinical trial [data], we need to do better. We know that the real-world data showed that there’s a great variance of care. How do we put this together?
Patients who have indolent MCL can be monitored for years and should not be enrolled in the standard clinical trials for MCL. They have very different genetic profiling and sometimes can have [or develop] TP53 abnormalities over time but can be very stable for a long time. When patients who have smoldering MCL or indolent [disease] need treatment this is an opportunity to use a doublet such as R2 [lenalidomide/rituximab]. That [combination was based on the Cornell data and] was a treatment [for] quite a long time because they got an induction for R2 for 1 year and then received maintenance of lenalidomide and rituximab and rituximab being until progression of disease, some of them have been on rituximab for well over 5 years. That’s an easy treatment in a population who are often not great candidates for chemotherapy.
More appealing is the BTK combination of ibrutinib [Imbruvica] and rituximab that clearly show a very high response rate and CR rate in that setting and that could be very appealing. We know that the patients who have molecular high-risk features, TP53 or complex karyotypes, respond and [there is] no difference in CR rates when they have a TP53 mutation. For example, they tend to relapse a bit faster, but they still respond better than on chemotherapy. The other end of the spectrum is the blastoid variant and this population clearly has very high-risk features and do very poorly regardless of the conventional therapy use including high-dose and dose-intensive regimens.
This is a population where the WINDOW approach [WINDOW-1; NCT02427620], which is a biologic combination doublet or triplet, ibrutinib/rituximab, followed by a shortened version hyper-CVAD for 4 cycles once the patient had responded to the biological induction. [Another example is] ibrutinib, rituximab, and venetoclax [Venclexta], this is ongoing in the WINDOW-2 trial [NCT03710772]. The early data show a very high CR rate in that setting and that’s not surprising. The ibrutinib/venetoclax in the relapse/refractory setting had a very high CR rate even patients with TP53 abnormalities and was sometimes so durable that some patients had stopped therapy and had been in remission 2 years later. That’s a promising direction.
In a patient who is not a candidate for chemotherapy in that population, [treatment options consist of] the triplets that I mentioned ibrutinib/rituximab/venetoclax or acalabrutinib [Calquence]/venetoclax/rituximab or lenalidomide/venetoclax/rituximab to name a few or the OASIS II trial [NCT04802590] regimen, which was obinutuzumab [Gazyva]/ibrutinib/venetoclax. All of these are combinations a BTK, a BCL2 inhibitor, and an anti-CD20 [and they] elicit a very high CR rate, a lot of patients 70% or more are minimal residual disease [MRD] negative. That’s a very appealing approach.
The question that remains in that situation is: Do you need chemotherapy afterwards? We don’t have that answer yet. The WINDOW trial is trying to stratify patients based on the low molecular risk features vs high molecular features and [patients with] low molecular risk features that achieved the CR do not go on high-dose AraC or hyper-CVAD. That’s going to be an important question.
Then you have the other category, the in-between category, patients who have MCL and need treatment who don’t have high-risk features, but who still carry molecule abnormality. This is why NGS is becoming very important [to use] routinely. These patients traditionally have been monitored and managed based on their ability to tolerate high-dose therapy with or without transplant. Younger patients, younger than 60 or 65 years, depending on the series, would go on cytarabine/rituximab induction followed by transplant. Older patients would go onto bendamustine/rituximab, followed by maintenance and rituximab.
The VR-CAP regimen [bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone] has very impressive long-term survival benefits.
There was a lot of expectation of BR plus bortezomib that did not show [much] benefit. What it showed on a clinical trial nevertheless [was] that the bendamustine/rituximab plus maintenance rituximab gave a median PFS of over 6 years in this patient population. This is similar to what you see in a real-world setting.
Then you had bendamustine/rituximab plus maintenance ibrutinib, which was evaluated in the SHINE trial [NCT01776840], and there was a lot of expectation on the trial which was introducing these novel agents beside the doublet and triplet as part of the chemotherapy backbone. Instead of doing biological therapy followed by chemotherapy could we combine these biological agents with the chemotherapy? The data recently presented showed 2.5 years in difference in PFS in favor of bendamustine/rituximab plus ibrutinib.
However, it was a little bit disappointing because the CR rate was slightly higher but not significant, there was no difference in survival, and among patients who had TP53 mutations or high-risk features, there was no difference in both arms. A question that remains is if it might be more important to give this biologic early on and give the chemotherapy later rather than trying to combine.
There are additional ongoing studies trying to resolve if we can replace chemotherapy completely? There’s ibrutinib/rituximab vs bendamustine/rituximab in the ENRICH trial [ISRCTN11038174] in the UK [and those data] are maturing.
Finally, patients who are younger who can tolerate dose intensive-therapy, should again get a transplant and get a maintenance after induction with a cytarabine and rituximab–based conditioning regimen.
The unresolved question in that situation is how we handle these patients. What is clear is that the real-world data shows that we need to make progress still and [there is] still a great variance of care. The second thing that it shows is that the outcomes are not as good as clinical trials and I think it’s really time to dissect MCL among the different entities and take into account the molecular heterogeneity to try to refine our treatment. We don’t have yet the best sequence, [there’s options of] doublet or triplet followed by chemotherapy vs combination with chemotherapy; I would favor the first one and the data are maturing as we speak.
The question that comes now is maintenance. Maintenance has become part of standard of care even after high-dose therapy. Initially [these was] demonstrated in elderly patients, improving duration of response, relapse-free survival, and OS quite dramatically in European large, randomized data. The question is how long you have to do maintenance, and the answer is not entirely clear.
I would argue that maintenance still benefits patients because we don’t have enough of a deep response early on. That leads me to the last unresolved question in MCL which is the role of MRD.
MRD has shown to be impactful across the board. This is critical because patients who have a deep and early response do much better, both in PFS and OS. This was so impressive that in the Nordic [Second Nordic Mantle Cell Lymphoma trial (MCL2)] long-term data, the median OS of MRD-positive patients post induction was 3 years vs well over 10 years in patients who were MRD negative. This was a dramatic difference.
The question that comes with that is could we [analyze] MRD and identify a threshold to customize treatment? I think this is where the field is going and there’s a lot of opportunity to participate in clinical trials to answer some of these unresolved questions. Overall, I think it's clearly showing that we have a fresh look in MCL and are starting to refine opportunities.
I think that we are very fortunate to be part of these times in oncology where we have an ongoing revolution in a number of novel therapies. Some reports suggest that we have 10,000 new drugs in the pipeline for oncology; this is dramatic. We see a lot of novel therapies that are game changers such as cellular therapies with CAR T cells, bispecifics, as well and some targeted therapy combinations.
I think the lessons will continue to expand [and areas will be identified] where we can use more combinations of targeted therapy and replace chemotherapy. We’ll see MRD becoming an end point more, and treatments, particularly T cell–engaging therapy, will provide an opportunity to reset the immune system and not have to treat indefinitely, a one-and-done treatment.
Another aspect that is really transpiring in all these conferences is that diagnostics are becoming as important or more important than therapeutics because we have lots of options, but we don’t necessarily know how to define the best way to treat these patients because the number of options are raising the complexity of cancer care.
That brings me to the importance of looking at a real-world data to answer two of the most critical questions. Every patient wants to know: What’s my best option now? And what we want to know as a society [and] as providers: What’s the best sequence of care?
We [want to] provide the best and longest mileage for patients and optimize the resources. After years of accelerating understanding of cancer cell biology, of drug development, including cell therapy, immunotherapy, precision medicine data, that now these are [coming together] to continue to change the field. We together can continue to answer some of the critical questions that I spoke to and coming to this conference is important because we have the advantage of having world experts in the field who have a very good, deep insight on how to treat each of these blood cancers that we will review during the conference.
[This will be not] only what is the most current therapy, but just as importantly on the heels of ASH [2022 American Society of Hematology Annual Meeting], how are these new data changing the way we treat patients? How are priorities evolving? [This meeting will not only keep you] current in your practice, but all together we can improve as many patients lives as possible because that’s what we all want.
Focusing on aggressive lymphoma for example, but it's also approved now multiple indications in diffuse large B-cell lymphoma in the second line, in the third line for MCL, follicular lymphoma, transformed lymphoma, [and more].
This is something that is changing the field, [in particular] in large cell lymphoma where the unmet need was critical because patients did very poorly with high-dose therapy after failing chemotherapy/immunotherapy. We know that only 20% to 25% of patients actually who should get cell therapy do and [they] benefit from CAR T. There’s still a lot of education to do.
The second thing is understanding who the patients are who are on a long-term curve and because we cure [approximately] 40% of patients. [The question is:] Can we identify predictive markers that can really select this population?
And finally, combining CAR T or second or third generation of CAR T that can be dual CAR T, armored CAR T, and other cell platforms NK [natural killer] cells NK/ CAR that can really continue to expand the field. I think this is going to be the foundation of the future of cancer, no question about this.
I think there’s a lot of expectations on building upon the CAR T and particularly now that it’s approved in the second line and how this is going to change the outcome patients that do quickly do very poorly once they have a first relapse.
The other thing is that bispecifics. These are not approved yet clearly have a very high response rate and CR rate. We don’t know the durability yet, but I think there’s a lot of appetite because it’s another form of a T cell–engaging therapy where the original form of T cell–engaging therapy was checkpoint inhibitors. These have not panned out as much in Hodgkin lymphoma, so we think that bispecific would really have a role.