This video features Marcus Messmer, MD presenting on B-Cell Lymphomas. This presentation was given at our April 11th New Directions in the Diagnosis and Treatment of Hematologic Cancers Symposium in 2023.
Hi, I'm Marcus Messmer with the lymphoma group at Fox Chase. And I'm excited to talk to you today about key updates in B cell lymphoma. I have no conflicts of interest. Uh but I will be discussing off label use of medications. I'm gonna spend a good part of the talk today discussing the recent ash plenary session presentation of the triangle study starting with an introduction and review of management of young fit patients with mantle cell lymphoma. Next, I'll compare data on emerging bispecificity antibodies for D L BC L followed by a discussion of the remodel B study of adding BTA to frontline therapy for D L BC L. And finally, I'm gonna review three indolent lymphoma trials from ash that were of particular interest. So mantle cell lymphoma is a rare incurable form of non hodgkin lymphoma. It's defined by the 11 14 translocation resulting in constitutive expression of cycline D one. While all lymphomas have some variability in presentation, this is most extreme in the case of mantle cell. There are patients with G I only or leukemic mantle cell that can be observed for many years without treatment. On the other side. Some patients present with rapidly progressive lymphadenopathy requiring hospitalization and urgent treatment. Most important prognostic factors are the M PE score which combines age eco L DH and white blood cell count as well as the K I 67 with 60 with 30% being the most standard cut-off. M and K I 67 were combined to make the four T tier nippy C score with patients in the high risk having an overall survival of just 1.5 years compared to more than 10 years in the lowest risk group. Other important prognostic factors include T P 53 mutation, blast or pleomorphic morphology, which is often coincidental with T P 53 mutation and C N S involvement which is most often seen in blast morphology. T P 53 mutation is particularly important. Shown here in the bottom right is overall survival from the nordic study of intensive induction chemotherapy followed by a childs transplant patients without T P. 53 mutation had a median survival of over 10 years compared to only 1.8 years for T P 53 mutated outcomes for mantle cell lymphoma have improved significantly over the past 20 years with patients who remain disease free at two years after initial treatment, having a similar survival to age matched controls. This coincides with a shift in initial treatment toward B R for older patients and HYO containing regimens for young fit patients. Lastly, as a preview for the triangle study wanted to review a commonly accepted treatment paradigm for young fit patients with mantle cell lymphoma with the caveat that most of this um is not based on randomized trials in the modern era. And there's some controversy in the field about aspects of this initial treatment is generally with an intensive iota containing induction regimen. There are several options for this all with excellent outcomes and they've not been compared to each other. There's the nordic regimen of R maxi cho alternating with Rhyne, there's the European MC L regimen of R chop R alternating with R D hap. And this will serve as the control arm for the triangle study. Finally, my preferred frontline regimen is B R for three cycles followed by hyoscyamine for three cycles. This comes from a phase to study out of Dana Farber and was I like this regimen because the outcomes are excellent, which should not be surprising. Um because we know that uh from the bright and still trials that B R is superior to our chop in this disease starting with B R is also beneficial for patients who are borderline candidates for an intensive approach. Since it's generally better tolerated than the HYO following intensive induction, I recommend autologous stem cell transplantation. And this was studied in a randomized phase three trial and showed improvement in P F S over interferon maintenance. In a recently published post hoc intention to treat analysis. There was also an overall survival benefit. However, this study started in the pre rum era and in patients who did receive RXA with induction, there was no benefit in P F S or OS. Several retrospective studies in the riTUXimab era have shown a P F S but not an overall survival benefit. Finally, we're talking about maintenance should be used in all patients who are eligible after Athole transplant based on a randomized phase three trial showing an overall survival benefit. Now, moving on to the triangle study, this was a randomized phase three trial for patients with previously untreated mantle cell who were under age 66 eligible for transplant. The primary outcome was failure free survival. There were three arms. The control arm designated arm A was the European MC L regimen of alternating R chop and R D hop followed by a taus transplant. The A plus I arm added a Bruni to induction with our chop but not with the R D hap portion as well as two years of indu of maintenance toxin maintenance. ARNI after transplant arm, I included a brut nib during induction and maintenance, but without otologist transplantt during the course of the trial results were published showing a survival benefit for riTUXimab maintenance. So the study was amended to add this as an option in all arms. And just over 50% of patients did receive RXA maintenance. Baseline characteristics were balanced between the arms. But I wanted to highlight that this was a generally low risk population median age was 57. Almost all were eco zero or one and the majority were nippy low. So now onto the results on the left, you can see the failure free survival. Kale Myer Curves for the three arms. The blue line is the control arm green is transplant with a Bruni and the gray line is a Bruni without transplant. The statistical analysis was done in a sequential design. The first test was whether A plus I was superior to A and it was three year failure, free survival was 88% with transplant plus a Bruni compared to 72% with transplant alone for a hazard ratio of 0.52. The next test was whether transplant was superior to a Bruni alone and this failed with a three year failure for survival of 86% for a Bruni versus only 72% for transplant alone. They did not assess the reverse of superior superiority of a Bruni over transplant. Finally, they asked whether A plus I is superior to a Bruni alone, but it was too early to assess this endpoint three year overall survival was 86% with transplant alone versus 91% with transplant plus Aib and 92% for Aib alone. It was too early to assess whether this difference is significant. The failure free survival benefit of A plus I over A was similar across subgroups. However, there's one subgroup analysis, I wanted to highlight if you look at the curves on the right side of your screen, the upper shows patients with low P 53 expression and the lower shows patients with high 50 P 53 expression. We know from other studies, the P 53 over expression while not perfect is highly correlated with P P 53 mutations. Here, we can see that the benefit of a Bruni is much greater in the P 53 over expressed patients. However, as I previously showed, we already know that these patients with P T P 53 mutation do very poorly with intensive chemotherapy and autologous transplant. So it should not be surprising that they get the most benefit out of ARNI. If you look at the patients without P 53 overexpression in the top, right, the benefit of a Bruni is much less in terms of toxicity was slightly higher during induction in a Bruni arms. But where we really see the biggest difference is in the maintenance phase where hematologic and infectious adverse events were much higher with the Bruno. This was seen even more. So in the patients who received a Bruni after a transplant, in summary data has not yet been published. And there's still a lot of open questions before I would consider this as a standard of care. Here are my takeaway points. Although too early for comparison, a Bruni and transplant appears similar to a Bruni alone with much higher toxicity. In the former, I would not consider adding a Bruni to transplant for this reason. So what we're really interested in here is whether a Bruni alone is superior to transplant alone. But they didn't assess that in this analysis. Next. How much of the benefit of a Bruni is driven by the T P 53 mutated population subgroup analysis was not reported for transplant alone versus a Bruni alone just for the transplant plus a Bruni versus transplant alone. So I would not consider autologous transplant for patients with T P 53 mutation. Anyway. So my main question here is whether a Bruni is superior to transplant just in the P 53 low population. Next is failure free survival, which is the primary end point here, a meaningful outcome. If we can use a Bruni or other BT K inhibitors at relapse, overall survival is going to be important particularly for the P 53 low population. Next, the landscape of options at relapse is much different than during this trial. There's better BT K inhibitors, there's cart therapy. Um and we have by specific specific antibodies on the horizon. And finally, can we apply these results to other intensive induction regimens such as the Nordic regimen? And can we apply these to other BT A inhibitors? Since there's no safety data for these combinations, I would be very hesitant to do that. Next, I'm gonna talk about bis specific specific antibodies for G L BC L I'm gonna focus today on three agents that are closest to FDA approval in G L BC L RIB, GLIB and ADB are all CD three CD 20 by specific specific antibodies. But there are some key differences that I wanted to highlight first to highlight the differences in structure and administration unlikely tuma map for A L L. These by specific specific antibodies have a full length I G G structure which gives them a longer half life and allows for intermittent rather than continuous dosing. These are all t-cell engaging by specifics and all contain anti CD three for T cell binding and anti CD 20 to bind to lymphoma cells. Omma is unique in having two CD 20 fragments for increased affinity with the lymphoma cell. This 2 to 1 configuration increases the risk of C R S. So the makers have addressed this by giving obtusa as pretreatment seven days prior to the gloom mab, this depletes peripheral B cells and partially occupies CD 21 lymphoma cells reducing the risk of C R S. All of these also have a dose ramp up to reduce the risk of C R S. Adrea also requires split doses 24 hours apart for the first three weeks. AAB and ODGEN next are given weekly for 12 weeks and then every two weeks, while GYA is given weekly just for the first cycle and then every three weeks. So and another advantage for glyph mab in terms of dosing is that the therapy completes after 12 cycles. Whereas the other two continue indefinitely. Aura does have the advantage of subcutaneous dosing, which could be important if the infusion chair time is limited. A current a mapping map required admiration for sorry, require admission for the first full dose. While Adex mab required admission for all cycle one doses and cycle two day one overall, the efficacy of these agents appears to be similar. Although as you can see, not all the data is fully reported, the overall response rate appears to be higher with AAB at 63% compared to 52 to 53% with the others. Over the patients who truly have a durable response to this therapy are those with AC R and that's very similar between the agents at around 38%. The median duration of C R has not been reached for any of them. There's also efficacy post cart with C R rates just slightly lower than the overall population. In terms of toxicity, C R S does appear to be higher with GBA at 63%. Although in dexamethasone was used as premedication. This is similar to the others at 48%. Most of the C R S is grade one and two. Although grade three and four was seen adnexa with the final split dosing strategy at only a 35% rate of C R S with only 1% grade three G S is typically seen with the uh first dose or the first full dose and typically occurs within the 1st 24 hours. Neurologic toxicity such as I cans similar to what is seen with cart is rare but it does occur. So it's important to be aware of. This neutropenia is also relatively common with the bispecificity. Antibodies, fatal adverse events were similar across agents at about 5%. Many of these were due to COVID or other infection. So, in summary, by specific CD three CD 20 antibodies of encouraging efficacy in these heavily pre treated patients with D L BC L. The efficacy of these agents appears to be similar with around 38% C R which is durable for over a year in most patients but longer follow-up may uh reveal differences between these agents. Aab offers subcutaneous dosing while gyma has the advantage of fixed duration therapy, C R S. Neutropenia and infections are the most common adverse events and are similar across agents. Split dosing of odgen. Next has the rate of C R S but at the cost of frequent infusions for the first cycle. Next, for the remodel B study, this was an open label phase three trial of R chop plus or minus Borzi for cycles two through six. The original trial design stratified patients by cell of origin according to gene expression profiling. And previous analysis of this trial showed no benefit to the addition of Borzi with the updated analysis presented here at ash. They retrospectively repeated the gene expression profiling stratification with the addition of a new category that they're calling molecular high grade. The identification of this subtype comes from other data. So the classification system was not trained on the current data set. The molecular high grade subset shares gene expression signatures with or lymphoma including Mick overexpression and is enriched for Mick rearrangement and double hit lymphomas. Clinically. These lymphomas are also more aggressive with worse prognosis. You can see on the right, the inner circle is the original gene expression profiling and the outer is a new classification. As you can see, most of the MH G group comes from G C B out of a total of 1129 patients in the trial, 801 had gene expression profiling that could be classified in this retrospective analysis at a median follow-up of 64 months. There was no difference in P F S with the addition of Fortaz Aib in the overall population. However, with the new gene expression profiling analysis, the ABC subtype now shows a P F S and an OS improvement with Borzi. Additionally, the molecular high grade subtype shows improvement in P F S with Borzi. So, well, I think these results are very interesting and so should certainly lead to additional studies um for these patients who have traditionally had poor outcomes. I would not consider the study practice changing. It's a retrospective analysis based on a new classification scheme. So in my view should be, should be viewed as a hypothesis generating rather than definitive. Finally, um a a few um indolent lymphoma updates um from ash 2022. So you're probably all familiar with augment, which is a randomized phase three trial of Lino Liam with RTO versus RTU alone and reals refractory follicular and marginal zone lymphoma. This was previously reported showing a P F S advantage to R squared leading to FDA approval. An updated five-year analysis was presented at ASH. Now showing a statistically significant overall survival benefit for R squared with a hazard ratio of 0.59. Importantly, these patients were not previously refractory to riTUXimab. So for patients who have relapsed, especially with chemotherapy, I would only consider riTUXimab alone for patients who would not tolerate R squared. Another important study that was presented at ash 2022 is the randomized phase three study of watch and weight versus riTUXimab with or without maintenance for asymptomatic follicular lymphoma. This had previously been reported to show that riTUXimab improved time to next treatment but not survival. They now report updated analysis with a median follow-up of 12.3 years at 10 years. 28.8% of patients in the watch and weight group had not started a new treatment compared to 49.4% with Raab induction and 64.5% with riTUXimab induction and maintenance. They also looked at time to second new treatment, which was similar between the three arms. There was also no difference in overall survival at 10 years. So my takeaway from this is that while riTUXimab may be an option for some patients based on preference, the majority of patients with asymptomatic follicular lymphoma can be observed with no detriment to overall survival or time to second new treatment. And over 28% of patients in the watch and weight arm still had not needed any treatment at 10 years. Finally, I wanted to talk about a study of Perroni and relapse and refractory. Waldenstrom's macroglobulin anemia for those who aren't familiar Perroni is a novel non covalent BT K inhibitor with high selectivity that has previously been shown to have efficacy in patients with C L L and mantle cell lymphoma who have progressed on covalent BT K inhibitors such as a Bruni, a Cali or Zana Bruni. The study looked at the efficacy of Peri in a heavily preached population of patients with Waldens from his macroglobulin anemia with the majority of patients in the study receiving both prior chemotherapy and prior B G K inhibitors. 66% of the patients treated with prior BT K inhibitors in this study had stopped the BT K due to progression rather than due to toxicity. The results of this study were at 68% of major response including 24% with very good PR S and this was similar in patients with prior BT K inhibitors while still early, these responses appear to be durable with a six month duration of response of 86%. So this is an exciting new option on the horizon for patients with Waldenstrom's macro globule anemia who have progressed on a prior BT K inhibitor. So this concludes my talk today. As you can see, there have been a lot of exciting updates in B cell lymphoma recently. And I'm happy to take any questions.