This discussion is a recording of the South Asia iCMLf Regional Discussion Group held on July 2 2025
Regional Experts:
Professor Mehreen Ali Khan
Armed Forces Bone Marrow Transplant Centre
Rawalpindi, Pakistan
Professor Raghunadharao Digumarti
KIMS ICON Hospital
Visakhapatnam, India
International Experts:
Professor Mhairi Copland
Institute of Cancer Sciences
University of Glasgow
Glasgow, UK
Dr Jeff Lipton
University of Toronto and
Princess Margaret Cancer Centre
Toronto, Canada
00:00 Welcome and Introduction
04:00 Case 1
06:59 Discussion of Case 1
17:16 Case 2
28:19 Discussion of Case 2
33:26 Case 3
36:55 Discussion of Case 3
46:37 Case 4
56:12 Discussion of Case 4
01:03:27 General questions and discussion
01:11:14 Closing comments, thanks and farewell
Um, as you get settled in, I’ll take a moment to let you know a little bit about the International CML Foundation. Um, who we are and what we do. So, the the International CML Foundation is a physician and researcherbased organization with two key priorities. Both of them working towards improved outcomes for CML patients around the world. So, firstly, the foundation is raising the bar of CML management through CML education and that includes meetings like this. Uh over the last 15 years, the foundation has been working via preceptorships, meetings, symposia, and online, for example, with the knowledge center trying to make sure that no matter where you are in the world, CML physicians and researchers have access to the best possible knowledge, opinions, and experience. The other side of the foundation’s work is harnessing the power of global research. The ideal of course is a cure for CML but along the way they are trying to improve treatment pathways with patient outcomes as much as possible. So we have the genomics alliance we have the TFR alliance they did a lot of work around CML and COVID there’s a hepatitis B survey out there and then looking at pregnancy in low and middle inome countries pediatric treatment in low middle- inome countries and much more to come. So that’s a brief overview of the International TML Foundation, who they are, what they do. Let’s move on to our topic for today, which is difficult cases from across the region. And we have some really excellent and very challenging cases to share with you. Um I’ll introduce our speakers today. So our experts today, I’m really delighted to introduce Professor Mari Copeland from the UK. Uh, Professor Mari is globally a globally renowned hematologist and professor in translational hematology at Glasgow University. Mari is a great friend and contributor to the International CML Foundation and it’s really lovely to have you here today. Thank you Mari for also stepping in and managing the waiting room. From India we have professor Ragu Digamarti who amongst many other things is a senior consultant and medical oncologist who has pioneered cancer treatment research and education in the state of Andra Pradeshan India by building a comprehensive cancer care center at the Nisam’s Institute of Medical Sciences in Hyderabbad u and he’s worked with the government to bring optimized cancer care for people living below the the poverty line. Welcome Ra Reagu. It’s an absolute honor to have you here. Thank you. I am also very pleased to introduce Professor Mari Khan from the armed forces bone marrow transplant center in Rahul Pindi in Pakistan. Now, the foundation very first got to know me when she did a preceptorship at the MD Anderson uh in Texas in the USA with Professor Horge Cortez and she’s been a friend to the foundation ever since. A leading woman in the field and we’re delighted to have you in the hot seat today. Welcome Mary. Our fourth expert today is Dr. Jeff Lipton. And I’m not sure if Dr. Lipton has yet been able to join us. I hope so. If not, um, we will welcome you very soon. Uh, but it’s a great pleasure to have, uh, Dr. Lipton from Toronto in Canada. Again, giant in the field and the foundation’s go-to person for really difficult cases and the questions that have other people scratching their heads. Um, he is trying to retire apparently, but I always hope that that just means he has more time to contribute to the foundation and to events such as these. So, it’s such a privilege to have you here today. Welcome Jeff. I hope when you join us in the um for room. Okay. So I will take my slides down and I will invite Ragu please to get your slides up and we will move on to your first case. Good evening or good morning everyone. uh so uh I’m presently at the M&J Institute of Oncology which is a regional cancer center at Hyderabad in the other state the uh the state of Telangana which was originally a part of Andhra Pradesh. So here is my first patient uh she’s a 37 year old lady uh who was already uh on treatment for chronic maloid leukemia since 2018 and she presented with mele weakness facial puffiness and increasing palar for about a week. So her investigations at this time showed she had anemia 7.2 g. She had uh a a low WBC count 2950 with an absolute neutrfil count of 1570. The platelet count as a lac and 14,000. Serum chemistry was normal. BCRel again this time was 33% but what we noticed from 2018 was that she never achieved a major molecular response during the entire treatment. Uh the bone marrow aspiration and biopsy along with flowcytometry showed a CML in myoid blast crisis. Uh we also did a BCRable kynise domain mutation which was negative. It has been done in the past three occasions. We repeated it again and it is still negative. And we did a a cytogenetics as well. There are no additional cytogenetic abnormalities. uh she was put on nilotinip for a year initially and uh she was switched to datanip 100 milligrams daily even though the was negative and she required dose reduction to 75 mg and finally to 50 mg in view of persistent cytoenas she wasn’t tolerating datanip because of the cytoenia she was hardly ever on the drug and months went by without her taking the treatment so she was shifted to imagat 300 mg and presently she is on in myoid blast crisis. So uh we have the following dilemmas in her. She’s not tolerating the required dose of a TKI never attained a major molecular response although she was drug compliant as far as permissible. The mutation analysis is negative but the bone marrow shows a myoid blast crisis. So with no mutation detected what’s the road ahead for us? Uh I can stop sharing my slides so that we can have a discussion. Mari what do you think? So I I think this is a really difficult case. It’s a it’s a young woman who’s never really had a proper response to her CML. Um I I wonder did she have cytoenas on the notanib as well from the start? Has that been a longstanding? Yes problem always. So whatever was the tyrrosin kindness we have used we noticed that she always had the counts on a lower side. Initially we thought this was because of a high tumor burden and what little count we are seeing is the actual normal cell which was quite all right on the differential count. We didn’t find myocytes, metamalocytes or bralytes. So we were quite happy thinking that this is expected because most of the cells are pH positive and they’re getting eliminated. But the persistent low count since 2018, it’s about 7 years now, is pretty worrisome. So it never actually recovered back to normal. It never actually crossed 4,500. And and now that she’s in blast phase, has she got um high counts or is she pansy panic? Is she still pansy panic? She doesn’t have a high count. The counts I have given are this week’s counts. Okay. I mean if if if this was my patient and and her bone marrow was showing blast phase, I would be giving her um myoid blast phase, I would probably want to give her AML type chemotherapy and then probably with penatanib um and then work her up for bone marrow transplant um assuming she’s got a suitable donor would would be we can we can plan the 3 + 7 induction that should not be a problem. Uh that’s quite routine for us for myoid blast crisis in CML. So adding ponotinip I I was always a little bit hesitant about that uh because of the it complicates it. It’s almost like giving chemotherapy. So sometimes we used I I still remember my first the ICMLF preceptorship when I start I first noticed it’s used in a clinical trial uh in Portland and it used to wipe out the marrow. So that used to be a major problem. So I was a little bit hesitant. Do you want me to first start the ponotinip or do you want me to first start the 3 + 7 and then add slowly add the ponotinip? I I mean I think I think in her case because she’s panytoenic and her marrow’s full of blast I I think it’s it’s important that she gets the chemotherapy first. Um so the 3 plus 7 um we would tend to use flag ida but I think 3 plus 7 is as good. Um, and then add in the add in the penata um afterwards if if you need to hold her with something to get her to transplant would be how I would do it. Um um majority of the time we often find in myoid blas in CML that they don’t ever enter a remission. Um, sometimes that is pretty worrisome and doing a transplant when you have full-blown disease often complicates the matter even more. I I I think she might be one of these poor patients that has no normal hemopolesis left so that you’re never going to clear it. So maybe giving her a new immune system if you can get get her back into a second chronic phase is really the most important thing to do. So getting her back to a second chronic phase and then a transplant I think would be what I would do. But other people may have other opinions. I think Newman’s asked a question online. They’re asking how about checking TKI domain mutations and I think you’d done that and there were no mutations on the disatinib. Is is that correct? We we have only checked for uh I mean imagatib resistant mutations and of course we did cytogenetics this time just to be very sure that we didn’t miss something uh on the PCR. So uh we don’t have a mutation in the cytogenetics and we don’t have an irrma as well. I might take this opportunity to ask professor Ali Khan uh to give us her view. I could see you nodding quietly in the background there. What do you think? What would you do if she was your patient? Thank you Arin. Uh thank you professor Au for a very wonderful case. Uh we come across such cases very frequently. So when we started transplant uh in our institute 25 years ago, we used to transplant every CML because uh TKI was so expensive that we would prefer transplant in chronic phase as well and then gradually with the passage of time with the availability of first line, second line, third line and now fourth line TKI uh the transplant are limited. However, our institute has done most transplant in CML that is 110 in chron as chronic m and leukemia with 50% of them being in blast crisis. So had she been my patient she’s a young patient 37 years old having CML since 2018 that makes seven years of agony with CML. So I would if her ECO performance status as well I will give T3 A7 with ponatin for induction. I will uh check the status. If she’s in CR2, I would like to take her to transplant but with fully HLA match donor. However, with HLO match donor, I would be a bit hesitant. CML is notorious for GBHD with fully matched donor as well. But with HLO match donor, we have faced quite problems in other disorders as well as CML. So if uh she’s she has homage donor I would think of it. Um if a fully match donor is available so the patient should be taken to transplant and there’s no other way because it’s minor plasticis and then postrplant two years postrplant we would like to continue with panatilate so we have done many cases of CML. So this is all from my and if the patient is frail and cannot tolerate D then we’ll give hypomethylating agent with venatax and with TKI to um achieve CR uh to trans yeah that sounds good. uh we do typically use uh in the elderly um as I cited in plus venitolax and we have had very good results pushing a few of them to transplant later we have started using it in the pediatric age group also if they for children with AML and all who don’t go into a remission so we have good experience with that and we are sending those children also for transplant uh but I have never used it in a myoid blast crisis in CML. But if you say so that it’s going to be helpful uh and of course it’s going to be a little more gentle than a standard flag eye or 3 plus 7. So probably we will try that since we have good access to venax plus as a cited in as well. Oh she has she has plenty of sips and we are ready to do their typing. I’m so sure we will find a a match donor then we won’t have to go for a hlo match at trans. So another suggestion from my side is that for every blast crisis we do go for flowcytometry because some uh in 75 this is diagnosed on flowcytometry only. Yeah and we have noticed two empenotypic acute leukemia post CMN so majority is AMN blast crisis my blast crisis uh 25% are lymphoid blast crisis and two to 3% are mixed you know typic leukemia which are then uh not very sensitive to hypomethrating agent and vetic and we have to give flaga in those case flag or flag or what is whatever is available with punatinip of course there was a A paper published last year in Lancet Hematology by Nicholas Short and colleagues from the MD Anderson looking at the triplet of decitabine venita clax and panatanib in patients with myoid blastphase CML and they got really good results with it but they had problems with cytoenia so they did have to dose reduce so it might be worth having a look at that paper as well and there’s also Philipe rouselo’s data on panatinib with aocyitine as well as a combination again um it seemed to be better tolerated than the triplet. So there’s a couple of options that are non that are not flaga or daff plus 7. That’s very interesting paper. I went through it and another suggestion is that we can reduce the dose of venatlax rather than giving for 28 days we can do 7 plus 7 uh we can do 14 days ventols. So all these are options for CML blast crisis but it has to be followed by transplant. Yeah, we might be able to um to share those references with the audience afterwards with our little um post uh postevent package. Thank you. Thank you. Thank you very much. I think we can go to the second case from uh Brigadier Maharin. Super. Thank you very much. That was a great case Ragu and a wonderful discussion. Um, Professor Alikhan Marin, would you like to please share the slides for your first case with us? Yeah, first of all, I would like to thank uh ICMLF for encouraging all of us from low and middle inome countries, Southeast Asia to share our difficult cases. So, um I have two cases. I have my two brilliant registars. Uh I would first like to invite Dr. Fahim. Uh he is Dr. Mohammad Fahim is my registar. he would present the case and the followed by then second case. So Dr. Fahim kindly share your slides. While the slides are coming up, I’ll say it’s it’s always an honor to work with you and to work with um our physicians in low middle- inome countries. I’d really like to thank Professor Copland Mari. Um unfortunately um Dr. Jeff Lipton still hasn’t been able to join us. I’m not sure what’s that what’s happened there but um Jeff is always a great contributor and very timely so something has happened there which has prevented him joining us um and professor Mari Copland will step in as the international expert thank you Dr. Fahim hello am I yes audible hello my name is Dr. Mohamad Fahim. I am resident of resident in clinical hematology at armed forces bone marrow transplant center. I am the resident of Brigadier Mahini Khan. So I’m presenting a case of I am presenting a case of 52 years old male with no previous commands. He first he first presented to armed forces bone marrow he first presented to armed forces bone marrow transplant center in April 2024 with easy fatigability night sweats and weight loss. Uh on examination his spleen was palpable 5 cm below the costal margins and his soal was 1.9 means he was highest. So we did work up on CBC. He had um luccoytosis with the BBC count of 51,000 multiply by 10^ 9 per liter. His hemoglobin was 9.8 g per deciliter and platelets were 353. So bone marrow examination was done and it revealed CML and accelerated phase with 10% blasts. His cytogenetics were done and it showed 46xy with 922 transllocation. His PCR BCR ABL1 P210 was positive and it was 26.68%. So he was started on neotinib at 100 mg per day and his he was advised PCR per BCR ABL1 at 3 months interval. At this time we had a plan. So has fully matched HLI donor was available at that time. Uh all plan was to perform allergenic bone marrow transplant after CR1. Uh so he had then followup visits uh in follow-up visit on 10th of June 2024. He had WBC count of 3.2. Uh his hemoglobin was 13 g per deciliter and his platlets were 13,000. So we decreased the dose of notinip from 800 mg per day to 600 mg per day. In further followup visit on 12th of August 2024 his WBC count was 3.8 hemoglobin was 14.4 g per declet were 220 uh thousands. So he was advised notilip 800 mg alternating with 600 mg per day. At this time his uh PCR per BCR ABL1 was done uh at three month interval and it showed optimal respon he had another follow visit uh on 16th of September 2024. Uh this time his WBC count was 5.0 hemoglobin was 13.0 and platelets were 194. So notin dose was escalated back to 800 mg per day. Next point. He then presented to FBMTC um with the complaints of fever andia for 10 days. Uh on general physical examination he had arythmatiso papar leion on both arms which was leukemia cutis and his systemic examination showed dull percussion note and absent breath sounds on the right lung basis. other systemic examinations were normal. Uh and we did work up and his CBC showed WBC count of 21.6,000. His hemoglobin was 13 g per deciliter and his platelets count were 17,000. His peripheral smear showed 45% blast. His bone marrow examination was done which was sudan black positive and there were interstial and focal infiltration by blast confirming CML transformed into AML. Has flow psychometry showed weak CD4, CD45 positive, weekly positive and CD34 positive, CD3, CD33, CD 117, CD38 and CMP of double positive. His BCR, ABL1 at six month interval was done and it showed u 21.9%. So he was started on IV antibiotics like meopen and vencomyin, steroids and diuretics and he improved with it. uh his ECOP score at that time was two. Uh so we started him on punatin 45 milligram and esavoc and mentolex. Uh this cycle was complicated by fibral neutropenia exelis bilaterally and cytoenia. So because of that ventocle was withheld under 14. uh he was managed with antibiotics, antifungal, tactile grass, buffy code and HLM genocide infusion at that time. Next has bone marrow examination post esavin was done on 15th of January 2025 and it showed that marrow is not in remission with 14% blast. So at the time of discharge he was given me legs uh for 7 days. At this time expert consultation was done from the international CML foundation team and experts were consulted. One of them is Jeff Leptton who is a staff physician under allergenic blood and bone marrow transplant services Princess Margaret Hospital Canada as opinion was to give him a punatil followed by allergenic hemopitic stem cell transplantation and early punatinum maintenance at the patient get second CP. Uh one of them was Mary Copeland. Um she is a professor of translational hematology university of Glasgow Scotland. Uh she was of the opinion that if there is no response to then switch to plya plus followed by allergenic hematopitic stem cell transplantation. Another one was phostoagneti. She he is the professor in hematology university of bologna Italy. He was of the same uh idea as Mary Copeland. So as the patient was f so we started him on D3 S7 and conotin 45 mg. His donor remission was also given at the dose of 45 mg per meter squared. This was complicated. This cycle was complicated by primary neopenia and prolonged cyupenia as it always does with the with this patient. So he was managed with broad broadsp spectrum antibiotics. His peripheral smear on day 34 of 37 showed 9% blasts. Uh this uh so he was readmitted for salvage chemo on 10th of April 2025. This time he had fibbrinia and he had decreased air entry bilaterally. So and his blood CS was run which showed no growth. HRCT test was unremarkable and his galactoinan was positive. So he was started on broadspectctrum antibiotics and importin ST were settled. Then so he was given salvage chemotherapy with flavven from 15th of April 2025 to 21th of April 2025. He was also given SMB and punatilip combination due to their synergistic effect. This cycle was also complicated by nephrotoxicity. Uh it nephrotoxicity was secondary to empowering on day 11 of clubin. It was managed with IV fluids and uh with drug do adjustments. It was also complicated by fibrillion neutropenia. Uh and the day 12 of clubin uh and it was managed with antibiotics, antifungal and buffy coat infusion. See uh he had also a CV line infection on day 18 of flavven. So we removed the CV line. Uh he also had uh hyperbubmia on day 22 of flavven. So emperin was changed to isobonazol. His current status is that his blood CP was showed WBC count of 3.4 HB of 8.3 g per deciliter and plate rates were 18,000. His bone marrow respiration last then showed that his bone marrow is not in remission. He was on palative care with antibiotics, fluids and electrolytes, cyto reduction with hydroxyura and cetarabin and blood components. Uh but the patient has now expired. Thank you. Thank you very much. Over to Brigadier Alihan. Thank you very much Dr. Fahim. Um I had many CML patient but this patient was very very close to my heart as we were trying to pull him up. He had fully matched donor and everything available for transplant you know all the pre-ransplant assessment has been done but unfortunately with all the efforts with all the international opinions and availability of old TKIS we were unable to achieve CR u for CML and mid class crisis. So my question to the expert professor Mari is here, Professor Ragun is here. Uh we are missing professor Jeff Lipton though. So uh what you could have done differently for this patient. My first question. My second question is the combination of and ponatinib which has reported to be cyogistic in few cases however not uh the standard of care. Uh would you advise that? Uh and third despite availability of all the resources for transplant uh we couldn’t uh take this patient to transplant and he passed away. He was just 52. So my just question is uh what you would have done differently. Thank you very much Mary and a very complicated case indeed and beautifully presented. Thank you so much to our guest presenter Bari. Would you like to start? Yeah. So I think this is a very difficult case and I think you did everything you could and more and and you had access to I think more drug combinations and more lines of therapy than than we would have. I think the combination of leukemia cutis and myoid blast phase is the outcomes are are really really terrible. Um, and I’ve not seen a patient get to transplant with with that combination with blast phase CML unfortunately and get into remission. Um, I think you did everything you could um in in terms of your question about the asim and panatinib I think that’s quite interesting from the data I’ve seen with a sim as a single agent. I don’t think it’s effective in blast phase or in pH positive alll, but I think potentially in combination it could it could certainly help with mutation development, reducing mutations. Um but but we wouldn’t have access to that like likewise we wouldn’t have access to um black ida with venita clax either. Um, so I think personally you you’ve done everything you could for this patient and I’m really sorry it didn’t have a more positive outcome but I think he had really terrible disease. Yes, thank you very much Professor Mari for your valuable comments. We value that and that’s why this uh international CML foundation forum helped us out. Whatever we were doing, we were continuously in touch with the international experts and this was all uh we can do because there’s a certain limit to the medical expertise as well. You’re right. Um Dr. would you have done what would you have done? Uh I personally wouldn’t have given Simmonip. I I have not much of an experience with that. But um in my opinion anything which has a leukemia cutis in fact for that matter even a solid tumor which has a cutaneous metastasis has an extraordinarily poor outcome. Uh I sometimes feel it is worse outcome than having liver lung or brain metastasis. So anything which is in in cutaneous metastasis uh performs very poorly and even otherwise even if they’re non-chronic myalide leukemia in blast crisis and you get a leukemia cure outcomes have in my opinion have been very poor nothing seems to work very well it it’s something a disease with a a big vengeance on its own so I don’t know if we could have ever pushed this patient to a point where we could have utilized the matched donor at all and I I know you did try uh mined buffy codes as well for the infection. Um I sometimes hope it it actually enrafts but it doesn’t do that in CML for some reason to exploit at least uh I mean uh transfusion associated GBHT it doesn’t happen at all. Thank you very much professor Ragu. In fact in this case both the times patient was in septic shock onotropic support and HLA match genocite really rescued him at that point in time. However thank you very much for your comments about leukemia. Let’s go to our second case which is another CML blast crisis and leia. Sorry to stop you but we’ll go back to to Ragu for Ragu’s second case first and then we’ll come to you. So, we’ll do the cases alternately, but um as uh as Ragu gets his slides back up, Mari, would you like a closing comment on Meen’s extremely difficult and rather sad case? I I mean, I I I I think you did absolutely everything you could and unfortunately CML can still be fatal in some patients. And I I I think a lot of our colleagues don’t realize that anymore. And and I think this is just a salary tale that CML can still carry a poor prognosis and it’s really important to do the marrow to get the blast percentage to make sure there’s no additional cytogenetic abnormalities and properly work up these patients because you knew from an early stage that he was high risk because you’d done that maro and you started him on a frontline second generation TKI so you’d done everything you could. So I I I think he was a very hopeless case. Thank you very much. Thank you very much for that discussion. Excellent discussion. Rago, would you like to I I hope you can see the second set of slides. Uh this is a 70 year old gentleman uh who had a long history of type 2 diabetes for about 40 years. In 2021 he was diagnosed to have CML in chronic phase. Uh and at this presentation he had a grade three diarrhea and melina. Um so at at this presentation these are the investigations. His hemoglobin is 8.3 g. Uh the total WBC count is a lakh 89,480 and the platelet count is 36,000. And of course as I told you he had a diarrhea and melina. So he had prenal esotmia ura was 92 creatin was 3 mg but the electrolytes and liver function tests were fortunately normal. Uh we did a kynise domain mutation it was negative. The bcrable rtpcr was 30%. The bone marrow this time was still in chronic phase. there were no cytogenic abnormalities on routine cytogenetics. Uh let’s go back a little bit into his treatment history. He was initially on imagat for 400 mg daily for 2 years. He had very frequent thrombocytoenia and the luccoytosis never actually came down. So he still maintained a count over 10,000 to very occasionally uh reaching 20,000 and above. So it was abandoned after two years. He was then changed to desatonyip although there was no mutation. Uh and he was given 50 mgs of desatinip. Again there was no response. the same uh thrombocytoenia luccoytosis persisted and there was no remission in the BCR able at all and he was then changed to basotinip 400 mg daily and after he started 400 mg of basotip he presented to us with diarrhea and an acute renal failure for his diabetes of course he was on glimiperide plus metformin metformin three times a day and gliporide in the morning along with breakfast and of course he was taking basatinip just two weeks prior to his coming here. So when he came here we held the basatonyip because of the mean renal failure. Uh but fortunately for us we hydrated him and quickly brought him under the acute renal failure under control and he could we could recover the entire renal function back to normal. So the dilemma is he has a failure to at least three t at least two TKI should say. We haven’t given batony for quite some uh good length of time except for two weeks. He continues to be in chronic phase. There is drug intolerance at every occasion. Uh there is no positivity and we would like to know what would be the appropriate drug. Now thank you very much Rago. Another very complicated case beautifully presented. Mari, would you like to open? Yeah, sure. So, this is quite a common occurrence unfortunately that we get patients with multiple intolerances. He so so just for me to to fully understand he didn’t respond to the amatib and that he didn’t go into complete hematological remission is is correct. He he always stayed in chronic phase. The count was absolutely never below 10,000 at any time and we did not dare to increase it to 600 and 800 mgs of imagat because of the thrombocytoenia. So essentially the total WBC count never returned to normal and the platelet count always stayed low. That was the major problem for us. Okay. And now is his platelet count still low? Yes, the spirit count platelet count is uh quite low. Uh so uh it is just about 36,000 now. Okay. So um we in order to avoid the diarrhea with the butinib we always automatically start anyone that’s getting butinib on um leeramide at the same time. Um, and in patients that are frail or or have known renal impairment, we might start at 300 or even 200 milligrams. Okay. Um, once a day um and then gradually build the dose up if we can over a period of a few months. I I think in terms of other TKI the data in view of his platelet count I think is challenging and and if he if his platelet count was 3 36,000 on or or that level with 50 milligrams and he wasn’t responding um I’m not sure that going down to 20 milligrams and then trying to build the dose up would help although that might be better in terms of his renal function I wouldn’t give a lot of in view of his diabetes um penatinib I wouldn’t give again in view of his diabetes and and his cytoineas. So I I might rechallenge with a low dose of butinib with umamite and advising the patient to drink you know so try and drink two liters a day um and see where he goes from there. I think if he’s not responding um and you don’t have access to a sim I think I think that becomes more um a is phenomenally expensive uh even under a patient assistance program um but I think it’s not available for uh in the public health system I work in the public health system uh so we do have uh I mean nilotinip Datanip and Bosatinip now available but we have not yet gotanib into the public health system so it will still be very expensive. I I I personally would try and optimize his dose of maybe starting or even if you maybe need to give him some EPO if his hemoglobin goes low um GCSF if his white cell count goes low I know it doesn’t help as much keeping up hemoglobin with transfusion and giving GCSF is not a problem for us okay we can we add any anything to keep up the platelet count like how we do with some of the breast cancer um giving elrombop. Yeah. So there there’s a couple of I’ve never done it, but there are a couple of case reports of people giving elrombop to support platelets in patients with CML, but it’s not something that I’ve done. Can we give romlastin? Yeah, that I think maybe it was elro or romy plast. Yeah. Yes, it’s worth considering if if you are able to do that. Yeah, both are in the public health system. So, yeah, I thought we we can give that and try maintaining a lower dose of basatanip. I will try that next. Professor Marin, what would you what would you do if this was your patient? Thank you very much, Professor Ragu for another very interesting case uh more than 70 years of age. So u I agree with the continuation of burgenib at lower dose. However, increasing plated count would not be um my objective in this particular case. I have never seen anybody bleeding with a plated count of more than 30,000. U and of course as professor lagu has said uh eltomopac and plastin both are expensive medications. So if this uh gentleman at 70 years of age is continuing with the low levels of PCR BCR ABL with low dos of TKI that’s fine we are not uh hitting transplant in any way. Arlene I finally managed to get in Jeff welcome welcome brother Lipton. Thank you. I’m having a lot of trouble this morning. That’s okay. We’re glad that you’re okay and you’re with us. You are always such a wonderful contributor and very timely. So, we were worried about um uh what might have what might have happened to you. So, welcome. My link disappeared. It disappeared. Didn’t know what happened. Okay. Glad to see your video as well, professor. It’s nice to have you here. Um so, we have just been discussing um Dr. Rago’s second case um which of course unfortunately you haven’t seen um but you are now part of the group. Welcome. Um okay just close off perhaps uh with Dr. Ragu’s case and uh um but we’re just sort of in the middle of doing that but it’s very nice to see you. Um Mari, might we go back to Mari about this case? So, so I think I think to sum up this it’s an older patient with coorbidities um I I would rechallenge with the lowd dose butinib with um transfusion cytoine support um and and I I think I think for this patient you’re you’re maybe not aiming for major molecular remission you’re aiming to keep the BCRable level around 1% or less if you can and not to add to their other coorbidities. Thank you. Thank you. Just inter interject something here. I think people forget that the literature shows that if you can get at least a two log response or or a 1% response as Mary just commented on the survival is the same as if they had a five log response. So, you know, are you trying are you pushing for TFR? No, I think you need a balance between toxicity and and survival. And I think if as said, if you can get with low dose bud even some people respond on 200 and I’ve even had someone 100 milligrams a day, survival is normal. Good. That’s wonderful to hear. Okay. Basaton has just been launched in India by an Indian company. We are a little new to that. Uh so the diarrhea was a little unexpected for us. The main thing with basut nib is the ramping up phenomenon is don’t come up with in with the full dose right away. Start maybe with maybe 100 milligrams a day for three four days and up to 200 and then maybe up to 300. You find you might have a response already by two or 300. May not need to go higher. So that’s some that’s something we’ve learned and actually there’s some literature now on that that hardly anybody uses the full dose and the ramping up phenomenon approach usually eliminates most of the severe diarrhea. Thank you. Thank you. And we make sure all the patients have got leeramide with them when they start. Yeah. With the ramping up most of them don’t even need it. Okay. Okay. Right. Thank you. Thank you very much for your I’ll stop sharing my screen so that uh Brigadier Maharin can present her. Thank you very much Ragu. Yes indeed a very very complicated case and and beautifully presented and what a great discussion and thank you very much Jeff for making yourself known at the very end of that case and still having something very useful to say. Meen can you please get your second case up and I believe that one of your residents will present this case. Yes Dr. Ain yes Dr. Ashin is my registar very brilliant one very hardworking and she’ll present a case so previously we presented the case with leukemia cutis which we could not rescue and professor Lipton also knows that case because he has already given opinion on ICMLF forum professor Mari also knows because she has also given the opinion as we shared previously. So this is a case of CML um transformed into my plus crisis with leukemia which we could whom we could rescue. So over to Dr. Ashin Jagat. Ashin can kindly start. Welcome Dr. Ashin. Good evening. I’m Dr. Ashin Yagat register clinical hematology from Pakistan. I’ll be presenting a case of a 29 years old male with no previous comorbid. He presented to a local hospital in April 2024 with the complaints of shortness of breath on exertion for 2 weeks. The systemic examination revealed a massive spleen. For initial assessment, we found out that he found out that there is a deposytosis with homocytoenia and ania. After initial supportive management with the RCC’s transfusion, he was referred to a tertiary care hospital. In the tertiary care hospital he was again found that there is alcohocytosis along with the anemia anthropocytoenia with a suspicion of leukemia. He was given a TLS profiles and advisor bone marrow examination. His first bone marrow examination from the same hospital revealed a primary micro fibrosis. However, there were certain descriptions mentioned that he has a 12 to 15% loss in the spirate. There’s a grade two to three fibrosis and the suspicion of transformation to acute leukemia was inquiry. So keeping in view a suspected my productative neoplasm he was advised a PCR further nutritional analysis which was unremarkable including the BCR ABL rearrangement. However the cytogenetics reveal a complex schedule that is 48xy along with a deletion of seven tricom 8 triom 17 and transportation 922. It was started on a first generation TTI that is MIT report referred to our hospital. It presented to our institute in May 2024 with a complaints of easy fitability and shortness of breath for the last 1 month. But however, there’s a additional nodular rash on the trunk for the last 15 days which was noted. The sparse medical surgical android history was unremarkable. On examination, there was aus noted rash over the trunk which was likely a leukemia disk. This is the picture. An abomin examination revealed a 20 cm per below the left costal motion. Respirator as smear showed that WBC comp was 9.2 hemoglobin was 9.2 g per decilator but the comp was 128. There was a mark basopia which was about 15% on this smear. With the provisional diagnosis of chronic myoid leukemia, he was advised a further work up. The bone myster was diluted. There was a good length refine biopsy with the EPS architecture due to increased fibroastic activity. But the retoline has been showed my uh show the fibrosis of grade three. The CD34 highlights the occasional blood cells. The immune phenotyping revealed 3 to 6% of the total population that contains the CD13, CD33, CD117, HADR, NPO and CD45 positive myite cells. The fish for BCR ABL rearrangement was detected in 30% of cell but the fish for deletion 17B was negative. The skin biopsy reate myoid saroma. So he was made a diagnosis that he has a chronic myite leukemia in blast crisis with a complex stereotype and extra medularary involvement in the form of the leukemia tutus. For the induction chemotherapy we have given the two cycles of disablex and politenate along with the antimicrobial prophylaxis. His disease was reassessed after the two cycles of the induction chemotherapy and we found out that on the clinical assessment there was no skin leion and the screen size regress and there was only 3 to 4 cm of pulpable below the left horse. The morphological assessment now showed that the basops are present only to 2% in the sphere. The aspirate was still diluted while the CD34 highlights only the endothelial lining cells. There was normal fish study with no evidence of VCR ABL rearrangement. But the white screen showed no evidence of malignancy or marrow uptake. For the consolidation, we obtained the allergenic stem side transplant as he has a fully HLA massing donor available. For the to bridge the transplant period, we have given another cycle of the TCA vintolex. On 12th of November, this patient underwent allergenic cell transplant with a fully HLA match brother with no AO mismatch. We have given a mileative conditioning regimen that contain the blue sulfide cyclloposomite and ATG. A total stem cell dose of 2.21 into 10^ 6 per kg was infused. But the cycllosporine and methite was given in a GBHD profile access. His post-rplant period was complicated only with a mucositis of grade two. He achieved neutrfilic and plated engraftment on day plus 15 and day plus 17 respectively and after that he got discharged. On day plus 30 we assessed the drop function that revealed a complete donor chimeism in B blood NCD3 but there was no BCR ADL rearrangement was detected on the fisher study on day plus 44 when he was on cycllosporine 150 mg BD and and on the count recovery we have started the ponit 15 and god he got cmd reactivation for which we have started a wan cyclloware on day plus 83 the wan cyclloware was a stop with the two consecutive negative CMV PCRs for the cycllosphorine and ponet was continued. However, on day plus 90 while assessing his graph function we found out that he has a mixed donarism that is in the mood marrow it was 89% CD3 was 81% and CD15 was 84%. Keeping with this presentation, we have started the ting of the cyclosphorine while the conne was increased from 15 mg to 45 mg od and we planned DI on day plus 91. He was given the first dose of DI with the 5.5 into 10^ 7 per kg. His CSA at that time was gradually tapered for net and he has a stable blood counts. On day plus 134 the again the grow function was assessed that reveal a complete donor chimeism in the whole blood. However there was a mixed donor chimeism still present in CD30 in CD3. At that time this patient was on the cycllosporine 25 mgbd while the same dose of was continued and has a stable count. Keeping in view the graph uh function we have given the second dose of the DI in form of 1.1 into 10^ 7 per kg dose on day plus 155 and we obate the cyclloscorine to enhance the GVL effect. On day plus 186 his he was on with a stable count. On day plus 195 again the draw function was assessed. There was a complete donor cardism in CD3 and CD5. This patient has recently lost followup visit in outpatient department on day plus 223. He is clinically improved. He has a stable count and he is only on 45 and g. That’s all for me. Thank you. Thank you very much Dr. Afen. Um Maren, would you like to quickly summarize the key issues and questions around this case and then we’ll we’ll move on to Jeff for first comments. Thank you very much Dr. Ashind for very nice case presentation. This young guy 30 years old male from a small town 300 km away from um Islamabad that is the capital came to us. So first point I want to highlight for the residents is diagnostic dilemma. So it’s not always um PCR BCR ABN positive where sometimes we have cryptic transllocations which could not be picked by PCR and this was fish which was positive and cytogenetics revealed 922 along with complex kotype and finally we reached at a conclusive diagnosis of CML in AML CML transformed into millet plus rises. So for this we gave as you saw hypothetic agent with ventolac that is BCL2 inhibitor along with poninate. It worked very well. The patient was brought into CR and fully agility match donor transplant was done. After transplant we faced um the challenge of uh mixed donorism which was solved by DLI and escalating two were given and the patient is uh feeling very well in himself. He has joined his office. He’s enjoying his children and uh he is on ponatin 45 migram daily and we plan to continue it for two years. So uh my question from professor Lipton is um for induction of CML transformed into AML would you prefer hypomathating agent monitol and ponatinip or would you directly go to da that is D37 and second question is uh would you like to give the third DLI when the chimeism is complete or would you stop there as we did thank you professor great questions I think the first thing I want comment is on is something you mentioned earlier which I think is really important and that is doing cytogenetics and molecular. I think a lot of part of the world particularly the western world has now gone to CML diagnosed on a molecular no one ever does cytogenetics and there are cases like you have shown that that are extremely important also suppose this person had been diagnosed in chronic phase and did well then lost response and then you did the cytogenetics and showed what you showed here was this here at diagnosis or did this occur on therapy and that makes a big difference. So I’m a big believer you must do cytogenetics. Also the fibrosis was there. You must do a bone marrow because you’re never going to detect fibrosis without it. And in fact in a lot of cases when people don’t recover blood counts when you initiate a tyrin kynise. One of the first things you should be doing is doing a repeat marrow to show that it’s not fibrodic and that is the reason. So you made some great points there. In terms of induction regimen, you know, I’m not sure that anybody has randomized the study to show anything different. I think what’s really important is to use the third generation TKI right up front, which you did. I think that’s really an issue. Uh I noticed in a previous case maybe you misdussed that Nott was used in blast crisis and you know Novartis never sought approval in most places for blast crisis for for so that’s but so panatib is definitely the way to go. Now, here’s where I think I would do everything you did. I would agree completely. Here’s where I differ. What is the most important aspect in terms of treating CML with a stem cell transplant? It’s not the dose intensity, it’s the graph versus leukemia. In fact, there is now some literature out there which has compared reduced intensity transplants to full malablative and shown no difference in outcome when the patients are the same. What I would have done with this individual would have probably have started tapering a cycles born by about 6 to 8 weeks and in the absence of GVH I would have had him off cycles born completely by 3 months. that may have also helped with your uh mixed chimeraism issues because what are you doing with DLI? Exactly the same thing as you would be doing by reducing the cycllospor. So one of the things you did is you kept them on cycllospor and g gave di and these are really competing events. I I would normally not give someone DI until they were off cycllospor. So in this gentleman I would have probably tried to get him off the suspens or still having issues with mixed chimyism. Then I would come in with DI. The DI would do two things in this case. Help with your mixed chimeis but also helped with an anti- leukemia effect because it may generate some do some donor some graph versus leukemia. So I think there are those issues in terms of coming in postransplant with your ponet bree completely. I think the literature isn’t out yet on how long to continue the panic and that’s really very interesting. It’s really controversial and I know with Philadelphia positive alll people are now talking about truncating punat at about two to three years. I’m not sure with blast crisis CML there’s any literature to suggest it and I probably would continue panat indefinitely on this individual and I think you could probably go with 15 milligrams daily. So I think the big issue is I think get the graph versus leukemia effect and the way you do that is get off immunosuppression. So that I think needs to be done promptly in the absence of GBH. Thank you so much Jeff. We’ll move on to Can I ask you a small question? What is the uh role of the other cytogenic abnormalities in this? Do they have any bearing or no bearing whatsoever? Additional chromosome abnormality well only doesn’t matter doesn’t matter at all. I don’t think it matters. They’re typically associated with blast crisises always generates additional chromosome abnormalities. So they may very well have been that this this gentleman missed the whole chronic phase was moving into blast crisis and had already developed these additional chromosome abnormalities. In fact new chromosome abnormalities are really a hallmark very often of what we used to call acceleration which has now disappeared. Continue monitoring them professor Lipton. No no no I think you monitor BCO that’s all you need to monitor. I think if there shows any sign however that response is being lost he becomes cytoenic or you start showing some funny differential I would repeat cytogenetics again totally looking for those things but otherwise I think your your primary marker is going to be buriable as I think you are doing. Thank you very much professor Leptton for your very very valuable comments. Yes, we should have started psychosporing tapering earlier. In our institute, the policy is to start tapering at 90 days which we are thinking to shrink to uh 8 weeks and by day 120 the patients are of imunosuppression. Uh how yeah so that’s why I completely agree with GBL effect and I think that’s patient driven. I think if you got a really high-risisk patient, I would get them off earlier. And there actually is some literature which has compared the CML relapse in cyclpornne that’s been tapered after 6 months and seclus tapered before 3 months and the relapse rate definitely goes up with a late taper. Yeah. And uh a very important question which you already mentioned uh taking punatin for two years postrplant at the dose of 45 migram it’s very hard for the patients. So with your advice I will start uh reducing ponatanib to 30 migram and then 15 migram t but I will give for two years in this gentleman. No no no minimum of two years. Yeah, minimum. As I said with blast crisis, I don’t think we know how long, but I think there’s now evidence that’s come out, at least in chronic phase disease, that if you get a good deep response, Yeah. you know, by tapering down to 15, tapering down to 15 is well, fish, remember, is only a 1% sensitivity. So, you know, if you can do moleculars, you you’re probably better off. I I I definitely think that uh that’s the way to do it. So inviting Mari into the conversation. Um and I’ll draw attention to a question from Asma Nasia saying good evening everyone. My question is as routine cytogenetics can miss some cryptic mutations. Should we advise fish testing on all the patients of CML? So taking that question with you and inviting your response Mari. Okay. Thank thanks Arlene. So in in answer to the question I we would do fish if we had if if we had a negative qualitative BCR able result and if cytogenetics failed we would try to do fish but we wouldn’t always do fish if we’d got a positive result from either qualitative BCR able or cytogenetics but we would always do the cytogenetics to look for additional cytogenetic abnormalities. In terms of the last case, I I think it’s is a really nice case to finish on because it’s got a positive outcome. Um I I think we we have a we we tend to start tapering the cycllospor around day 60 so that patients are off cyclist born by day 100 and we try to restart TKI around day 45 to cover the but it’s not always possible because patients might still be cytoenic they might have abnormal liver function so we probably only manage that in about half of the patients I think with panatinib in particular particular after transplant especially maybe a TBI based transplant we’re really concerned about accelerated cardiovascular disease with a 45 milligram dose of penatinib so we would monitor the BCR aable level and for patients where it’s less than 1% we would reduce the dose to 30 milligrams and MMR to 15 milligrams and um I I think how long you continue for it is very difficult. So I have a patient at the moment where I’m probably never going to stop it and he’s on 15 milligrams on alternate days because he had a T315i mutated blast phase which occurred on treatment and I’m too scared to stop. But he’s completely he’s back at work. He works full-time. He’s very well, but I’m very conscious of his cardiovascular risk. And there’s other patients that have had to stop after a couple of years because of chronic side effects, even at the 15 milligram dose. But I would try and keep it going for at least three years if I could post transplant and some patients indefinitely. Yeah, you see the first thing we the first thing we’re all doing is taking our own pulses here because we don’t know what to do. So what Mary has said I can completely I think Mary brought up an interesting point is the role of fish. Fish does not replace cytogenetics. Fish is a molecular test for the one probe that you’re using. So if you’re using BCR able it would miss everything else. So unless you’re using a whole spectrum of things you’re not going to pick it up with fish. I think the bone marrow on the molecular tested diagnosis are important because as this case showed you have a sigenetic test with negative molecular it’s probably not negative molecular probably has unusual break points which occur in about 5% of patients and unless you use patient specific primers you won’t pick this up the commercial kits will not pick it up on the other hand you also get cryptic cytogenetic abnormalities studies. So that if you have people with normal cytogenetics apparently but molecularly positive but VCR able they’re about 5%. So this is why you do both. Now where does fish have a role? Fish may have a role in a case where you don’t have a molecular. So you follow it by fish. But remember when molecular depending on your assay, you’re looking at MR4, MR5 or something like that. It’s sensitivity. Fish is only MR2. So I’ve had patients like this. It’s the best you can do because I lab wouldn’t make patient specific primers, but that’s all you can do. But it is remembered any not anywhere near as sensitive as doing the molecular. So I think Mary said made some really great points there. Do them both and follow with what you can but remembers things like sensitivity. And another point I would humbly like to add is that whoever has cryptic transllocation is not a candidate for TFR. So uh patients with cryptic transllocation which cannot be picked by PCR BCR ABL which is the quickest test so they don’t are not the candidates for TAR. So I completely I agree. Yeah. And remember as well the whole thing I think the Italian group and the German group had some great data on this. Remember there are patients at diagnosis who present with additional chromosome abnormalities high and low risk and they do respond to treatment just as well as the ones who don’t but maybe the dur durability of the revision isn’t as good. So that’s another reason to look is because if you find someone with an additional chromosome abnormality you may want to watch them a little more closely. So if you’ve got someone who has a great response who you normally would be monitoring every six months, someone like that I may monitor every three months but remember that does occur in about 10 to 15% of patients. There are additional chromosome abnormalities at diagnosis. Ragu you asked some interesting questions earlier but would you like to give us your broader thoughts and views on this case and the matters discussed around it? Uh phenomenally helpful learning points from all of you. Uh looked like a very difficult case to treat but uh yeah uh I do agree about this uh uh early withdrawal of cycllosporin. Uh I I still remember doing that in the earlier days but sometimes the GBHD can be overwhelming. uh so most uh Indian physicians tend to give it a bit longer than uh what professor Lipton has voiced uh something like what Brigadier Maharin has said uh to up to 100 days and then start tapering. Yes, I know that that is what that we have been doing. uh but I will keep this in mind and see if that is possible to withdraw it earlier if you are getting a kimeism earlier. So that seems to be a very good point. Uh I did understand that there is uh we are defeating the purpose of uh holding on to a full dose of cycllosporing and then giving DLI. So one seems to defeat the other’s uh role at at the same time. So possibly the best way to go about doing that is lower your dose and then get a GVA graph versus leukemia effect and then see if there is still a crop up of uh the chimeism try the DNI. So that’s a very good learning point for me. Thank you Meen. Thank you very much. I would like to thank um ICMLF and especially professor Lipton, professor Mari, professor Ragu um and Ardin for such a fruitful discussion uh especially for our resident junior consultant and for ourselves. So every day is learning and uh we should never stop learning. So it was a wonderful discussion and I hope to continue such discussions in the future as well. Thank you very much. Thank you very much to our presenters. Uh Jeff and Mari, would you like to have some closing comments? Well, again, my apologies for not being able to log on right away. I don’t know what happened. But no, as usual, some some really great cases and some wonderful learning points just on that second case without even knowing what went on the following. So, I think it’s really important to to learn some of the things. Don’t don’t do things that may be conflicting and don’t take shortcuts as some people are tending to do and because I think this is a case which not taking the shortcut led to you due to your diagnosis and just to add to that I think it’s been four really interesting cases and and I think as well they really highlight the importance which you you did of of fully investigating the patients at the start and having all the information such is the cytogenetics and the bare and knowing the coorbidities. So I I think that’s really important so that you can risk stratify the patient from the start but they were they were great cases. So thank you very much. Rago would you like a last comment? Um wonderful discussion uh lots of learning from everybody who participated especially from Brigadier Maharin for me and professor Copeland and professor Lipton of course I’ve I’ve heard professor Lipton from 1992 uh when I spent my first uh I mean ASCO there with uh in the transplant unit there for in 1993 in 1992. Yes, I was there in Princess Margaret. So you have changed quite a lot but yes I think you have voiced more in the past. You used to be quite silent if I remember right in the clinical meetings but now I can hear him very well very often in our ICMLF meetings. Wonderful. Then no one’s ever accused me of being too silent. I did not know about that pre-existing relationship and I find that so hard to believe if you allow I would like to uh encourage our youngsters as well. Um as professor rau has mentioned profess dratasum who picked up cases for professor ragu busy hod’s have very less time to pick the cases and by registars Dr. Fahim and Dr. Rakshin Lyakut uh it’s uh 8:10 p.m. in Pakistan. Uh and they are supposed to be in the hospital at 700 a.m. So it’s 13 hours on the campus. So we would uh like to encourage uh all the registars for more uh learning and birds of wisdom professor people like professor Lipton are here professor Mari is here so that they should uh get as much knowledge about uh CML as they remember we’re not just here the email is great you know unless you want an instant answer you can always email questions and I I’ll be happy to get back to you with comments so you know you You don’t have to wait for a special occasion in order to do that. I think it’s I do that, you know, I have my go-to people around the world when something is strange to me because no one knows everything. Yeah, no one knows everything. Absolutely. And that’s a wonderful note to finish on and that’s where the International CML Foundation um takes much of its it it being. We are incredibly well connected as you can see. any questions, any issues, any difficult cases, if you don’t have direct connections to Professor Mari or or or or Dr. Jeff, please come to me through the ICMLF and I will make sure that we get a response to your case. Um, I’d like to thank all of our excellent experts tonight. Um, Maria Copland, Marine Ali Khan, Jeff Lipton, Raga Digga Marty, our guest presenters, and to you the audience. Clearly, there have been some technical problems tonight um that Jeff has encountered in getting on. Um I’ve stepped into the hot seat. I was not meant to be our moderator tonight, but it’s been an absolute pleasure to be here. But um Dr. Chararmmo hasn’t been able to join us. I hope he’s okay. Um yes, I think we’ve had some some technical issues, but a fantastic conversation. And of course, even for those who have um been unable to join us live in person, we will share a link to the recording of this conversation. We will follow up with some post- discussion materials. Thank you very much to our experts. Thank you to you, the audience. Um, I hope you’ve enjoyed the conversation as much as I