Venetoclax May Play Role as Salvage Therapy in Multiply Relapsed MCL
May 12, 2020 07:00pm
By Danielle Ternyila
Andre Goy, MD, discusses some of the recent changes that have been seen in the treatment landscape for patients with MCL and some of the ways these subsets of patients are being identified in order to find the best treatment option for an individual patient.
Andre Goy, MD
There has been a shift in the treatment landscape for mantle cell lymphoma (MCL), according to Andre Goy, MD. Clinical trials are now investigating options for various subsets of patients based on their ECOG status, molecular features, and other identifying factors.
“This is a really exciting time in MCL. There’s a shift in really identifying the subsets of patients that are high-risk that should receive biologic therapy upfront and then chemotherapy, those who are frail [and] who can’t get chemotherapy, and the patient that can receive, based on their situation, a different regimen,” said Goy at the 23rd Annual International Congress on Hematological Malignancies.®
In an interview withTargeted Oncology,Goy, chief in the division of lymphoma, chairman and director at John Theurer Cancer Center, discussed some of the recent changes that have been seen in the treatment landscape for patients with MCL and some of the ways these subsets of patients are being identified in order to find the best treatment option for an individual patient.
TARGETED ONCOLOGY:What are the most notable changes we’ve seen in the treatment landscape for MCL?
Goy:Typically, MCL, to be treated, needs to be recognized in its different subsets. There’s clearly 5% to 15% of patients who have indolent disease; they have a high white blood cell count, minimal lymphadenopathy, if any, asymptomatic, and can be monitored over time. We can monitor this patient for quite a while. We still have to monitor them because over some time, they can acquire p53 abnormality and can transform more aggressively. It’s rare, but that can happen. However, these patients can be monitored and not treated early on.
For the patient who presents symptomatic that needs treatment, [presenting as] classic MCL, the most important factors are their age and the fitness of the patient. We can say the ECOG status helps you identify how to treat this patient. In a patient who [can receive] high-dose intensive therapy, they can receive a cytarabine/rituximab (Rituxan) combined induction followed by with or without stem cell transplant. These patients typically do really well. In maintenance, there is also benefit in the younger patients. In the older patients, bendamustine/rituximab has become the backbone, then adding ibrutinib (Imbruvica) to acalabrutinib (Calquence), dose depending. We alluded to VR-CAP where the data is replacing bortezomib (Velcade) in the R-CHOP backbone. The result is very impressive in terms of the complete response rate, durability and even survival advantage, so it is an option for older patients.
What comes from this that’s really important is beyond this classification of age and how fit the patient is for intensive therapy in the ECOG status, is to really look at the molecular factors and identify the molecular high-grade features, particularly p53. P53 deletion of 17p is actually not very frequently found in MCL, contrary to CLL where it’s the most common way to find the abnormalities and deletion of 17p. We actually look at expression of p53 and do sequencing if needed. We have published and shown that you can find 23% to 25% of these patients at baseline. In those patients, they should not receive chemotherapy upfront. We actually use ibrutinib and rituximab as a window of opportunity, followed by chemotherapy consideration.
Finally, for the patients that are frail and not eligible for chemotherapy, it’s probably better to not give them chemotherapy. We are moving towards exploring doublets and triplets in clinical trials. Venetoclax (Venclexta) with ibrutinib, for example, in the relapsed setting where the activity was so impressive will definitely move, with combination of an anti-CD20 antibody, in ongoing trial as we speak.
The last aspect that is important in MCL is the aspect of minimal residual disease (MRD). Achieving MRD-negativity really translates to a better outcome. It might be able to guide maintenance in the future, so this is something that will enter routine clinical practice in the future. This is a really exciting time in MCL. There’s a shift in really identifying the subsets of patients that are high-risk that should receive biologic therapy upfront and then chemotherapy, those who are frail who can’t get chemotherapy, and the patient that can receive, based on their situation, a different regimen.
TARGETED ONCOLOGY:What challenges still exist in this space?
Goy:There are still a number of challenges that we face in MCL. One of the first ones is that the median age of diagnosis is the mid- to late sixties, so that’s difficult for intensive therapy. We still don’t really know if high-dose therapy is beneficial after induction therapy, particularly in a patient who is MRD-negative. Achieving a deep response and CR in MRD-negative early MCL matters. This is being looked at in the TRIANGLE study in France. We are looking at the same induction they have had in the past, with or without transplant, and replacing the transplant with maintenance by ibrutinib. Those are the options to see if we really need to do the high-dose therapy.
I would say the other challenge is the subset of patients that present with blastic variant, high-proliferative disease, and complex carrier type, p53 mutated. These patients can do very poorly, and that’s where the chimeric antigen receptor (CAR) T cells in the ongoing ZUMA-2 trial seems very promising as an option for these patients, either by itself or with transplant after failing induction therapy.
TARGETED ONCOLOGY:What agents or regimens look particularly promising in the field of MCL?
Goy:The BTK inhibitors like rituximab are very impressive in the salvage setting. The triplet, also in the salvage setting, of venetoclax combination with ibrutinib, and they are going to move toward the frontline. The R-BAC data outside of a clinical trial is very impressive in patients, even in the relapsed setting. It definitely also [looks impressive] in the frontline because if we adjust the dose of cytarabine, this is something that is feasible, also, in elderly patients. This is also important, as we discuss for other types of lymphoma, to really make sure we do a full pathology, that we have ECOG status, at least, and [check for] p53.
TARGETED ONCOLOGY:What is important for oncologists to understand about the field right now?