Managing Malignant Hematological Disorders and Role of HSCT
Dr. Manas Kalra
So, good evening everybody and welcome to the video. I am a dear, unconscious, sonara hospital and I will be talking about health, magic and dignity at the logical importance of health. In the book, doing a matter of extent, self-help, health, health, health, health, health, health and health, health, health, health, health, health, health, health, health, health, health and all that. What are the types, what is its role, what are the indications and even pediatric practice, how many we use this morality as treatment for children with blood cancers. So, this is the disclaimer. The discussion is meant for physicians to discuss updates on managing malignant and matological disorders. It is mainly for education purpose. So, Sennofi is not responsible for this and this is the basic disclaimer that Sennofi has projected. The matological malignancies are classified based on, you know, where they are into the region of occurrence. So, if they develop in the bone marrow, it leads to myeloprolifritium malignancies, which are for the other classes, right, by the WHO and the CAAP system. If it happens in the lymphatic system, then it leads to lymphoprolifritium malignancies like lymphomas. So, you have leukemias, which are originating in the bone marrow. You have lymphomas, which happen in the lymphoprolifritium system. You may have multiple malomas, which I don't treat because I am a pediatric oncologist. It happens in adults and then you have myelodysplastic syndromes. Again, you know, usually the origin is in the marrow. So, how do you diagnose this condition? The basic test is a complete blood count. We always ask for a peripheral smear. Your CBC and peripheral smear may show anemia. May show thrombocytopenia. It may show leukopenia or may show leukocytosis. If there is too much of a leukocytosis with abnormal cells, the diagnosis becomes obvious from the peripheral blood film because you can see the blasts in the pet field blood. But if there is leukopenia with anemia with thrombocytopenia, often you make the diagnosis from the bone marrow because the blasts have still not come outside into the marrow and you are just developing the signs of pan-cyto-pemia. If the CBC is perfectly okay, but you find lymph nodes, then often the diagnosis is made from a lymph node biopsy. Once you find that the bone marrow has got leukemic cells based on your morphological examination, then you further subject this bone marrow sample to immunofino-phenotyping of low cytometry to find out what are the markers on these abnormal cells. The relymphoid markers, myeloid markers and you are able to differentiate between them. Then you do further testing, you do cytogenetics by doing the chromosome examination, you may do a fish study, fluorescence in C2 hybridization. There are you know options of doing a PCR, but it is less preferred as compared to fish study and nowadays you also have access to next generation sequencing and you try to identify the markers, the typical markers of a particular type of malignancy. The treatment is depends upon the type of malignancy. So you have diseases like CML where only one tablet is enough, take a tyrosine kinase inhibitor because the other spectrum is acute lipoblastic leukemia or acute myeloid leukemia where you have to do aggressive chemotherapy and in some cases you have to do bone marrow or hematopoietic stem cell transplant and nowadays we also have access to immunotherapane these patients. So again it depends on a proper staging, it looks essentially it is there everywhere in the body but you need to have a test, you need to do a lumbar puncture and see if there is leukemia in the brain or the seridose spinal fluid and that kind of completes your staging evaluation. And then based on the type of leukemia you treat these patients. So as I said acute leukemia and chronic leukemia, chronic leukemia will have more of mature leukemic cells whereas acute leukemias mainly will have a lot of immature leukemic cells. Acute leukemias are obviously a big life threatening emergency and you need to start treatment early. One Hodgkin lymphoma, certain types like berkit, lymphoma, they are also medical emergency, chronic myeloid leukemia, you know again by the time we diagnose them in India the disease burden is quite high but generally they are not very life threatening at the time we diagnose sometimes they also can present with very serious complications. So that means the leukemia was still there so by doing a consolidation you are trying to bring that leukemia level even further down. Okay and then you have brought that leukemia down or ALL generally we give them high dose methotrexate blocks, we give them a reintroduction, re-consolidation and then put them on a two-year maintenance therapy. In AML generally we give a couple of cycles of chemotherapy. Once the remission is induced we give them further two to three cycles of chemotherapy and in some cases we take them up for transplant especially the high-risk ones or the intermediate risk ones where we get a good matched donor and the MRD was a little high and we feel that the chance of relaps in these patients is. So in all these cases our goal is that you know we avoid that risk of we bring down the risk of relapse and we want to take the patients up for transplant once they are actually MRD negative that is their minimal residual disease is negative. So the first stage as we said is remission induction where we are trying to eliminate the malignant cells from the marrow. This is given over four to five weeks generally it is a combination of drugs, never a single drug, neither in ALL nor in AML, it usually combination drugs. The outcome is that you know if by the end of this four or five weeks if your marrow is in shows very less amount of leukemia that means you are happy and your leukemia is under control. Consolidation is to prevent the disease recurrence after revision is achieved and to eliminate any malignant cell that may be there. You know most of the time it is there so we want to remove those cells as I said sometimes transplant is used as a consolidation tree. Maintenance why because you know you have achieved a good remission you have brought down the leukemia cells further. Now you want to sustain this remission for as long as possible and usually in ALL we give this maintenance for a period of two years. AML the role of maintenance is not very much there some of the newer drugs are being tried. A lot of studies have been done but clearly the role of maintenance has not been established in AML. You know in ALL we give them low dose chemo therapy which is not very toxic and we try to bring down the leukemia level by giving that. So we now talk a little bit about the anti cancer drugs from basic things. So anti cancer drugs they are classified into cycle or phase specific drugs. So there are certain cell cycle specific drugs and cell cycle non specific drugs. They have the biochemical mechanism of anti cancer action and then the chemical structure also needs to be looked at. They also help us to classify. There is a G2 cycle G2 phase then there are some drugs which attack the G2 phase like gliomycin, topoisomerase in the because M phase may be in chylcholoid, taxia in the G1 phase you know LS parage in his work which actually is an enzyme and then there are anti metabolite you know which act on the synthetic phase which is the S phase. Non specific drugs which you know kill drugs that all the phases are like alkalating agents, platinum compounds like cisplatin, carboplatin, anti tumor antibiotics like donor rubis and doctor rubis and things like that. Then drugs based on biochemical mechanism and based on biochemical action. So sometimes they block the DNA RNA spires and this is like methotrigsate, mercaptopurin you they are usually used in the maintenance phase okay and then some are inhibit reaction to the DNA replication like gliomycin, cisplatin, cyclophosphamide interfering with the transcription where they block the RNA synthesis again anti cancer antibiotics comes there and where they are inhibit the proteins synthesis and function, vancent and taxins come in that area. You know some of them affect the hormone of the cyst which are not very commonly used in children but the moxepane, flutamide are used in this. Based on the chemical structure alkalating agents like cyclophosphamide, bethyl amyl, bucal plan, thiotipa okay they are alkalating agents. Anti metabolites like methotrigsate is an anti metabolite. Microprotubule inhibitors, vancalculoids, taxins come in that topo isomerase inhibitor, anti topo site comes there, antibiotics, dorno, toxoblyomycin, hormonal agents as we just you know highlighted these are the hormonal agents. So let's come to the hematopoietic stem cell transplant for major management disorders. So what is hematopoietic stem cell transplant? So intra penis infusion of autologous stem cells or allogenic stem cells collected from bone marrow or peripheral blood or umbilical cord blood is basically hematopoietic stem cell transplant. It re-established the hematopoietic function in patients with damaged or defective bone marrow or immune system and it has put potentially curative action for a wide variety of diseases. So the first successful transplant was done in 1959 with the Nobel Prize was given for Donald Thomas and Joseph G. Moore 50 to 60 thousand transplants are performed worldwide and number of countries you know it is increasing by 10 to 20 percent each year more than 20 thousand have survived for more than five years after getting a transplant. Transplant types are either it is an autologous transplant where you take your own cells, save those stem cells, give big dose of chemotherapy and because that big dose of chemotherapy will damage your bone marrow also then you will give them this stem cell so that the bone marrow recovery happens. This is called autologous stem cell. Allogenic stem cell is done from some other person so a brother, sister, some unrelated donor or your donor who is not a fully matched so like a father or a mother who is not a fully matched person or it can be from a medical stem cell which had been stored by the from the sibling okay. So these are the types of transplant that you can do. Now what are the indications of autologous transplant? In pediatric age group the commonest indications for autologous transplants are neuroblastomas or lymphomas okay. So neurostage for neuroblastoma relapse or refractory hot skin lymphoma sometimes non hot skin lymphoma, even sarcoma you know these are the conditions where you can do. Hido schemeotherapy autologous stem cell has also been tried for medioloblastoma especially the infant medioloblastomas and there is some upcoming indications for autoimmune diseases not routinely used for common autoimmune problems. Under the indications of allogenic stem cell transplant. So malignant disorders like AML is a very important indication high risk ALL again you know you want to do a transplant so not for all pH positive ALL but you know sometimes if they have relapse so this is an older indication that has been highlighted in this presentation pH positive ALL you know normally we manage them with TKI and ALL therapy but some of the pH positive ALL we try tyrosine kinase in it but else okay. Then the other thing is obviously a relapse or refractory ALL or AML some CML cases which are not responding to TKI you may have to do but there are a host lot of newer TKI where we don't want to do a transplant JMML condition you know juvenile myelomoneotypic leukemia myelodysplastic syndromes we would consider a dual finger transplant very strongly in these expressions. The other indication since for allogenic transplant are inherited metabolic disorders like you know Harler syndrome adrenal eukodystrophy osteopetrosis inherited in bond immune disorders like skid you know see where congenital immune deficiency this got a direct syndrome you would think of doing transplant. So, in the cell disorders hemolytic anemia like sickle cell anemia and thalassemia major you know homozygous sickle or thalassemia major you would consider doing a stem cell transplant especially if you have a matched donor and then marofhelia states where your bone marrow stops producing blood like aplastic anemia inherited bone marrow failure syndromes like tyancone anemia, schwam and diamond syndrome see their congenitinuteropenia that is not responding to GCSEB, discaratosis congenita you may think of doing a stem cell transplant then how will you identify the source what kind of a source you would use you could either use the bone marrow from the donor you could use a PBSE that is you can drive the stem cells into the blood and then use them or you can use umbilical cord for a transplant so conventionally all the transplants were done through the bone marrow it is you know a good way of using the stem cells because the chances of graft-versus-host disease is also less the chance of other side effects of transplant are also less with this but again you know the donor has to undergo an anesthesia we have to get the stem cells from the donor so that that can be a bit of an hurdle especially in the mud transplants where you know you are using an unrelated donor often the donors are not willing to give their bone marrow donation but they are happy to give a peripheral blood stem cell donation where we give GCSEB to the patient and you know you can get the stem cells out through the peripheral blood this is a more popular way of getting stem cells there is easier collection of cells more rapid recovery decrease cost because you don't have the theatre costs in this and we can also use this method in certain instances of allogenic transplant in pediatric patients so you know often for our children also we use PBSE as the graft now as far as umbilical cord stem cells are concerned the issue is that you know they are usually associated with delayed end graft and poor chances of infection viral infection can be poor however a little bit of HLA disparity is still acceptable in a medical cord stem cells so it comes with certain advantages and disadvantages but overall with the haploidical transplant coming up the usage of cord blood transplant is going down by the best donor is usually a challenge in mass brother or a sister and as I said only 25-30% cases there can be a chance major obstacle in treatment of patients who benefit from an allogenic transplant is the identification of a donor and that we have to be very careful with the haploid and the haploidical transplant the soft sticker is coming down are a good way as I said that you know in certain communities there is so much of motivation to be a bone marrow donor and you know the campaigning is so good the colleges and you know armies and all these people are very sensitized so a lot of young people you know want to hear themselves to be donors and you know in Caucasian population it's very good chance that you'll find a donor for a patient who needs a transplant but in India you know we still have very less mud donors available and you know this becomes a hurdle that is why the haploid and the clinical donation has become more popular so the condition phase usually lasts for like you know from 5 to 10 days you give intensive treatment chemotherapy radiotherapy you know a suppressive agent and you want that you know that it should have an anti-leukimic effect or the cure techniques basic of a arrow for the stem cells to come and start working the type of conditioning regimen in allogenic is either a myeloblative or a non-myeloblative a conditioning myeloblative is where you know you give that strong chemotherapy or radio therapy that the bone marrow will not have the capacity to recover on its own okay so you have to put the grafts now the non-myeloblative it induces a metatoxicity but you know there can be if there is possibility that your bone marrow can still come up on its own okay reduced intensities where the intensity of chemotherapy or radiation should be reduced by at least 30% as compared to a myeloblative regimen and you know the stem cell transport support is again important but then you know here in the reduced rig regimen you are trying to work mainly by the graft versus leukemia effect you know in myeloblative you are trying to just kill that cancer stem cell whereas in the rig regimen you are hoping that there will be a fight between the donor immune system which is the healthy immune system and the recipients leukemia cells and the donor healthy immune system will kill the leukemia that's the intention so as the intensity goes up you know the regimen related toxicity also goes up it does have more anti-tumor effect in it but then it is toxic whereas if you give a lower intensity there is decreased regimen related toxicity but there is a chance that you may not kill the leukemia cells stem cell you know you may or kill may not be that deep and then later rely on a graft versus tumor effect there are various regimens recommended for pediatric ALV generally prefer a TBI based regimen if the child is about three years old for less than three weeks you go with the chemo therapy based conditioning which could be abuse, health and flu deribin based treatment regimen or you may lose a pre-osomal fan flu deribin type of base regimen okay and for above three weeks generally give them TBI and ittochocyte or cyclophosphamide based test regimen to kill the leukemia cells that's how for AML cases we generally use pew flu malphalante these are the common drugs that are used for these patients together leukemia and then we put in the grafts so you can see that these are like the myelobletin regimens with you are using full dose of use and pran cyclophosphamide TBI and you know very intense treatment very and it does come with side effects and you know flu deribin based regimen that generally you know reduced intensity regimen and you can have a reduced toxicity regimen but instead of blue pure self and use trio self and again you know the side effect profile is a little better so once you have given the chemo therapy you have evaluated the marrow you have to give the stem cells that you have collected either from the marrow or from the peds or from the umbilical cord usually over half an hour to one hour you would even fuse these stem cells these stem cells are given just through the peripheral line the pick line or the hickman line whatever line that you have put it to the patient you would inject them and you know it's not really mandatory to give a lot of pre-medication for that the stem cell collection the peripheral blood can be done through these apheresis machines and you know you give the donor some gts of injection whose stem cells are mobilized they come into the blood and from blood you collect them through the apheresis machine because they have got you centrifuge them and based on the density the kind of settle at a particular speed and those stem cells are collected and you can inject those stem cells to the patient bone marrow harvesting is done in OT and you know you anesthetize the patient and then by certain calculations you can calculate the amount of stem cells that you require you may sometimes once you have got the stem cells out you may need to do some manipulation and the manipulation may require a T cell depletion you know if you are using a haploid integral transplant which can be an in vitro or in POT cell depletion you may have to remove certain isoeic putinins or RTCs if it's a major mismatch and then you know you may want to do a CD34 positive selection again in cases of haploid enricle transplants where you want the chance of drop versus whole disease to go down so to reduce the graft was a little bit the cases of haploid enricle transplant you can either do an in vivo or in vitro depletion so in vitro you know you may want to do a T cell depletion or a CD34 positive selection and in vivo you can try both transplant cyclopostomite and then do the transplant there you can see how the stem cells are being infused they just look like a normal blood bag that you are administering and then you know once you've given the stem cell then comes the field of neutropenia where children can have bacterial infection usually you know it's like lasts around 14 days to 21 days and then graftment is generally quicker if you be BSC and slower in cases of bone marrow and even slower when you use a cord blood stem so you need to have a very aggressive neutropenic protocols when you are doing the transplant then the entrapment phase happens when these stem cells start producing blood so you see it every day that the neutrophid count will rise a little bit like a bit and it can take plate at a time for the platelets to go up and then you'd see a steady rise in the neutrophils and then you do not need support from GCSF and the bone marrow is able to produce the new wide cell on its now it is not very see and it sounds a lot of complications can happen and we'll just a little bit talk about those complications so you know a major concern a major concern that is associated with allogenic stem cell transplant is graft versus host disease okay so this graft versus host disease is the fight between the donor T cells and the recipient's body you know these two fights because the recipient says that okay this is not my cell these are not my cells and they kind of mount a fight to parties and this leads to graft versus host disease their cube graft versus host disease is defined as the time period you know is the first hundred days whatever graft versus to go to these features are happening and generally after a hundred days it is called graft chronic graft versus it's not really strict the time points have you know kind of fluid because you can have features suggesting of a cube graft versus host disease even after hundred days so mainly it comes as diarrhea you know jaundice and skin rashes whereas chronic graft versus host disease comes as as clear as klirojama you know you have these skin changes you can have these eye changes you can have problems in the joints you can have fibrosis inside the mouth and you know genital areas so those are you dryness those are the manifestation of chronic graft versus host disease so you know a lot of children and adults develop the acute graft in gbhd and they are actually a very big hurdle that we have to face while doing transplant of these of patients so why does acute graft versus host immunity develop you know because there is actually incompatibility even if you say it's a 12 by 12 measures certain things which are you know not completely matching gender mismatch donor parity you know if the donor is the lady who is multi-para then the chances of graft versus host disease is more okay if you give too much of tpi then this leads to a lot of damage to the host body which leads to a lot of antigen exposure and that can also lead to a graft versus host disease you know you use these gbhd drugs if they are not very effective anti gbhd measures they are prophylaxis and also you can have an advanced lascp and age and you know it is more common with pbsc than with the marrow so as i said you can have all these skin rashes redness blistering palms and soles which you know can be involved and they can be redness and they can be this whole erudymatic macular papillarache which can even lead to a very severe form with bloodstream blistering and peeling which can be skin gbhd your liver symptoms are mainly like you know in the form of a colostatic jaundice normal liver functions and your gi symptoms can be that of upper gi or lower gi abnormality mainly in the form of diarrhea in extreme cases it can be like a bloody diarrhea and it can be like you know horrible protein from your gut and upper gi mainly comes with you know loss of appetite nausea vomiting and you can have cramby abdominal pain so the treatment for a qgbhd mainly comprises of immunosuppression because it's the immune system which is causing a problem so steroids are the drug of choice and you know you may use drugs like you know cyclo sporein which is a profile actic agent mycophinolate mofatil you have all these entelukin receptors and tnf alpha inhibitors and these are drugs for a qgbhd and now we have these jacket nibiters which again work very well like root gbhd management and and chronic gbhd factors again you can have this hl incompatibility prior to qghd advanced age you know bbsc you know certain types of infections can pre-dispore and eat an adequate profile access can lead to a ton of gbhd again you can see that the dryness of the mouth sensitivity to lead cold you can have difficulty opening the mouth you know skin changes and you can skin can be tied itchy change in color and you can have nail changes which are all the manifestations of a chronic gbhd you can have hair symptoms premature loss graying you can have a bit religious patches lung can be affected which can lead to like a chronic lung disease you get the patient can be breathless and may have persistent cough or wheezing you may have gd ity symptoms and you know this also can be seen in patients with chronograph or some muscular skeletal system may be called as male to join stiffness muscle weakness cramps genital symptoms can be there which i know try this which i know signic your formation narrowing you know males can have urethral stricture in changing scarring irritation skin changes and mucosal changes over that area which are on manifestations of chronic gbhd again for treatment of chronic gbhd you may require again you require immunosuppressants so steroids you know mycophane only cyclosporin you may have to use extra corporean photophoresis you may have to give you know ages like you know rooks alternate for a very long time mito trigzid may be used for certain patients and all these agents may help manage in chronic gbhd other problems encounters are like hemorrhagic cystitis where you bleed from your urinary bladder you know again it is the effect of these alkalating agents and the other agents that you you give for the treatment your liver may be damaged where you can have vino occlusive disease okay and then you can have organ toxicity like lung, liver, heart, kidney you may have a idiopathic pneumonia, symptom of your patient may not accept the graft which can be like a graft failure or a graft rejection may happen and gbhd as we talked about becomes the big problem. Atg is one of the drugs that we use for conditioning of these most of these patients sometimes we use it for the treatment of graft versus hose disease this drug is used as a conditioning regimen in reduced intensity myelo ablative allogenic transplants and to prevent the acute and graft versus hose diseases it is used to reduce the risk of late transplant mortality in patients and to improve the quality of life post transplant especially in unrelated donors, apple identical donors now we always use atg sometimes even for math sibling donors you know atg if used in malignant transplant but generally you know those conditions are basically dependent on the type of donor the risk of gbhd and you know these drugs are very helpful in managing and preventing this drastic complication which can have life-threatening effect on patients post transplant so with that i would like to conclude this talk on basics of hematopoietic stem cell transplanted children it's a field which is you know growing very rapidly in the last few years and now more and more children are being transplanted more and more children are being cured and transplant is also becoming safe and safe as we are progressing forwards thank you so much for the patient listening
