Luhua (Michael) Wang, MD, reviews Mantle Cell Lymphoma therapy options, and recalls patient responses and outcomes to treatment.
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it is now my pleasure to introduce Dr Michael Wong, professor in the department of lymphoma and myeloma at MD. Anderson Cancer Center. He has a very large clinical and research expertise, and practice is focusing on Mantle Cell lymphoma. MD. Anderson. Today he will be talking to us about treatment approaches to Mantle Cell lymphoma. Dr. Wang is well known for his work in this field, and we appreciate him taking the time out of his busy schedule to deliver this lecture to us today. If you do have a question during his presentation, please use the ask a question function in the chat box, and we will address them afterwards during the panel discussion. Friends and colleagues My name is Michael Wong. I'm the Putin Clark and our professor in the Department of Lymphoma myeloma. M. D. Anderson Cancer. Same term. Today it is my honor to share with you the novel therapies for Mantle Cell lymphoma. Post Dash 2020. Here are my disclosures, as we all know that the lymphoma therapy has evolved from chemotherapy to targeted therapies or chemo free therapies, then to email therapies and then such as the checkpoint inhibitors for Hodgkin's lymphoma, then to the novel New Era of Curtis on therapy. Where we are in in the future, I think will welcome the preceding medicine era where we have proceeding with the molecular medicine. So, um, in the Ash 2020 my group to present the hybrid with the tax man and a short course of a high perceive that it's very if it teaches, improves the untreated. The young patient with the mantle cell lymphoma. This is the clinical trial designed to progressively decrease the amount of chemotherapy we used for newly diagnosed patients. As you can see, this is a window design. In the past, we go straightforward to eight cycles or high perceive that very intensive chemotherapy in this clinical trial. Instead of going straight YouTube Kim intensive chemotherapy, we have a window of chemo free therapy with a retired member I put up to 12 months before we introduce chemotherapy as consolidation. This is why we call it is a window of opportunity trial. As you can see, we have 131 patients and rode on the study with a 61 in the lower lower risk group and 70 in the high risk group for all patients. That response rated with Kim of free therapy alone before Kim. Consolidation was 100% I repeat, in 131 patients. The overall response rate for with chemo free therapy alone was 100%. CR was 88%. After the chemotherapy consolidation, they see the O. R. R remains that 100% the CR went up to 98%. They are M R D, and activity was in 74%. The median survival and meeting duration of, uh, fill your freezer bible have not been reached. After a long term fallout, there was no difference in responsible between high or lower key. I see seven or maybes as you can see the failure free survival is very extensive. Long and also the also the curve, separated by K I. C seven also looks very long, and both both arms has not been reached for failure for survival. So the follow up in this trial within 40 months and as you can see with the chemo free therapy, the security through foresight toxicities was few, including anemia from Saudi opinion, neutropenia, fatigue, nausea, diarrhea and you post the chemotherapy with three or four toxicities still was in moderate amount. And that's why we should for work further gradually, to reduce the chemotherapy with a more powerful targeted therapy combinations in concluding This is a very effective therapy, and we look forward to publish this manuscript very soon. And, uh, that was in the young patients with newly diagnosed How about with the elderly patient newly diagnosed with Madison Informa? So we designed this study called our our study Our means retouch map. I means I burned them. And as you can see, the overall response rate in the elderly population was 90%. The C R was 62% So the best MRG was 87% negative, and a meeting follow up was 43 months almost almost approaching. Uh, three years, 3.5 years and the meeting failure for several and overall survival us, after it's such a long follow up, has not been reached. So look at the failure free survival, and they are still very impressive. And so look at the side effects. Uh, we need to pay attention. The intra population was in 22% 11 out of 50 patients. We this This study was designed a long time ago. We did not put a script trick to cardiac risk of criterias on this trial. And that's that's why we think that that's this high rate of all its operational occurred in the future. We will scrutinise our patient against with the stricter rules on cardiology risks in concluding I Britain pretax map is very effective in elderly population. And, uh, it's reformulation need to be paying attention to so as this clearly this ash 2000 and 20. We also, uh, presented a hybrid nib and renewal class Dr Content from Australia, the first author with me as a senior author. This is a two hour therapy combination in this trial called Sim particle. Simpatico means good looking in China in Spanish. So in this clinical trials impractical, there are three poor portion. First portion is those escalating portion. The second portion is more than 200 patients. Right on my session, the port randomized trial and the third portion is the front line therapies portion. So this position is only for the those climbing first portion of the simpatico trial. As you can see, doses was escalated gradually to higher doses up to hybrid and 55 60. And the middle past 400 side effect was reported largely, uh, green three or one. And as you pursue your orange, there are some great through four toxicities and, uh, so overall response rate was for all patients was 83% with CR 67%. And for the patient with a high risk, high risk response rate was also very little. About 80% CR, 60% not significant. Low risk 81% 16% similar to high risk. So the the investigator assessed the failure for survival has not been reached for a meeting after a long time or follow up 18 months. The next study at Presented an Ash by myself was locks all through five in next generation, highly selective, non convenient BDK inhibitor in previously treated the mantle cell lymphoma, waters, drums and other Hodgkin's lymphoma in the first one to Peru in study. This is a study that, uh, have a lot of patients with the 61 mentally ill informed patient, 26 warning swarms and other lymphoma patients. Please note for the mental sound and former waters from the prior therapies were three prior therapies, but for the other and farmers with the prior for lines of therapy. As you can see, no D o T s was with locks or through five. Therefore, the feast to dose was recommended at 200 qd orally. Only five out of 323 patients at the rate of 9.5. Stop the therapy due to a yes. As you can see, they agreed to three. There's no 3 to 4 toxicities among 323 patients, but only a few grade three toxicities occurred in the in this single in this, uh, lots of single agent alone trial. This is a very impressive toxicity to with such a big number of patients over 320 patients, as you can see at 1/4 line, lots of single agent orally induced response rate. 52%. If we could include that. The majority of patients who received that 93% who received the prior between inhibitors the response rate was still 52%. This is very impressive. Also, 9 14% received a stem cell transplant and the 64% of those people respond to locks on to patients received the car T cells relaxed and two out of two responding to locked on single agent postcard the relapse. As you can see, the water plot, suggests that this agent is very effective. So next slide, as you can see, although the meeting follow up is only six months. But there are some people The patients have long respond bonding remissions approaching a year and a half for 18 months. So how about involving storms after three prior therapies and the overall response rate was 68%. So if we include those people who get prior BDK inhibitors, the response rate was even higher. At 69%. As you can see in the waters from the data is really good. This is fourth line therapy data. Please keep that in mind. How about the other Informa's? Remember those lymphomas are fifth line. All pieces received the meeting prior four lines. As you can see, Richter's confirmation 75%. Only in eight patients, 50% in for lymphoma, only eight patient nine patient, A 22% in marginals informa. But among the 25 patients of diffuse large B cell lymphoma at the baseline with four prior therapies, the overall response rate was 24%. CR was in 4%. So, as you can see, although the follow up of time is short but some of the patient has responded for a long time with a single agent, Locke saw at the finish line in concluding, Laakso is very powerful and safety profile is very favorable and it should be further studied for FDA approval. So the next exciting study presented, You know, the for the man who, solemn farmer by myself is a real s y know why our r and targeting anybody Drug congregate, which demonstrated a prop, indictable safety profile and clinical efficacy in patients with heavily pre treated mental son and former and diffuse already be selling and former receptor terrorism kind is often receptor are one provides attractive therapeutical target. Why? Because this addiction is only present in the human embryonic development in human cells. After birth, this antibody disappeared a few from adult from after after bursting the cells, therefore, and and it only shows up when it's malignant. So as you can see, the different the person levels of R O R in different lymphomas. CML aml diffuser of the selling former medicine and from a c o. L has also a very high expression level. So So we will s 11 is a novel a D C. That targets are are one with monoclonal antibody. Deliver any Let's look at the molecule. On the left side is the monoclonal antibody against the our our wine. There's a long linker which is inside medically clear verbal And then there's a toxin Monami Theo always study when the whole molecule binds to the r R. One R R one has the future of rapidly internalization. After internalization, it went to the license arms where the enzyme would click open the linker, release the toxin. Toxins will in turn kill the cells. So this the mechanism of their action. So this clinical trial, like look so three or one is the first thing in homing three or five. The first human this trial. It's also a Phase one trial first in human trial. As you can see with those climbing cohort on the three plus three scale, and if you can see the 32 patients that was a road at the meeting. Prior therapies was four prior therapies. Please remember the long So I'm sorry. The real s 11 was giving at the 4th. 5th 9. As you can see, that toxicities are mainly MME related adverse events, including new opinion and, uh, which respond to G CSF Iraqi, which was managed with a dozen talking and modification diarrhea managed with the evaluation of causes, anti diarrhea and the modern kitchen with doses alopecia which rarely happened. However, there was no infusion reactions to witness irritation. There was no pre medication with nausea magazine, but there's no nausea, vomiting, no human lives syndrome, no evidence or ocular skin. Cardiopulmonary renal hepatic metabolic toxicities. No drug exposure related to QT prolongation. No clinical significance of immune deficiency immunogenicity so ideal drug which avoid interacting with the normal tissues. As you can see, the overall response really, At the fifth line, therapy for Madison Informa was 47% five CRS and so five prs to see ours, as you can see in the in the well diffused piece 1000 pharma, although only in five pieces. But a five out of five responded with a response rate of 80% here is a 63 year old man with a heavy probably treated with the four prices 10 therapies for double hit large cell lymphoma, and the fourth line was car T cell therapy. But he unfortunately progressed after car T cell therapy into this picture where the Larsen and following infiltrated into the bone and the skin and the flesh of the right leg, which was amputated out of desperation and but after amputation, there are still a lot of informal, as you can see in the right leg, in the left growing, and but that cleared up of the three cycles will as therapy as you can see, he achieved the metabolic completely reports of the three cycles of us one way after six cycles, stating the CR and this question stating CR for a long time until now. In conclusion, Real s 11 is if Ignatius and tolerable with a terrible side effect profile, these two studies should be should be performed, is and is on the way for F D. Potentially approvals in medicine and pharma enlarged an informant. And at this Ash 2020 we also presented a one year follow up. Zuma to the multi center revision study. Katie X. 19 one year follow up means one You're more follow up after the position in 2019. At that time, the meeting follow up with 12.3 months. This this could one year follow up could bring a lot of confusion. But basically the follow up meaningful up was 17.5 months, using with such a relatively long follow up, the overall response was 93. In the beginning, now it's 92 barely changed the CRE the state at the 67% cr the 1st 2080% of treated with the meeting for up to 32 or three months in this patient approaching two almost three years full, up 39% of state in long term remission. And so this is very important to notice. Okay, so, uh, duration response after sending 0.5 months has not been reached, similarly has not been read to fulfill your free survival and overall survival with the extensive follow up of additional almost six months, more than seven months of follow up, uh, you know, spending 17.5 months. The there's no added toxicities, no additional deaths. So along the longer follow up, B cells recover slowly but surely, and genetic markers of Carty cell measurement can still detect. The 56% of the patients at the 24 months still have significant amount of car T cells. In concluding at the meeting for up to 17.5 months, similar to study maintained a very high profile efficacy. And, uh, it resulted into a manageable safety profile, even with the extended follow up, the pharmacology findings of similar to point to a different mechanism responsible primary and secondary treatment failure, relapse. Mendelsohn informal at this ash. Another exciting trial against City 19 card itself from the Juno BMS trial was presented by my colleague Dr Leopold MBA from Memorial Sloan Kettering with me at the senior author. This clinical trial explodes CD 19 different with Zuma to Yuma tools that caused the lesion molecule was 4 2028 instead of here in the 41 B. B and also the city. Eight and City Force also are separated, uh, and and it was refused at one per minute ratio, which is considered to be the optimal ratio. The overall response rate is 84% CR eight or 63% the CRE rate, although we cannot compare with the trials. But remember the Zuma to trial was actually uh, 67%. The meeting follow up was only short with the four or 5.15 months and 5.9 months. Please remember, the severe toxicity of CRS is very low at 9% the severe neuro toxicity even lower at 3% all the the toxicity was very manageable, although the meeting follow up is still short. But there's long responders, as you can see, indicated in the blue. Patients have long responders up to 12 24 months in c R. As shown in blue. In summary, this is again a very executions therapy and reduce the toxicity and enrollment is still ongoing. In summary, those are the main, uh, main advances in the for the man whose own from a because these discussions only for 30 minutes I did not have the times include other third other good studies, including M R D studies. But we did, including 15 abstract obese Richard from my lab spending from a single car T cell, Mr uh, single cell Army analysis of cereal clinical samples on the car T cells and including overcoming car T cell resistance, new drugs and etcetera and that I could share united session. So thank you for listening to my talk and thank you to witness the rapid progression and of Madison lymphoma therapy. Bye bye.
