Christopher Melani, MD

Christopher J. Melani, MD, assistant research physician in the Lymphoid Malignancies Branch at the Center for Cancer Research, National Cancer Institute, discusses the combination regimen from the ViPOR study (NCT03223610) evaluating patients with aggressive lymphomas.

The ViPOR regimen consists of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid).

According to Melani, previously data from the ViPOR study have proven to be safe and effective in patients with relapsed/refractory aggressive B-cell lymphomas. Data for all patients with relapsed/refractory follicular lymphoma treated in the dose-escalation and expansion cohorts of the trial will be presented at the 2022 American Society of Hematology Annual Meeting.

ViPOR is a novel combination targeted therapy regimen. It was originally developed in aggressive lymphomas, mainly focusing on the ABC subtype of diffuse large B-cell lymphoma. It was originally a phase 1 study and we've now expanded into a number of different lymphoma subsets, both aggressive diffuse large B-cell lymphoma, as well as follicular lymphoma, and mantle cell lymphoma.

At the National Cancer Institute. We used our preclinical models to show synergy between a number of agents and BTK inhibitors, mainly ibrutinib. Three of the most synergistic agents in killing are leading to cytotoxicity. In diffuse large B-cell lymphoma included the BTK inhibitor ibrutinib, with venetoclax, an inhibitor of BCL2, as well as the immunomodulatory agent lenalidomide, which has multiple effects on DLBCL cell lines, reducing NF-kappa B activation and promoting cell mediated death. Based on those preclinical synergy studies, we combine them with the glucocorticoid prednisone as another mechanism of cytotoxic stress or genotoxic stress to the lymphoma, as well as the novel type 2 CD20 antibody obinutuzumab to develop the ViPOR regimen.

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Christopher J. Melani, MD, discusses the combination regimen from the ViPOR study evaluating patients with aggressive lymphomas. 


About the ViPOR Regimen in Aggressive Lymphomas

Christopher J. Melani, MD, assistant research physician in the Lymphoid Malignancies Branch at the Center for Cancer Research, National Cancer Institute, discusses the combination investigated in the ViPOR study (NCT03223610) of patients with relapsed/refractory or untreated mantle cell lymphoma (MCL).

According to Melani, previous trials have examined Bruton's tyrosine kinase (BTK) inhibitors, single-agent ibrutinib, the EPOCH-R regimen, consisting of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab, and more, across multiple lymphoma types.

Data from these previous studies led to this phase 1b/2 clinical trial which aimed to assess the ViPOR regimen, consisting of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid). Investigators looked to evaluate the safety and efficacy of this combination in several disease types, including MCL.

 A lot of the data that led to the development of this regimen was done in the activated B-cell subtype of diffuse large B-cell lymphoma, so we did a lot of the original studies using single-agent ibrutinib. We showed that ibrutinib is effective in relapsed/refractory large cell lymphoma, and it was more active with a response of about 37% to 38% in patients with the activated B-cell subtype vs the germinal center subtype where there was only about a 5% response rate.

We did present data using a newer BTK inhibitor called acalabrutinib [Calquence] in untreated large B-cell disease and we are finding that other types of diffuse large B-cell lymphomas, such as the germinal center, do have activity and double-hit and diffuse large B-cell lymphoma. There is an activity of BTK. But historically, we thought it to be more active in the ABC [activated B-cell] subtype. Building on that study, we did a lot of preclinical testing and we worked with a collaborator to do high synergy screening of BTK inhibitors with multiple molecules of all different types. Some of the key agents that were shown to be the most synergistic with ibrutinib or BTK inhibitors were BCL2 inhibitors, so venetoclax as well as immune-modulatory agents such as lenalidomide. Those 3 key components were very synergistic together, meaning that the effect was not just additive, it was a greater effect than would be expected with just an additive benefit of both.

 We initially combined ibrutinib, and lenalidomide with chemotherapy, in EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] in the relapsed/refractory setting of diffuse large B-cell lymphoma. Building upon that, because many of these relapsed/refractory lymphoma patients are resistant or refractory to chemotherapy, we ended up taking out the chemotherapy keeping the steroid and the CD20 antibody, and then added in venetoclax, which again was very synergistic. We originally did that in diffuse large B-cell lymphoma, follicular lymphoma, and other non-Hodgkin lymphomas, because there is a risk of tumor lysis that is higher with either chronic lymphocytic lymphoma [CLL] or mantle cell lymphoma.

Christopher J. Melani, MD, discusses the combination investigated in the ViPOR study of patients with relapsed/refractory or untreated mantle cell lymphoma.


Discussing the ViPOR Regimen in Mantle Cell Lymphoma

Christopher J. Melani, MD, assistant research physician in the Lymphoid Malignancies Branch at the Center for Cancer Research, National Cancer Institute, discusses 

the results of a trial investigating a combination regimen

 in a cohort of patients with mantle cell lymphoma (MCL).

In a phase 1b/2 clinical trial (NCT03223610), the combination of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid), or ViPOR, was assessed for safety and efficacy outcomes in several disease types, including MCL. Melani says that this regimen showed very low toxicity compared with cytotoxic chemotherapy in the cohort of 13 patients with MCL as well as other cohorts.

In addition, it showed high efficacy as all 11 patients who completed therapy had a radiographic and biopsy-assessed complete remission. All of these patients were minimal residual disease (MRD) negative after treatment.

Melani notes that this is a fixed-duration therapy with no maintenance regimen, unlike some other effective therapies in this setting, so it is not yet clear if these remissions will be durable and potentially curative. Further reporting from this trial will provide longer follow-up on these patients, the phase 2 portion of the trial will explore these results further in patients with B-cell lymphoma, including a cohort of patients with MCL.

 The first thing that was very remarkable was the lack of a significant toxicity and how well tolerated it was. And as expected, it was very effective. So far, in the patients who have been treated, there's 13 patients on study, 11 of them completed therapy, and in the patients who have finished therapy, all 11 achieved a complete remission by a negative PET scan and negative end-of-treatment bone marrow biopsy. Out of those patients, we also did do MRD analyses using circulating tumor DNA. We collaborated with Adaptive Biotechnologies using their ClonoSEQ VDJ sequencing platform, and actually found that 100% of patients were MRD negative at the end of therapy, indicating that this is a rather deep remission.

The question at this point in time is now going to be how durable are those remissions because, with our study, compared [with] a number of the other doublet and triplet studies, we give this as a fixed-duration time-limited therapy similar to chemotherapy. [Dosing is] 6 cycles every 3 weeks, so 18 weeks or a little over 4 months with no maintenance. Other regimens often give maintenance of a year or 2 or even 3 or an indefinite therapy. It's going to be very important now with the follow-up to determine if these remissions are very durable or not, and whether we're potentially curing anyone or not. But again, it's too soon to know at this time; the follow-up for this cohort of the study is still too short.

Christopher J. Melani, MD, discusses the results of a trial investigating a combination regimen in a cohort of patients with mantle cell lymphoma.

ViPOR Regimen Shows High Complete Response Rate in MCL Cohort

Christopher Melani, MD, assistant research physician, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, discusses the unmet needs remaining in the mantle cell lymphoma (MCL) space.

Findings from phase 1 portion of the ViPOR study (NCT03223610) were presented during the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition. ViPOR is a novel combination targeted therapy regimen consisting of venetoclax (Venclexta), ibrutinib (Imbruvica), prednisone, and lenalidomide (Revlimid).

 findings of the phase 1b/2 ViPOR study appeared safe

 for use in patients with MCL and has demonstrated preliminary activity, most therapies have not been able to cure patients with MCL, leaving the field with a major unmet need.

MCL is still in general not curable with most therapies. We know that with high-dose chemotherapy we can get 3 or 4 years of remission. When you incorporate induction chemotherapy with autologous stem cell transplant, we're still able to get maybe out to 5 years or 6 years of remission. But again, there's still a continuous rate of relapse even after these intensive therapies.

We know that patients who relapse and then go on BTK inhibitor and progress, the median progression-free survival is about 2.5 years, but I think 1 of the current unmet needs is these BTK patients who progress on BTK because again, retrospective studies have shown the median survival is very poor in patients who progress after BTK so what the most appropriate therapy is for those patients. In the ViPOR study, 44% of our patients were BTK had relapsed or refractory to BTK inhibitors. The fact that we're seeing CR rates, even in these patients who were exposed to prior BTK is pretty exciting.

I think the BTK failures are certainly some areas in which we have to work on novel therapies. P53-mutated or deleted, patients often have very poor prognosis with standard chemotherapy, and then the blastoid mantle cell patients as well tend to have very aggressive disease and patients don't often respond well to chemotherapy. Whether some of this resistance of blastoid and p53-mutated mantle cells can be overcome from some of these newer novel combination therapy regimens, is still to be determined. We are assessing, we are sequencing our tumors and looking for those mutations to see if I may have overcome some of these negative prognostic markers.

Christopher Melani, MD, discusses the unmet needs remaining in the mantle cell lymphoma space.

Christopher Melani, MD | Authors

Articles

About the ViPOR Regimen in Aggressive Lymphomas

Discussing the ViPOR Regimen in Mantle Cell Lymphoma

ViPOR Regimen Shows High Complete Response Rate in MCL Cohort

Revolutionizing Treatment for Patients With Relapsed/Refractory or Untreated MCL