1 00:00:07,040 --> 00:00:11,040 Greetings and welcome to EHA Unplugged, the official podcast 2 00:00:11,040 --> 00:00:14,960 channel of the European Hematology Association EHA. 3 00:00:15,640 --> 00:00:19,280 OK, good afternoon. I would like to welcome 4 00:00:19,280 --> 00:00:22,880 Professor Rusbecker from the University Clinic of Leipzig in 5 00:00:22,880 --> 00:00:25,880 Germany. Well, Platt Speaker has been 6 00:00:25,880 --> 00:00:29,800 working with MD's as long as I can remember and has been 7 00:00:29,800 --> 00:00:32,800 running a lot of clinical trials, but also translation 8 00:00:32,800 --> 00:00:35,840 research. And I think you have at least I 9 00:00:35,840 --> 00:00:38,680 remember a lot of trials also in low risk MD's. 10 00:00:38,680 --> 00:00:42,920 And I think that's the main topic of of today is low risk 11 00:00:42,920 --> 00:00:46,680 low and, and how can we use these prognostic indexes. 12 00:00:48,160 --> 00:00:51,640 So what do you think about using prognostic indexes and low risk 13 00:00:51,640 --> 00:00:54,520 MD's? Can you sort of elaborate a bit 14 00:00:54,560 --> 00:00:56,080 on that? Yeah, thank you. 15 00:00:56,280 --> 00:01:00,920 Just also I would also for this complex question, I would like 16 00:01:00,920 --> 00:01:07,560 to challenge you in in reverse about the terminology low risk. 17 00:01:08,080 --> 00:01:11,840 I mean, you know, you, you, we both know that this terminology 18 00:01:11,840 --> 00:01:16,080 is still coming from the old days when MD asked at least at 19 00:01:16,080 --> 00:01:21,720 some point was not considered to be a cancer, maybe mild anemia, 20 00:01:21,760 --> 00:01:24,920 thrombocytopenia, whatever. And it was not clear what the 21 00:01:25,240 --> 00:01:28,400 cell of origin and also the mutation, the landscape I think 22 00:01:28,400 --> 00:01:32,400 at this stage was not not known. So I think from from the old 23 00:01:32,400 --> 00:01:38,000 days, the MD's subtypes were differentiated into low risk or 24 00:01:38,000 --> 00:01:41,640 lower risk and higher is based on the natural course of the 25 00:01:41,640 --> 00:01:44,560 disease. And you mentioned the scoring 26 00:01:44,560 --> 00:01:49,560 systems which at the very beginning like IPSS were a 27 00:01:49,800 --> 00:01:53,440 reflection of patients who actually received only 28 00:01:53,440 --> 00:01:57,120 transfusions or antibiotics, sometimes growth factors. 29 00:01:57,120 --> 00:02:00,800 So the natural course of the disease was served and therefore 30 00:02:01,240 --> 00:02:04,080 patients were differentiated into lower risk and higher risk. 31 00:02:04,080 --> 00:02:10,000 Meanwhile, the recent update of The Who classification reflected 32 00:02:10,080 --> 00:02:15,040 or is now reflecting much better that MD's is not renal anemia. 33 00:02:15,040 --> 00:02:18,080 It's now called myoplastic neoplasm. 34 00:02:18,880 --> 00:02:22,480 Still the terminology MD's remains, but I think it's 35 00:02:22,480 --> 00:02:25,480 important to say that it's it's a cancer sometimes very 36 00:02:25,480 --> 00:02:28,080 aggressive with immediate survival in higher risk patients 37 00:02:28,080 --> 00:02:31,960 of less than six months based on also recent molecular work up. 38 00:02:31,960 --> 00:02:37,320 So now I will try to answer your question what what is low, what 39 00:02:37,320 --> 00:02:40,800 is low risk and how to differentiate. 40 00:02:41,280 --> 00:02:47,240 I think we have the IPSSR which I think we both now use for a 41 00:02:47,240 --> 00:02:51,560 couple of years. And also the IPSR has come also 42 00:02:51,560 --> 00:02:53,880 has been introduced into clinical trials and also 43 00:02:53,880 --> 00:02:58,440 approval of agents like lispatacept where the clinical 44 00:02:58,440 --> 00:03:00,800 trial was actually based on IPSSR. 45 00:03:01,920 --> 00:03:05,880 On the other side, the majority of the drugs we still have in in 46 00:03:05,880 --> 00:03:10,520 MD's like azazidine E PO, both are improved on the IMPSS. 47 00:03:10,600 --> 00:03:15,560 So the old classification and I will give you I think a very 48 00:03:15,560 --> 00:03:19,960 good example why the IPS is valid and is, is, is is very 49 00:03:19,960 --> 00:03:26,440 good for for prognostication. But we're also the molecular 50 00:03:26,440 --> 00:03:30,120 work up I think is important with regards to maybe also 51 00:03:30,280 --> 00:03:33,760 treatment decisions. So for instance a patient with 52 00:03:33,760 --> 00:03:40,440 ring sylloblastic phenotype with neutropenia O .7 with mild 53 00:03:40,440 --> 00:03:43,680 thrombocytopenia but being heavily transfusion dependent 54 00:03:44,800 --> 00:03:50,040 and an SFTB 1 mutation can still can or basically will be in the 55 00:03:50,040 --> 00:03:55,160 box of so-called IPSSR intermediate being eligible for 56 00:03:55,400 --> 00:03:57,880 loose patacet for instance as a second line therapy. 57 00:03:58,360 --> 00:04:01,600 On the other side, the same patient maybe also with ring 58 00:04:01,600 --> 00:04:05,160 cytoplastic phenotype just by morphology, but with other 59 00:04:05,160 --> 00:04:09,640 splices of mutations and maybe also with AP53 mutation, which 60 00:04:09,640 --> 00:04:12,880 sometimes occurs also ring cytoplastic phenotype. 61 00:04:12,880 --> 00:04:18,399 Patients outside as if we want may still be just from 62 00:04:18,399 --> 00:04:23,000 morphology, blood counts and blast counts in the same box 63 00:04:23,000 --> 00:04:27,920 intermediate, but the prognosis is much worse in patients. 64 00:04:27,920 --> 00:04:31,760 So this is a long answer to a short question, but I think you 65 00:04:31,760 --> 00:04:37,640 touched base with a very complex and puzzling thing, which I 66 00:04:37,640 --> 00:04:42,160 think now also when talking to fellows and also to to 67 00:04:42,400 --> 00:04:46,920 hematologist, I think they are sometimes puzzled which score to 68 00:04:46,920 --> 00:04:48,680 use. So I think the bottom line 69 00:04:48,680 --> 00:04:54,320 message is IPSSR is still a valid score and very low, low 70 00:04:54,720 --> 00:04:58,480 and parts of intermediate I would say are the lower risk 71 00:04:58,480 --> 00:05:02,080 where prognosis even with supportive care can be 72 00:05:02,080 --> 00:05:05,760 considered as in years and therefore it's they are lower 73 00:05:05,760 --> 00:05:09,000 risk. But IPSSM, and I guess you come 74 00:05:09,000 --> 00:05:13,000 to that in a second, has challenged this a bit. 75 00:05:13,440 --> 00:05:17,440 Absolutely, Yeah, Yeah, I think this was very foreign nice 76 00:05:17,440 --> 00:05:20,080 explanation on how this can actually really change the way 77 00:05:20,080 --> 00:05:22,520 we see some of these low risk diseases. 78 00:05:22,520 --> 00:05:26,320 So, so do you think we can use this also when we when we want 79 00:05:26,320 --> 00:05:29,840 to select which patients to transplant early, I mean to 80 00:05:29,840 --> 00:05:32,960 transplant in the lower states? Have you any? 81 00:05:34,440 --> 00:05:43,120 I think we can, but transplant is not like mild surgery. 82 00:05:43,240 --> 00:05:46,040 As you know, the intention is to replace the bone marrow and and 83 00:05:46,040 --> 00:05:50,400 to to reset the immune system. But still there is an 84 00:05:50,400 --> 00:05:54,320 unpredictable risk of mortality which is in the range of five to 85 00:05:54,320 --> 00:05:58,680 10% in the in the during the first year, irrespective whether 86 00:05:58,680 --> 00:06:02,360 you do everything right, you select the right donor, it's 87 00:06:02,360 --> 00:06:07,360 it's unpredictable and therefore you again touch base in a very 88 00:06:07,360 --> 00:06:10,040 important thing. We have very good scores. 89 00:06:10,400 --> 00:06:15,120 We can select patients being lower risk by traditional tools, 90 00:06:15,120 --> 00:06:20,320 but now being higher risk by implementing also the genetics. 91 00:06:20,640 --> 00:06:24,360 But we only have a couple of agents. 92 00:06:24,360 --> 00:06:28,360 Basically we have one agent as a Sidon and we have an approach 93 00:06:28,360 --> 00:06:30,880 called allogeneic stencil transplantation and that's it. 94 00:06:30,880 --> 00:06:36,840 So we don't have anything or only limited armamentarium of 95 00:06:37,120 --> 00:06:43,440 weapons, if I may use this word here in this, in this context to 96 00:06:43,440 --> 00:06:45,040 change the course of the disease. 97 00:06:45,040 --> 00:06:48,520 And I think that's the dilemma we have now. 98 00:06:48,680 --> 00:06:53,280 I think we should not stop to score patients, but I think we 99 00:06:53,280 --> 00:06:58,040 should rather work on agents which may patients with let's 100 00:06:58,040 --> 00:07:01,880 say lower, higher risk may benefit and which may alter the 101 00:07:01,880 --> 00:07:04,960 disease course. So also talking about these new 102 00:07:04,960 --> 00:07:08,480 classifications, you know, how, how, how good are they? 103 00:07:08,480 --> 00:07:12,400 If you go to the very early stage MD's, you know, the sea 104 00:07:12,400 --> 00:07:16,640 cost and I mean, can we use them there or because I think, you 105 00:07:16,640 --> 00:07:19,840 know, that creates a new type of this thesis that we see in our 106 00:07:19,840 --> 00:07:23,200 departments and we all discussing what to do with them. 107 00:07:23,280 --> 00:07:25,560 Should we follow them? Should we, what should we do? 108 00:07:25,560 --> 00:07:27,840 And what's your opinion on that? What you do? 109 00:07:27,840 --> 00:07:29,600 What would you do and do you do in life? 110 00:07:30,320 --> 00:07:34,080 Yeah. So the, let's say IPSSR and also 111 00:07:34,080 --> 00:07:39,920 the IPSSM are not traditionally developed for CKAS patients. 112 00:07:39,920 --> 00:07:45,080 There are numerous papers of course on CKAS where the bottom 113 00:07:45,080 --> 00:07:49,560 line message basically is the number of mutations, the type of 114 00:07:49,560 --> 00:07:53,320 mutations and the allelic burn and the level of cytopenia. 115 00:07:53,320 --> 00:07:58,400 So very, very clear. I think a prognostic variables 116 00:07:58,400 --> 00:08:03,000 predict the disease progression and I think, but still it's, 117 00:08:03,000 --> 00:08:06,880 it's there's a great variability and many of these patients are 118 00:08:06,880 --> 00:08:08,880 older. So the question is what is the, 119 00:08:09,200 --> 00:08:11,160 what is the workflow? What is the follow up? 120 00:08:11,520 --> 00:08:14,520 I think this is still under investigation. 121 00:08:14,520 --> 00:08:19,440 The way we do it at least in life sick is that we look for 122 00:08:19,440 --> 00:08:22,200 all these variables. So type of mutations for 123 00:08:22,200 --> 00:08:26,960 instance TET DMT 3A is rather neutral from a prognosis of 124 00:08:26,960 --> 00:08:32,520 mild, whereas ASAX one or additional mutations like 234 125 00:08:33,440 --> 00:08:39,120 predict a much higher risk to undergo or to develop MD's. 126 00:08:39,360 --> 00:08:42,320 So these patients let's say with a higher risk, we follow up 127 00:08:42,480 --> 00:08:47,400 every three to six months or the other ones we see maximum once a 128 00:08:47,400 --> 00:08:50,400 year. Yeah, I think I would say the 129 00:08:50,400 --> 00:08:52,400 same. You know, that's about what we 130 00:08:52,400 --> 00:08:52,840 do. That's good. 131 00:08:53,360 --> 00:08:56,720 To hear of. Course, I think what about now 132 00:08:57,000 --> 00:09:00,000 to go a little bit back to what you talked about before, because 133 00:09:00,120 --> 00:09:02,360 now that we have this new classification, what do you do 134 00:09:02,360 --> 00:09:04,360 with all the results from before? 135 00:09:04,800 --> 00:09:07,200 I mean, from the clinical trials that we have? 136 00:09:07,200 --> 00:09:11,000 Are we going to go back and try to to to sequence the material 137 00:09:11,000 --> 00:09:14,280 if we have it and and maybe re evaluate for example, the 138 00:09:14,280 --> 00:09:17,600 indications for those peticept or you know what's, or do you 139 00:09:17,600 --> 00:09:23,560 already have those data? No, I mean we, we don't or at 140 00:09:23,560 --> 00:09:27,120 least I myself don't doesn't have it. 141 00:09:27,120 --> 00:09:31,680 But what we what we know from already published data. 142 00:09:31,680 --> 00:09:35,960 For instance, Matteo de la Porter just published a paper 143 00:09:35,960 --> 00:09:41,880 where we were Co authoring and we also provided some some some 144 00:09:41,880 --> 00:09:47,080 data or some data set of patients is that the IPSSM has a 145 00:09:47,120 --> 00:09:54,440 new scoring system is prognostic irrespective of what you do. 146 00:09:55,000 --> 00:09:59,960 So let's say if you transplant, of course the, the patients with 147 00:09:59,960 --> 00:10:05,760 a, with a, with a high or very high do much better than if you 148 00:10:05,760 --> 00:10:09,160 gave Azacitin or if you basically observe the natural 149 00:10:09,160 --> 00:10:12,480 cause of the disease. But the demarcation between 150 00:10:12,720 --> 00:10:17,160 these groups remains the same. So let's say that the there's a 151 00:10:17,160 --> 00:10:20,640 little upgrade with the survival curves, maybe also based on 152 00:10:20,640 --> 00:10:22,880 selection of age and common abilities and so on. 153 00:10:23,280 --> 00:10:28,400 But the IPSSM at least in the majority of analysis published 154 00:10:28,520 --> 00:10:31,480 or now presented at the ASH meeting where there were a 155 00:10:31,480 --> 00:10:35,400 couple of IPSSM based on analysis with retrospective, 156 00:10:36,280 --> 00:10:40,680 they all look the same. So the IPSSM remains valid 157 00:10:41,320 --> 00:10:44,360 irrespective of what you do. And I think this is also 158 00:10:44,360 --> 00:10:50,960 something where we could learn from and the, the concept, I 159 00:10:50,960 --> 00:10:54,640 think the next concept should be that we are as precise as 160 00:10:54,640 --> 00:10:58,240 targeted as possible and maybe improve the prognosis of 161 00:10:59,000 --> 00:11:03,080 molecular defined or molecular driven subgroups of patients 162 00:11:03,080 --> 00:11:06,760 like IDHP tailed patients for instance, or yeah, 50P mutated 163 00:11:06,760 --> 00:11:09,480 patients. I think this, this should be the 164 00:11:09,480 --> 00:11:14,000 next, the next step because what we, the kind of therapy we 165 00:11:14,200 --> 00:11:17,760 currently apply is very broad and very unselected. 166 00:11:17,760 --> 00:11:24,880 So therefore I think the IPSSM is still valid across all these 167 00:11:25,720 --> 00:11:30,920 different unselected therapies. Yeah, and and how difficult is 168 00:11:30,920 --> 00:11:33,520 it to use the IPSSM? I mean, what does it take? 169 00:11:35,320 --> 00:11:38,360 Well, it takes a minute at least I would say. 170 00:11:39,680 --> 00:11:45,120 And of course #1 it, it takes, it takes an NGS based panel 171 00:11:46,280 --> 00:11:51,560 where I think we do it in our academic center because we are 172 00:11:51,560 --> 00:11:54,320 very curious and you know, we would like to learn but and so 173 00:11:54,320 --> 00:11:56,400 on. But would I recommend it on a 174 00:11:56,400 --> 00:11:59,400 broad scale for every patient? I wouldn't say so. 175 00:11:59,400 --> 00:12:02,240 I mean, it's also a question of resources, of course. 176 00:12:02,240 --> 00:12:08,080 But the question is if you have the 81 year old woman with a 177 00:12:08,080 --> 00:12:13,280 Dell 5 QMDS being reptiles as fusion dependent, I think I 178 00:12:13,280 --> 00:12:15,360 would go for P53 mutation analysis. 179 00:12:15,360 --> 00:12:21,520 But apart from this, maybe to go to look for flat 3 KMT 2A and 180 00:12:21,520 --> 00:12:25,480 all these things could be of course of interest, maybe you 181 00:12:25,480 --> 00:12:28,800 find very small clones. But the question is what does it 182 00:12:28,800 --> 00:12:30,840 change or does it change anything? 183 00:12:31,760 --> 00:12:35,880 So I think at this stage I would recommend it for every patient 184 00:12:35,880 --> 00:12:38,760 being eligible for allergenic stem cell transplantation. 185 00:12:38,760 --> 00:12:44,600 So every patient less the below the age of 70, all the patients 186 00:12:44,600 --> 00:12:49,240 above where you have a clear MDMS diagnosis based on genetics 187 00:12:49,240 --> 00:12:51,880 side genetics, morphology, Histology. 188 00:12:52,640 --> 00:12:56,080 So if if everything is clear and you have a treatment option 189 00:12:56,080 --> 00:13:01,880 which is valid, which should work let's say ESA or let's say 190 00:13:01,880 --> 00:13:04,760 lispatiscept in lower risk patients. 191 00:13:05,280 --> 00:13:09,160 So there is even if you know that the disease may be more 192 00:13:09,160 --> 00:13:12,800 aggressive or less aggressive, it doesn't change your treatment 193 00:13:12,800 --> 00:13:15,200 paradigm. This is, I think, the the issue 194 00:13:15,200 --> 00:13:20,920 and it may rather irritate or bewilder the patient who then 195 00:13:20,920 --> 00:13:24,720 thinks, well, I belong to the to the bad guys, although my blood 196 00:13:24,720 --> 00:13:29,320 counts are still very good. So I'm concerned now and and 197 00:13:29,360 --> 00:13:35,240 actually they will maybe suffer from a worse quality of life 198 00:13:36,160 --> 00:13:39,680 irrespective of a treatment of a treatment response which may 199 00:13:39,680 --> 00:13:44,520 occur irrespective of IPSSM. So this is I think needs to be 200 00:13:44,520 --> 00:13:48,840 balanced and also some patients want to know their prognosis, 201 00:13:49,240 --> 00:13:51,520 their putative prognosis, some may not. 202 00:13:51,640 --> 00:13:56,320 So I think before you tick Mark, you know on the on the lab 203 00:13:56,480 --> 00:14:00,800 report that you wanted 50 genes analysis, which is can be done 204 00:14:00,800 --> 00:14:03,640 as you know Kirsten within 2 seconds. 205 00:14:05,000 --> 00:14:08,880 And then you, you know, a lot of workload is generated before you 206 00:14:08,880 --> 00:14:10,160 do that. Think about it. 207 00:14:10,160 --> 00:14:12,320 I. Think that's a very good advice. 208 00:14:12,360 --> 00:14:15,960 And I think that's, that's where people have actually also come 209 00:14:15,960 --> 00:14:19,680 into trouble sometimes. I think particularly with also 210 00:14:20,000 --> 00:14:21,920 patients that do not want to know everything. 211 00:14:21,920 --> 00:14:24,960 And I think you need to, to be very clear about that before you 212 00:14:25,120 --> 00:14:28,960 you start also because some of the panel nowadays also have all 213 00:14:28,960 --> 00:14:32,880 the, the hereditary, the genes that are involved in hereditary 214 00:14:32,880 --> 00:14:34,000 myeloid cancer. So. 215 00:14:34,600 --> 00:14:42,960 So how do you handle that? Yeah #1 I mean, it's, we know 216 00:14:42,960 --> 00:14:48,440 now that for instance, DX 41 is not restricted to younger 217 00:14:48,440 --> 00:14:53,040 patients, you know, so this is something which can occur at the 218 00:14:53,040 --> 00:14:56,240 age of 7080. Even MD's, these patients seem 219 00:14:56,240 --> 00:15:01,520 to have a more, let's say B9A course of the disease. 220 00:15:02,240 --> 00:15:05,240 So how do we handle that? I mean, number one, in my 221 00:15:05,240 --> 00:15:11,640 country, if you go for inherited mutations, if you really do do 222 00:15:11,640 --> 00:15:17,960 this work up like the one I just mentioned or, or geta 2 or 223 00:15:18,000 --> 00:15:20,560 others, you need to get a consent. 224 00:15:20,560 --> 00:15:22,920 Oh yeah. I mean this is the same. 225 00:15:22,960 --> 00:15:25,800 Way do Don't you have it in the regular pens as well? 226 00:15:26,640 --> 00:15:29,480 We sometimes, yes, we some no, we, you are right. 227 00:15:29,480 --> 00:15:32,560 We just amended it. So I have to admit it's there, 228 00:15:32,560 --> 00:15:40,080 but still it requires consent. And again, this is something 229 00:15:40,080 --> 00:15:44,680 which also has consequences for the family, for everybody. 230 00:15:44,680 --> 00:15:49,640 And again, the, I mean, if the patient got MD's at the age of 231 00:15:49,680 --> 00:15:53,960 82 and before was basically was healthy, everything was fine. 232 00:15:54,640 --> 00:15:57,560 So you can get MD's at the age of 82. 233 00:15:57,560 --> 00:16:01,640 There's nothing weird about it and it's nothing which may cause 234 00:16:01,640 --> 00:16:04,040 a genetic work up of the entire family. 235 00:16:04,040 --> 00:16:07,520 So we counsel the patient, we counsel also with our genetic 236 00:16:07,520 --> 00:16:10,120 specialist, and then we draw conclusions. 237 00:16:10,920 --> 00:16:17,560 I I think I would do it genetic work up with inherited genes in 238 00:16:17,560 --> 00:16:21,040 every younger patients but below the age of 50, especially also 239 00:16:21,080 --> 00:16:27,000 those with -7 for instance abnormalities where this is a 240 00:16:27,000 --> 00:16:33,320 sign also of maybe inherited mutation, mutations like GATHA 2 241 00:16:33,320 --> 00:16:39,800 or also the Funcone. So I think a brief history is 242 00:16:39,800 --> 00:16:41,800 important. Cancer in the family? 243 00:16:42,320 --> 00:16:45,840 Also cutaneous malformation Source or something like this? 244 00:16:45,840 --> 00:16:47,880 And also of course, if you want to transplant then. 245 00:16:48,080 --> 00:16:52,400 It's yes, yes, also the donor. And if it's a sibling donor, 246 00:16:52,720 --> 00:16:55,840 this would also require work up. There are a lot of revenues now 247 00:16:55,840 --> 00:17:00,200 on this topic and I think it's a very, very fascinating arena. 248 00:17:00,200 --> 00:17:05,240 We we jumped in because there are many, many genetic traits 249 00:17:05,240 --> 00:17:08,359 and predisposition, predisposition for patients 250 00:17:08,359 --> 00:17:12,000 maybe more than we thought. But again, I come back to what I 251 00:17:12,000 --> 00:17:14,319 said before Kirsten, I think you agreed on that. 252 00:17:14,839 --> 00:17:19,319 Think about the consequences for a family trade and for all the 253 00:17:19,319 --> 00:17:27,119 people before you tick mark this analysis and to know that you 254 00:17:27,119 --> 00:17:32,360 may develop MD's in the next 20 to 25 years with the likelihood 255 00:17:32,360 --> 00:17:34,240 of 50%. Let's say it this way. 256 00:17:34,920 --> 00:17:38,800 Does it really help you and what what are do we have any 257 00:17:38,800 --> 00:17:43,000 interceptive medicine at this stage? 258 00:17:43,040 --> 00:17:47,960 I don't think we have and maybe you need an antidepressant pill 259 00:17:47,960 --> 00:17:52,080 then as an interceptive medicine because you get so depressed 260 00:17:52,120 --> 00:17:56,280 that you will maybe get MDFS in 20 years and you forget to live 261 00:17:56,280 --> 00:17:58,480 and. That's the worst thing that can 262 00:17:58,480 --> 00:18:00,960 happen, yeah. That's the worst thing which can 263 00:18:00,960 --> 00:18:03,080 happen. And therefore I think it 264 00:18:03,080 --> 00:18:07,120 requires into this interdisciplinary work up, 265 00:18:07,120 --> 00:18:10,040 interdisciplinary collaboration with people who understand the 266 00:18:10,040 --> 00:18:16,960 consequences not only I think from a life prognosis 267 00:18:16,960 --> 00:18:19,360 perspective, but also from an emotional perspective and 268 00:18:19,360 --> 00:18:24,160 psychological perspective. And that's what we what we 269 00:18:24,160 --> 00:18:27,080 basically do here or what we tried to do. 270 00:18:27,080 --> 00:18:32,200 But I think it is a very wide open box at the moment. 271 00:18:32,200 --> 00:18:37,640 And if you enter it, I think you may basically sequence almost 272 00:18:37,640 --> 00:18:40,920 every patient at the end of the day and also the family. 273 00:18:40,920 --> 00:18:42,920 And I'm not talking about resources here. 274 00:18:42,920 --> 00:18:46,400 This is not my subject because I'm a doctor and I wanted would 275 00:18:46,400 --> 00:18:50,800 like to help patients but it's about consequences. 276 00:18:51,200 --> 00:18:53,720 Yeah, yeah, yeah. This should have some 277 00:18:53,720 --> 00:18:57,000 consequences actually when you do these advanced things and 278 00:18:57,000 --> 00:18:59,160 when you challenge patients in that way. 279 00:18:59,520 --> 00:19:01,320 Also. I think this is also a little 280 00:19:01,320 --> 00:19:04,760 bit of an issue with if we go to the other end of the scene, sort 281 00:19:04,760 --> 00:19:08,960 of the you know, if you have mutations than Ted 2 and you're 282 00:19:09,200 --> 00:19:13,600 obviously not particularly sick. I mean if you have a secrets 283 00:19:13,640 --> 00:19:18,040 with Ted 2 so so so is this you know, is this another group 284 00:19:18,040 --> 00:19:19,880 where you should be a little bit careful? 285 00:19:19,960 --> 00:19:22,800 I mean, because the thing you know you we also know that can 286 00:19:22,800 --> 00:19:25,520 predispose to other things. And how do you inform these 287 00:19:25,520 --> 00:19:28,320 patients if you find, you know, a mild anemia with the tip 2? 288 00:19:28,320 --> 00:19:35,000 Mutation, I mean the immediate consequence for this is 289 00:19:35,000 --> 00:19:39,000 basically surveillance and observation, especially majority 290 00:19:39,000 --> 00:19:42,040 of these patients, it's just finding by chance. 291 00:19:42,080 --> 00:19:46,560 So just we'll put the work up at the GP and then yeah, if if they 292 00:19:46,560 --> 00:19:50,320 have a tech mutation, well, I mean this is definitely a clonal 293 00:19:50,320 --> 00:19:52,160 disease. This is this that the patient 294 00:19:52,160 --> 00:19:57,080 needs to know that this is not like reactive anemia, it's a 295 00:19:57,080 --> 00:20:00,040 clonal disease. But what I basically do is that 296 00:20:00,040 --> 00:20:05,600 I tell them that it's rather unpredictable when the disease 297 00:20:05,600 --> 00:20:08,840 may further. Further evolve of course with 298 00:20:08,840 --> 00:20:12,600 the tattoo mutation, the single mutation only maybe mild anemia. 299 00:20:12,600 --> 00:20:17,240 The risk to to undergo this disease evolution within the 300 00:20:17,240 --> 00:20:20,440 next 12 months into an MD's is rather unlikely. 301 00:20:20,440 --> 00:20:23,840 But you never know of course in a given patient. 302 00:20:24,080 --> 00:20:28,880 So I think the the immediate consequence is good. 303 00:20:29,480 --> 00:20:33,400 A good relationship with the patient is to comfort the 304 00:20:33,440 --> 00:20:39,160 patient and is also to implement a strategy of surveillance with 305 00:20:39,480 --> 00:20:45,440 rather blood count assessment, which brings the patient into a 306 00:20:45,760 --> 00:20:51,600 position of comfort where he or she feels embedded into a 307 00:20:51,600 --> 00:20:58,800 strategy where all the the risk are mitigated or basically are 308 00:20:58,800 --> 00:21:04,360 predictable and the patient feels safe and well with the 309 00:21:04,360 --> 00:21:06,240 strategy. I think this is the immediate, 310 00:21:06,280 --> 00:21:10,120 immediate the consequence of such findings rather than an 311 00:21:10,560 --> 00:21:14,400 interceptive approach or early EPO into production or these 312 00:21:14,400 --> 00:21:18,040 kind of things. I think it's rather the psycho 313 00:21:18,040 --> 00:21:23,120 oncology around this. I mean, if you measure things, 314 00:21:23,120 --> 00:21:26,000 if you detect things, you need to live with the consequences. 315 00:21:27,280 --> 00:21:29,520 And I mean this not for the patient, I mean this rather for 316 00:21:29,520 --> 00:21:31,680 the doctor. Yeah, that's true. 317 00:21:31,720 --> 00:21:34,960 It's also true. So I think one thing we didn't 318 00:21:34,960 --> 00:21:40,400 touch up on is the the P53 mutations, what I mean and the 319 00:21:40,400 --> 00:21:45,040 IPSSM and and and how we can use this in a good way I mean. 320 00:21:46,120 --> 00:21:51,640 I think the IPSSM, one of the novelties of IPSSM was the 321 00:21:51,720 --> 00:21:57,800 implementation of P53 not as a stand alone mutation, but given 322 00:21:57,800 --> 00:22:03,600 the risk of B allelic alterations or inactivations 323 00:22:03,640 --> 00:22:05,760 either by mutation or by deletion. 324 00:22:06,960 --> 00:22:10,800 Those are those one, those are the ones being associated with a 325 00:22:10,800 --> 00:22:15,920 very bad prognosis. Whereas a patient with a stand 326 00:22:15,920 --> 00:22:21,920 alone single Axon mutation is is still not a very good prognosis, 327 00:22:21,920 --> 00:22:26,000 but it's much better than the patients with this B allelic 328 00:22:26,400 --> 00:22:28,280 alteration. I think would you use that when 329 00:22:28,280 --> 00:22:31,280 you choose who to transfer? Yes. 330 00:22:31,320 --> 00:22:37,600 And I, I must tell you I would rather, I mean the B allelic are 331 00:22:37,600 --> 00:22:42,040 really the worst and whatever you do it it doesn't work. 332 00:22:42,040 --> 00:22:47,440 So I would, I mean maybe you have expected the answer that I 333 00:22:47,440 --> 00:22:50,920 say I would transfer the B allelic but I would rather say I 334 00:22:50,920 --> 00:22:52,640 would transfer the non B. Allelic. 335 00:22:52,680 --> 00:22:54,760 No, that's what I would do that. Too Exactly. 336 00:22:55,000 --> 00:22:57,480 Yeah, that's what I think. That's what our transplanted 337 00:22:57,480 --> 00:22:58,480 says too. I mean it's. 338 00:22:58,600 --> 00:23:01,880 Not yes, yes. I mean, we, we, we, we currently 339 00:23:01,880 --> 00:23:05,640 have a patient here with B allelic PP3 complex care type 340 00:23:05,720 --> 00:23:10,800 who had EB2 and developed AML very early. 341 00:23:10,800 --> 00:23:14,280 Thereafter got an induction chemotherapy, did not respond, 342 00:23:14,600 --> 00:23:18,640 got azocydin slash, decided when we switched because of P53. 343 00:23:18,640 --> 00:23:22,160 Then later when it took like 3 cycles, did not respond. 344 00:23:22,440 --> 00:23:26,480 Is still in a good condition, but it's basically full of MD's 345 00:23:26,480 --> 00:23:29,760 slash AML, the cells in the bone marrow. 346 00:23:29,760 --> 00:23:33,080 So we decide not to transplant because you would not get this 347 00:23:33,080 --> 00:23:34,560 patient into long term remission. 348 00:23:34,720 --> 00:23:38,440 So this is I think we need other tools, we need maybe car T's, we 349 00:23:38,440 --> 00:23:40,680 need immune therapy for these patients. 350 00:23:41,040 --> 00:23:44,400 There are also other agent as you know in development. 351 00:23:44,560 --> 00:23:49,520 But I would as you said before in the with the B allelic, I 352 00:23:49,520 --> 00:23:54,080 think the only chance of cure potentially cure is that you 353 00:23:54,400 --> 00:23:58,320 induce certain level of remission before transplant and 354 00:23:58,320 --> 00:24:01,960 then you go maybe you go for MRD driven approaches after or 355 00:24:01,960 --> 00:24:05,920 maintenance or whatever. A patient who has biletic 356 00:24:05,920 --> 00:24:10,560 disease and is uncontrolled still with excessive blast but 357 00:24:10,560 --> 00:24:14,200 before transplant, I would not under, I would not go for 358 00:24:14,200 --> 00:24:16,720 transplant. And then there are those very 359 00:24:16,720 --> 00:24:21,680 rare cases with less than 5% blast and maybe pancytopenia. 360 00:24:21,680 --> 00:24:25,520 So these are patients at this stage of developing higher risk 361 00:24:25,520 --> 00:24:27,400 MD's within the next three to six months. 362 00:24:27,720 --> 00:24:33,920 Those ones I think you may transplant upfront and don't go 363 00:24:33,920 --> 00:24:37,680 for any prior therapy, but again, still long term Disease 364 00:24:37,680 --> 00:24:40,960 Control can be achieved in less than 20% of patients. 365 00:24:41,280 --> 00:24:44,240 Yeah. So this is really still a tough 366 00:24:44,240 --> 00:24:46,040 case, I guess. Good. 367 00:24:46,040 --> 00:24:51,400 I think we were came around a lot of issues here whereas is 368 00:24:51,400 --> 00:24:55,440 there anything else you want to add or out prognosis and 369 00:24:55,440 --> 00:24:59,840 prognostication? I think what I would I'd like to 370 00:24:59,880 --> 00:25:02,520 add is that don't only look at the genes, also look at the 371 00:25:02,520 --> 00:25:04,480 patients. Yeah, that's so important. 372 00:25:06,000 --> 00:25:07,280 Yeah. Maybe we actually need a new 373 00:25:07,280 --> 00:25:10,120 prognostication where you actually include also 374 00:25:10,640 --> 00:25:14,680 comorbidities and, you know, age of the patients and sort of in a 375 00:25:14,680 --> 00:25:16,840 way in the future. I don't know. 376 00:25:16,840 --> 00:25:18,400 What do you think about immunology? 377 00:25:18,400 --> 00:25:21,840 Actually, yes, immunology ever be part of? 378 00:25:22,960 --> 00:25:25,920 This is very important. There is an initiative led by 379 00:25:25,920 --> 00:25:29,680 Sharam called St. Now to bring up a work group 380 00:25:29,680 --> 00:25:33,960 maybe into this, into this. I think we what would be #1 what 381 00:25:33,960 --> 00:25:37,080 we need is proper and homogenized assessment of 382 00:25:37,080 --> 00:25:40,920 immunologic factors in NDS at, at diagnosis. 383 00:25:41,400 --> 00:25:44,840 And also we need to understand be correlated. 384 00:25:44,840 --> 00:25:50,440 Now drag activity with mutations or blast counts or transfusion 385 00:25:50,840 --> 00:25:54,240 or EPO level, but we never correlate them with any 386 00:25:54,240 --> 00:25:56,120 immunological marker. So. 387 00:25:56,680 --> 00:26:00,680 If this work has to be done, and then yes, I fully agree that at 388 00:26:00,680 --> 00:26:05,880 the long run there's a high chance that this may be 389 00:26:05,880 --> 00:26:08,520 integrated. Yeah, that would be very 390 00:26:08,520 --> 00:26:11,120 interesting. And you know, the only thing 391 00:26:11,120 --> 00:26:13,600 that cures and yes, is immunology, some sort of 392 00:26:13,600 --> 00:26:16,560 immunology and transportation, right, Although we don't know 393 00:26:16,560 --> 00:26:19,600 exactly what it is. So yeah, well, I think we came 394 00:26:19,600 --> 00:26:22,560 around a lot of issues here. So thank you so much for your 395 00:26:22,560 --> 00:26:24,880 time. I know how busy you are, so it 396 00:26:24,880 --> 00:26:26,520 was really nice. Thank you. 397 00:26:27,080 --> 00:26:28,320 Thanks for having me.