All About Hypomethylating Agents

What are hypomethylating agents? These are uh not a new class of drugs. Essentially these are what we call they belong to Nicholas analoges family. Uh at the beginning when they start the drug development uh we usually we try to go to the maximum tolerated dose. So in cancer treatment we try to go up up up the dose till we get to a point where the drug is toxic. We cannot proceed any further. By doing so, we discovered these drugs are being toxic. But then what why do we need them for? Because already we have toxic drugs such as sitarabine that can really kill the chemic cells. But then investigators went back and they discovered the drugs can be effective at a lower dose and that is what they called hypommitating effect. So what does stand for and how it does work and here I will go into how these drugs work compared to other chemotherapy. There's something called epigenetics. Essentially when we are born our genome the genes we have are same whether we are in an eye cell or a kidney cell or a skin cell liver cell but yet they function differently. What that means means certain genes that we need their function in the liver that we do not need them in a brain they silence in the brain and vice versa. There's a process called silencing that happens early on at the conception from the first day of life and then uh there's silencing happening which is a normal process but then our body has certain gene they're supposed to suppress cancer from happening. They watch over abnormalities of the cells. Imagine these abnormal genes are being silenced. If they're silenced they cannot do the role and therefore what they silence because among others they have a metal group that get attached to this part of the gene. When we went back to this quote unquote hypoming agents we discovered that the lower dose they can remove the metal group and let the gene express itself and as such it can suppress the development of cancer and that is what hypometric agent. Therefore they are not strong chemotherapy but they have a specific effect to express certain genes supposed to be expressed but for a reason or another were silenced and cancer took place. That is in a simple mechanistic way how the drug work. How do hypomethylating agents work to treat AML? When cells are being renewed on a daily basis in cancer the hallmark of cancer cells do not die in our normal body so you have your skin that in the summer get done and then die and you have a new skin formed. So they're a cycle of life. Our cells are scheduled are programmed in a way they they're born they grow and they die. So cancer is there no death of cells. There's something called this we call program despotosis as a scientific term. So there's inhibition of this process as such cells are living normally essentially there are certain genes are being silenced not functioning and therefore they have zero function against AML by removing the met group CH3 and then by expressing these genes the genes supposed to suppress cancer are being active and that is hypothetically supposed to suppress development of cancer. This is how it works. So by removing the metic group and expressing these genes, we expect these genes to suppress the cancer and the cancer cells resume their normal cycle of life and go to die and therefore killing leukemic cells. What are the hypomethylating agents currently being used to treat AML? What are the currently hyper agents being used and how they are different? There's two drugs available there. The first one was five isocytoadine and the second one is a descabine. The five isadine is giving subq and intravenously over 7 days of uh treatment and the cyitabine is given IV uh daily for 5 days. The cetabine was explored as subq formulation as well and oral formulation. Sub formulation did not succeed both means will transform into the cytoine inside the cells the substrate to be to kill the cells and both were tried in the mal and both were effective uh in my mind they're both equivalent you can use either one how is aocyadine administered it can be administered either subq formulation or I formulation I offer either way either one to my patient depends on the patient preference. I can tell you when you give subq formulation some people can have pain at injection site. If they have low plates they can have some small hematomas and tempish may not like it and they prefer IV formulation. The IV formulation is 1 hour infusion. If I want to go to my work I'm in a rush I want to take the subcqure formulation. So I have two group of patients those who will tell me I don't care about the pain. I want to in and out. I want to resume my normal functional life activities and other I hate the pain I'm scared of the pain give me IV formation so both are equivalent and both can be used how is decidabine administered it's administered intravenously uh over 5 days I mean we have oral formulation but there are different uh different drugs in a way I say the oral acetine is different than the IV we give different indication different function compared to the IV formulation and then decided is given IV. Uh we tried subcq but that did not succeed. So we have IV formulation given daily for 5 days. This is the standard of care. We explored uh the oral formulation where we assess the pharmacocinetics of the cytoine given orally versus IV and we found the best dose it is equivalent to IV formulation when given orally and therefore today we have either formulation. Now that being said the oral dicyabine is only approved for MDS not yet for AML in AML is given off label but everybody is using it. who are the most appropriate patient to receive high pointing agents in clinic. We investigate this agent in different setting but where we've seen activity is in a disease called miloisplacive syndrome where we see this kind of silencing happening extensively and in older patient with AML. So in my displeas syndrome there's two drugs available and approved uh thisabine and five isocytoadine both are active and effective in MDS and therefore the the drug were first approved in this setting then these drugs were investigated in acute mild leukemia they found to be effective although the authorities did not approve this drug for AML in older population till recently when we had combination where we added something to HMA therapy and we can talk more about them later today. What are the common side effects of hypomlating agents? What are the common side effects of hyper medications to be there's minimal side effect essentially when we went to very low dose of the treatment compared to full dose as part of the family of citarabine we did not see the malo suppression we do see with high dose so essentially it's very well tolerated patient may experience some fatigue around day 7 8 and 9 but very mild fatigue and of course we can have a drop of the count but drop of the count is inherent to the disease by itself more than the drug. So I think these combin these drugs are really quite safe to be given compared to intensive chemotherapy and this is why they're really commonly used in community setting without major problems. How are these side effects typically managed? How are the side effects typically managed of HMA? As I said the side effect profile is very acceptable. I usually when I have patient in my clinic I explain to them what I'm giving to them how the drugs works why I do not expect side effect to be something of a major concern uh I explain to them the fatigue may happen few days uh around day 7 to day 10 so if you want to go for a big trip try to avoid it as a like communication always works with a patient and then uh low count and the low count I advise them to get blood test done weekly uh to see if the count is dropping patient may need blood transfusion uh plated transfusion uh to be given and of course when the count is low and the patient with AML have a very weak immune system they can have fever infection I advise them to go to the hospital uh to be on antibiotic therapy and on top of that I when the count is low when I do blood tests weekly I put them on prophylactic antibiotic a prophylactic antifungal therapy and antiviral therapy so to avoid such complications are hypomating agents used alone or in combination In MDS today uh they are approved alone. There are several combination done uh they were not successful such as histone disillus inhibitor or other compounds. Although today there's new drugs being explored among them uh bcl2 inhibitors uh pd1 pdl1 inhibitors uh immune therapy added to hypomic agents in MDS. They're ongoing randomized trials. We are eagerly awaiting the results to see if we can further improve on HMA alone because HMA are effective but they are not like a breakthrough. We need really to build on them to make them better. That is in MDS. In AML we succeeded to have a combination. In fact in acute mild leukemia especially in older patient population we add a drug called venitol or a bcl2 inhibitor. Again the idea is these cancer cells we need to put them to death because of this life cycle is being abnormal or perturbated. So this BC2 inhibitor can put the cancer cells to die. Therefore, they're synergistic with the HMA. And in that sense, there was a trial where we combined descabine or aocytoine with a BC2 inhibitor venitol. And we've seen the responses in AML going from 25% approximately to 65% and the survival went from 10 months to 16 months. And that was confirmed in a randomized trial where pat were randomized to either HMA plusbo or HMA plus BCL2 inhibitors. And the arm the new arm for BCL2 inhibitor ventolex plus HMA was asite 5Dine was found to be superior higher response rate better overall survival and more education of the disease and that has become our standard of care. So we moved from hypoating agents alone to a combination and that was successful and therefore now we have a new backbone to build on it. Building on it means maybe adding other target therapy uh be it ID IDH inhibitor fit inhibitors or others. So we're walking away from HMA to HMA combination to further improve the outcome. Can hypomethylating agents cure AML? I think cure is a big word. I'll tell my patients, you know, uh today I have somebody with acute mild leukemia. I want to do my best to get them in a better shape. Uh means I want them I want to eradicate the disease. I want to eradicate what you called minimal disease that we don't see it morphologically. These are cells hidden somewhere that can drive real transition down the road. And we know when we give HMA only in AML survival is around 8 to 9 months. So we need to improve on that. Now you can tell me the majority are having a short survival. But I can tell you if you look at the tail of the curve certain patients can have a long life and whether you could cure or not that is up to you. But I can tell you there are subset of patient who can be cured down the road who can have a long-term survival. Now I don't think HMA alone will make it realistically. We need a combination and we need eventually to get patient to transplant because while these hypomating agents are being given for older patients uh physician give up oh here's an old patient why want to go for a transplant but patient are sick often at the beginning because of their disease so if you can treat them you can improve their conditions and maybe do non-intensive transplant that can consolidate the remission and lead to long-term cure. So when I see somebody in my clinic and will tell me, "Hey doctor, I'm not optimistic. The numbers are scary." I tell you, "Yeah, the numbers are scary, but do not take the numbers to judge your future. You're a unique person. We're going to do everything to secure the best sequence that can lead to the best long-term outcome. Will I succeed in a majority?" The answer is unfortunately not today. But will I succeed in a certain patient? The answer is yes. And maybe this patient A is a unique patient where I can offer a long-term cure by presenting by admissing the best combination and the best sequence of treatment that can lead eventually to the best chances of long-term cure. What research is being done to make hyperthylating agents more effective? What other research is being done with hyperating agents to make them more effective? Id like to highlight that we have a new formulation of hypering agents because patient will not get the IV injection every day. I mean it can get the pill and be at home. Why would I go to the hospital? So we succeeded to get theabine IV we have a oral formulation as effective as the IV formulation. So now we have oral dicyabine that's been given for asocytoadine. We're not there yet. There's formulation approved for maintenance where patient with chemotherapy who are not transplant candidate can get a maintenance with pills but this m this oral pills this and these pills of are not the equivalent to the IV formulation unlike the citabine where you convert one pill to an IV infusion it's given 14 days every month but right now we're exploring uh oral a cited to be equivalent to the IV formulation or subq and to replace the way we give IV or subq decided that is being done right now but we're still behind the dite now the research are being done uh at two levels number one is to have a better understanding of the biology of the disease again I will say AML is not like one disease it's spectrum of diseases and we have to dig into that to each patient identify his or her own biology because this will dictate how I treat. Uh it's not smart to give a treatment that fits all. It doesn't work this way. So the first thing is have a better understanding of the biology and identify targets that we can go after them. Then I can design a treatment alakart and that will bring me to the second chapter of the research is what are the best combination to offer the target specific population. So we make progress in in this sense. We have different approaches. uh we have I discussed HMA BCL2 inhibitors. We have fit inhibitors to be added to HMA or added to HMA and BCL2 inhibitors. Idh1 and two the group of patients where the outcome is really still poor are the group who have the compass car type and the P-53 mutation. These are really really bad patients of for these patients. For example, we're exploring new agents that can target specific P53 abnormalities. uh the drug called McGronium map and others in that sense are being explored uh for these uh patients. These are happening right now. Uh I know for example you know CML was CML transformation into AML BL AML or CML blast crisis for example for this pat we can give tyrosinis inhibitors in combination with HMA uh that we hope to further improve the outcome. These are happening right now and I think the future is bright. We're going to make progress and patient will have a better outcome.