tag:blogger.com,1999:blog-94712782024-02-21T01:38:14.452+01:00Niels' views on MDS - Myelodysplastic SyndromesThis blog discuss issues around the blood cancer MDS - Myelodysplastic Syndrome including the role of patient organisations and worldwide umbrella organisations as well as living with MDS during pandemic times from process safety. It was re-purposed to patient safety from process safety.
The primary language of this blog is English but some will be translated to Danish. This is indicted by the word DANISH in the titel.Niels Jensenhttp://www.blogger.com/profile/14071035070040472470noreply@blogger.comBlogger6125tag:blogger.com,1999:blog-9471278.post-60854639490004833032023-02-04T16:49:00.000+01:002023-02-04T16:49:55.465+01:00When will the lab development result in both many new cancer drugs and a Nobel price in medicine and/or chemistry?<p style="text-align: justify;">The honest answer to the question of the title of this post is: We don't know! None the less it is not rare to encounter news stories from universities about exciting discoveries in the lab and their potential to change the way we treat cancer. Since being diagnosed with MDS more than fifteen year ago I have seen such press releases from universities several times a year.</p><p style="text-align: justify;">The latest - I think - was reported on <a href="https://scitechdaily.com/" rel="" target="_blank">SciTechDaily</a> at the end of January. A group of researchers at University of Tokyo's Faculty of Engineering reported success with killing cancer cells of cervical, breast and melanoma. Unfortunately the work is published in J.Am.Chem.Soc., which is behind a paywall, because the news release is not clear about whether this was a petri disc experiment or an experiment in mice. It simply say the cells came from mice. I think this is an important question, since if it was a petri dish experiment the result is further away from a drug, than if it was an experiment in a mouse model.</p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhxacAPvqWMHQ6DM5Rt9AnzWBl3mvfBjRG8U5oHn7LRnrwuWKBLpY9FYMZoYWzwkale1xJaaFlXhKCtgoJOS5ObNnxXmnCoPZmUir6L-97-KvhRazW0eOv_m76Q32PGKA0oAKdKzupcuRMHHBJ5z8MJMc6oTrubMicDrPZQE7ZWgwoebK5xVtc" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="" data-original-height="931" data-original-width="1328" height="224" src="https://blogger.googleusercontent.com/img/a/AVvXsEhxacAPvqWMHQ6DM5Rt9AnzWBl3mvfBjRG8U5oHn7LRnrwuWKBLpY9FYMZoYWzwkale1xJaaFlXhKCtgoJOS5ObNnxXmnCoPZmUir6L-97-KvhRazW0eOv_m76Q32PGKA0oAKdKzupcuRMHHBJ5z8MJMc6oTrubMicDrPZQE7ZWgwoebK5xVtc" width="320" /></a></div><br /><div style="text-align: justify;">So what does the <a href="https://scitechdaily.com/a-completely-new-way-to-kill-cancer-artificial-dna/" rel="" target="_blank">news release</a> tell us? It tells us, that a group of researchers led by <span style="background-color: white; font-family: "pt serif", Georgia, Times, "times new roman", serif; font-size: 21.26px;">Professor Kunihiko Morihiro designed a pair of chemically synthesized DNA, shaped like hairpins, which when injected into cancer cells attach to microRNA, which is overexpressed by cancer cells. Now to my knowledge cells are very small, so can you inject something into a cell? To me this sounds like "lies to children" as used in <a href="https://www.terrypratchettbooks.com/books/the-colour-of-magic/" target="_blank">Terry Pratchett's discworld novels</a>. I certainly which the experiment was described closer to what happened in the lab.</span></div><div><span style="font-family: pt serif, Georgia, Times, times new roman, serif;"><span style="font-size: 21.26px;"><div class="separator" style="clear: both; text-align: left;"><span style="background-color: white;"><br /></span></div><div class="separator" style="clear: both; text-align: left;"><span style="background-color: white;">Closer reading of the new release identify the following factual statements:</span></div></span></span><p style="text-align: justify;"></p><ul><li><span style="background-color: white; color: red; font-family: "pt serif", Georgia, Times, "times new roman", serif; text-align: left;">T</span><span id="docs-internal-guid-e2dbeb48-7fff-315d-5efa-afdd9e33f2ce"><span style="font-family: Georgia; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span style="color: red;">he method effectively targeted and destroyed human cervical and breast cancer cells, as well as malignant melanoma cells from mice. </span>This the key application result of the work. However, we don't know what forms of the three diseases the researcher tested.</span></span></li><li><span style="font-family: Georgia; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span style="color: red;">The team designed a pair of chemically synthesized DNA, shaped like hairpins. </span>How was the so called oncologic hairpin (oHP) DNA designed? We after later informed that the oHP attached to microDNA in the cancer cells, and that for the test reported here specifically mi-R-21, which is overexpressed in cancer cells of cervical, breast and melanoma. However, it is not clear if the design procedure is described in publication.</span></li><li><span style="font-family: Georgia; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span id="docs-internal-guid-64aae4d9-7fff-2157-8ce4-666adda5ed23"><span style="color: red; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;">The DNA pairs, upon attaching to the miRNA, unraveled and combined, forming longer chains of DNA that activated an immune response</span><span style="font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;">. How were these events observed? </span></span></span></li><li><span style="font-family: Georgia; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span><span style="font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span id="docs-internal-guid-1d27cce0-7fff-e65c-b051-fe896d2e6e0f"><span style="color: red; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;">The team was able to develop a hairpin-shaped DNA strand that can activate a natural immune response to target and kill specific cancerous cells. </span><span style="font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;">How exactly was the hairpin-shaped DNA strand developed?</span></span></span></span></span></li><li><span style="color: red;">The team created artificial oncolytic (cancer-killing) hairpin DNA pairs called oHPs.<span style="font-family: Georgia; font-size: 12pt; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"> </span><span style="font-family: Georgia; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">These oHPs were triggered to form longer DNA strands when they </span></span><span style="color: red; font-family: Georgia; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">encountered a short (micro) RNA called miR-21, which is overexpressed in some cancers.</span><span id="docs-internal-guid-dea977ab-7fff-c8e2-e57b-0f5262f72c82"></span></li></ul><p></p><p dir="ltr" style="background-color: white; line-height: 1.2; margin-bottom: 19pt; margin-top: 10pt; text-align: justify;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgsHP_hoDyWH9prqmlyesGgK70mKbJZqn0B1yM92EOR5PPoZr68M3znhMvbiMQhKEP9dLIsKz2FlkusaheqyaDFggoMp1HL-r8HSi8--KTv0npETkZA2xqZ5AlbjCJuoWtfLic_CEJU6TH_yqoAQP945abXAltCiTHxh0S52RIX4zYxMl_Ev3k" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="" data-original-height="769" data-original-width="1536" height="160" src="https://blogger.googleusercontent.com/img/a/AVvXsEgsHP_hoDyWH9prqmlyesGgK70mKbJZqn0B1yM92EOR5PPoZr68M3znhMvbiMQhKEP9dLIsKz2FlkusaheqyaDFggoMp1HL-r8HSi8--KTv0npETkZA2xqZ5AlbjCJuoWtfLic_CEJU6TH_yqoAQP945abXAltCiTHxh0S52RIX4zYxMl_Ev3k" width="320" /></a></div>This diagram from the news release visualize how the oHP attach to the miRNA in the cancer cells to create an elongated DNA duplex. It looks like the light green part of the oHP attaches to the miRNA and allows the innate immune system to see it. But what is the chemical structure of the light green part?<p></p><p dir="ltr" style="background-color: white; line-height: 1.2; margin-bottom: 19pt; margin-top: 10pt; text-align: justify;">My questions - I have just requested a copy of the research publication from the authors - at this point are:</p><p dir="ltr" style="background-color: white; line-height: 1.2; margin-bottom: 19pt; margin-top: 10pt; text-align: justify;"></p><ul><li style="text-align: justify;">Was it prior knowledge, that the oHP needed to target miR-21 in the three cancers? Are miR-21 overexpressed in all sub-types of these cancers?</li><li style="text-align: justify;">Was the work performed both in-vitro (petri dish) and/or in-vivo (in mouse model)?</li><li style="text-align: justify;">Was it prior knowledge, that the hairpin struture was unraveled after attachment to the mR-21?</li><li>How was the hairpin structure designed?</li></ul><div style="text-align: justify;">News releases like this one give hope, that eventually we will be able to control all cancers. However, the frustration I have is that the road to the goal the past 15+ years I have lived with MDS, don't appear to become shorter.</div><p></p><p dir="ltr" style="background-color: white; line-height: 1.2; margin-bottom: 19pt; margin-top: 10pt; text-align: justify;">That being said I certainly believe, that there is room for improvement in the way universities formulate and publish news releases. One example that could start thinking of another approach is this one: <a href="https://www.mdsnewunderstanding.com/">https://www.mdsnewunderstanding.com/</a>. A year ago something good appeared to come to high risk MDS. But it ended being one step forward in communication and two step back in science.</p><p dir="ltr" style="background-color: white; line-height: 1.2; margin-bottom: 19pt; margin-top: 10pt; text-align: justify;">But lets not forget that each news release about new approaches to cancer treatment is a small light at the end of the tunnel, that could bring a Nobel price to some researcher.</p></div>Niels Jensenhttp://www.blogger.com/profile/14071035070040472470noreply@blogger.com0tag:blogger.com,1999:blog-9471278.post-21053781803380658652022-09-02T08:15:00.006+02:002022-09-02T10:11:34.269+02:00Are we getting better at bone marrow transplants?<p style="text-align: left;"><span style="font-family: georgia; font-variant-east-asian: normal; font-variant-numeric: normal; text-align: justify; vertical-align: baseline; white-space: pre-wrap;">As an MDS or AML patient, sooner or later you hear, that the only curative treatment for these blood cancers is an hematopoietic stem cell transplant (HSCT). Previously - 10-20 years ago - such treatment was only offered to fit younger patients under the age of 60 years. Fortunately, this is no longer the case - at least not in Denmark, where HSCTs are proformed at <a href="https://www.rigshospitalet.dk/english/Pages/default.aspx" rel="nofollow">Rigshospitalet</a> in Copenhagen or <a href="https://www.en.auh.dk/" rel="nofollow">Skejby Sygehus</a> in Aarhus, and the two transplant teams work closely together to become even better at performing this treatment. Today the treatment is also offered to patients over the age of 70 years, provided they have a good general condition before the treatment. Patients with comorbidities are also considered for HSCT. Evil tongues suggest the age increase is just a reflection of the doctors being 10-20 years older.</span></p><h3 style="text-align: left;"><span style="color: #434343; font-family: Arial; font-size: medium; text-align: justify; white-space: pre-wrap;">The principle of Allogeneic Stem Cell Transplantation</span></h3><p style="text-align: left;"><span style="font-family: georgia; text-align: justify; white-space: pre-wrap;">In principle, the treatment consists of putting the patient's immune system out of action as much as possible, and then giving the patient blood from a donor. If all goes well, the donor blood takes over the patient's bone marrow and then begins to form healthy blood cells. Overall, this is a simple treatment, but quite an expensive treatment. A few years ago, a patient who had undergone an allogeneic stem cell transplant said that her doctor told her the cost of the treatment was around 2 million Danish kroner. Cost estimates from the USA are between 800,000 and 900,000 USD. Therefore, it is of course important that the treatment is only offered in cases where it is the right treatment for the patient and there are no other options or a high risk that the treatment will not be successful. However, the historical data for survival after an allogeneic stem cell transplant are not particularly encouraging.</span></p><span id="docs-internal-guid-c8f1e459-7fff-fb23-8543-0cb1e503fda7"><h3 style="line-height: 1.38; margin-bottom: 0pt; margin-top: 16pt; text-align: justify;"><span style="font-family: arial;"><span style="background-color: transparent; color: #434343; font-size: medium; font-style: normal; font-variant: normal; text-decoration: none; vertical-align: baseline; white-space: pre;">Elderly patients are also offered allogeneic stem cell </span>transplantation</span></h3><p style="line-height: 1.38; margin-bottom: 0pt; margin-top: 0pt; text-align: justify;"><span style="font-family: Arial; font-size: 11pt; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span id="docs-internal-guid-d809562c-7fff-7c68-092f-41b75fe3f9c1"></span></span></p><div style="line-height: 1.38; margin-bottom: 10pt; margin-top: 0pt; text-align: left;"><p style="text-align: left;"><span style="background-color: transparent; color: black; font-family: georgia; font-style: normal; font-variant: normal; font-weight: 400; text-decoration: none; vertical-align: baseline; white-space: pre;">In recent years, great progress has been made in allogeneic stem cell </span><span style="font-family: georgia;"><span style="background-color: transparent; color: black; font-style: normal; font-variant: normal; font-weight: 400; text-decoration: none; vertical-align: baseline; white-space: pre;">transplantation, <br /></span></span><span style="font-family: georgia;"><span style="background-color: transparent; color: black; font-style: normal; font-variant: normal; font-weight: 400; text-decoration: none; vertical-align: baseline; white-space: pre;">so that the treatment is now also offered to patients over 70. Already in the fall of <br /></span></span><span style="font-family: georgia; white-space: pre;">2015 a leading doctor at Rigshospitalet told a group of Danish MDS patients about</span><br /><span style="font-family: georgia; white-space: pre;">percentage of patients </span><span style="font-family: georgia; white-space: pre;">surviving </span><span style="font-family: georgia; white-space: pre;">a HSCT from 50% to 70-80%. </span><span style="font-family: georgia;"><span style="color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre;">Greek researchers <br /></span></span><span style="font-family: georgia;"><span style="color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre;">published in 2017 in </span></span><a href="https://www.astctjournal.org/article/S1083-8791%2816%2930523-7/fulltext"><span style="font-family: georgia; white-space: pre;">Transplantation and Cellular </span></a><span style="font-family: georgia; white-space: pre;"><a href="https://www.astctjournal.org/article/S1083-8791%2816%2930523-7/fulltext">Therapy</a> that pretreatment with </span><br /><span style="font-family: georgia; white-space: pre;">fludarabine </span><span style="font-family: georgia;"><span style="color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span style="white-space: pre;">and treosulfan (FluTreo) </span></span></span><span style="font-family: georgia;"><span style="background-color: transparent; color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span style="white-space: pre;">reduced </span></span></span><span style="font-family: georgia;"><span style="background-color: transparent; color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span style="white-space: pre;">relapse 1 year after HSCT from over </span></span></span><br /><span style="font-family: georgia;"><span style="background-color: transparent; color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span style="white-space: pre;">40% to under 10% of </span></span></span><span style="font-family: georgia;"><span style="background-color: transparent; color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span style="white-space: pre;">transplanted MDS patient.</span></span></span></p><div style="line-height: 1.38; margin-bottom: 10pt; margin-top: 0pt; text-align: left;"><p style="text-align: left;"><span style="font-family: georgia;"><span style="background-color: transparent; color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span style="white-space: pre;"></span></span></span></p><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEitMFCIvWCg4AyVxeg2yFgvsHfSjsKlLEO2K3tZtWsEbPipqMw7k9ZxhOaCFJr6QleLvrClRYzBECqoN7trKoRM9SUJRTUwZQQ7X8J0gkdKKa8Y6cj1itKG_5KER-3Yn2dKOKXxI3VHecvzx9QuUEFLUBJIALMuCkpjm38j0nIWKOfN-0VrNks/s512/2010_Greek_MDS_relapse_after_HSCT.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="332" data-original-width="512" height="260" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEitMFCIvWCg4AyVxeg2yFgvsHfSjsKlLEO2K3tZtWsEbPipqMw7k9ZxhOaCFJr6QleLvrClRYzBECqoN7trKoRM9SUJRTUwZQQ7X8J0gkdKKa8Y6cj1itKG_5KER-3Yn2dKOKXxI3VHecvzx9QuUEFLUBJIALMuCkpjm38j0nIWKOfN-0VrNks/w400-h260/2010_Greek_MDS_relapse_after_HSCT.png" title="Figure show cumulative incidence of relapse among Greek MDS patients pretreated with either conventionally or with FluTreo. Source: Transplantation and Cellular Therapy 23(3),2017, pp 445–451." width="400" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span style="font-variant-east-asian: normal; font-variant-numeric: normal; text-align: left; vertical-align: baseline; white-space: pre-wrap;">Figure show cumulative incidence of relapse among Greek MDS patients pretreated either conventionally or with FluTreo. Source: </span><a href="https://www.astctjournal.org/article/S1083-8791(16)30523-7/fulltext" style="text-align: left; text-decoration-line: none;"><span style="color: #1155cc; font-variant-east-asian: normal; font-variant-numeric: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space: pre-wrap;">Transplantation and Cellular Therapy 23(3),2017, pp 445–451.</span></a></td></tr></tbody></table><p style="text-align: left;"><span style="font-family: georgia;"><span style="background-color: transparent; color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span style="white-space: pre;"><span style="white-space: pre-wrap;">In 2020 the Danish HSCT team at Rigshospitalet published data in the same journal showing 1-year survival of MDS patients with FluTreo pretreatment of over 84% and 3-year survival of over 71%. </span></span></span></span></p><p></p><p style="text-align: left;"><span style="font-family: georgia;"><span style="background-color: transparent; color: black; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span style="white-space: pre;"><span style="white-space: pre-wrap;"></span></span></span></span></p><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi73HiCaD35ffKoe352Qgfo3HiTksxe7mTS7TEcQ5hdF1GybcGkQcdIBo9EPT1daxSSmjKh3qQV80saVhNFWGY2gA2tUOQ6RDYAHIFc2HVi5eMwE2lcrDzAFYIG9dcQ-JufGJYf-ZyJH4gTRg13MdbruSDF1t37Hl7Iz7MFJzGDI2jCP5V2GFQ/s512/2022%20Danish_MDS_Survival_after_HSCT.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="413" data-original-width="512" height="323" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi73HiCaD35ffKoe352Qgfo3HiTksxe7mTS7TEcQ5hdF1GybcGkQcdIBo9EPT1daxSSmjKh3qQV80saVhNFWGY2gA2tUOQ6RDYAHIFc2HVi5eMwE2lcrDzAFYIG9dcQ-JufGJYf-ZyJH4gTRg13MdbruSDF1t37Hl7Iz7MFJzGDI2jCP5V2GFQ/w400-h323/2022%20Danish_MDS_Survival_after_HSCT.png" width="400" /></a></td></tr></tbody></table><p></p><div><span><span><span style="font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline;"><span style="white-space: pre-wrap;"><span style="font-family: georgia;">Figure show overall survival of MDS patients undergoing HSCT at Rigshospitalet with 3 different pretreatment regimens of which FluTreo (yellow) is clearly the best. </span></span></span></span></span><span style="font-family: georgia; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">Source: </span><span style="color: #1155cc; font-family: georgia; white-space: pre-wrap;"><a href="https://www.astctjournal.org/article/S1083-8791(20)30095-1/fulltext" style="text-decoration-line: none;"><span style="font-variant-east-asian: normal; font-variant-numeric: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline;">Transplantation and Cellular Therapy 26(6),2020, pp 1091-1098.</span></a></span></div><p style="text-align: left;"><span style="font-family: georgia; white-space: pre-wrap;">Unfortunately, as can be seen from the Danish data, there are still patients who die within the first 1-3 years after an allogeneic stem cell transplant, and methods to avoid this are therefore intensively researched around the world. One study pursuing this is the joint Nordic </span><a href="https://www.nmds.org/index.php/clinical-trials/73-nmdsg14b.%20Accessed%20May%204" style="font-family: georgia; white-space: pre-wrap;">NMDSG14B</a><span style="font-family: georgia; white-space: pre-wrap;"> study to predict relapse early.</span></p></div></div></span><div style="text-align: left;"><h3 style="text-align: left;"><span><span id="docs-internal-guid-a7fc36c4-7fff-ed1e-ff34-ff1463734229"><span style="font-family: Arial; font-size: 16pt; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">Can one predict relapse in MDS patients after allogeneic stem cell transplantation?</span></span></span></h3><p style="text-align: left;"><span style="font-family: georgia;"><span id="docs-internal-guid-ec6ed107-7fff-b2e9-7bc6-464a4e002244"><span style="font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">Regardless of how many patient experience relapse it would be good for both the patients and society if relapse could be predicted early enough for intervention to be possible. At the EHA Congress in Vienna </span><a href="https://journals.lww.com/hemasphere/Fulltext/2022/06003/S167__PREDICTION_OF_RELAPSE_AFTER_ALLOGENEIC_STEM.68.aspx" style="text-decoration-line: none;"><span style="color: #1155cc; font-variant-east-asian: normal; font-variant-numeric: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space: pre-wrap;">Dr. Magnus Tobiassen</span></a><span style="font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"> described how researcher in a joint Nordic project attempt prediction of relapse by following mutations specific to the individual patient. The Nordic project </span><a href="https://www.nmds.org/index.php/clinical-trials/73-nmdsg14b.%20Accessed%20May%204" style="text-decoration-line: none;"><span style="color: #1155cc; font-variant-east-asian: normal; font-variant-numeric: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space: pre-wrap;">NMDSG14B</span></a><span style="font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"> tries to follow the development of mutations by a technique called </span><span style="background-color: white; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">droplet digital Polymerase Chain Reaction, which is abbreviated ddPCR, and is a technology developed by the company </span><a href="https://www.bio-rad.com/en-dk/life-science/digital-pcr?ID=M9HE2R15&WT_mc_id=210930032378&WT_srch=1&WT_knsh_id=b1e41934-17d8-423c-9f42-376c6e579fcb&gclid=Cj0KCQjwgO2XBhCaARIsANrW2X3vlNfMjTr9z9aP2AQdwxswNzBj5Kv5n0AH0JUoSM466wYVO8oRYVoaAkEcEALw_wcB" style="text-decoration-line: none;"><span style="background-color: white; color: #1155cc; font-variant-east-asian: normal; font-variant-numeric: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space: pre-wrap;">Bio-Rad</span></a><span style="background-color: white; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">. Before the HSCT, a sample is taken for gene sequencing for identification of patient-specific mutations and the design of the ddPCR primer. After the stem cell treatment, blood samples are taken every month and bone marrow samples every 3 months until 24 months or relapse. The samples are analyzed in groups, and the attending physician does not receive the results of the analyses. Before this year’s EHA Congress in Vienna, the MRD analysis included 221 MDS patients, of these 31 had died without relapse, 53 had relapsed, and 137 were without "disease signs".</span></span></span></p><div><span style="font-family: georgia;"><span><span style="background-color: white; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><br /></span></span></span></div><div><span style="font-family: georgia;"><span><span style="background-color: white; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgCw7MLB2FkY-OJn9OHiGfiUa_GwUi0_s2XdhHODm5VZUWLivH_cTFGXpMDcTEJ4Olg4ndtpn0wEMBPt57bICi5GUUYNs6p4widV_gQSO0BGcltv_h2MJF4jo7WGMG-YvDAFiHY47z8gt1kYfQHyLI1XbL95jwbAWAE9XA_0PbwBgHvxdoXo_I/s512/2022_Nordic_MRD_predict_relapse_after_HSCT.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="275" data-original-width="512" height="215" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgCw7MLB2FkY-OJn9OHiGfiUa_GwUi0_s2XdhHODm5VZUWLivH_cTFGXpMDcTEJ4Olg4ndtpn0wEMBPt57bICi5GUUYNs6p4widV_gQSO0BGcltv_h2MJF4jo7WGMG-YvDAFiHY47z8gt1kYfQHyLI1XbL95jwbAWAE9XA_0PbwBgHvxdoXo_I/w400-h215/2022_Nordic_MRD_predict_relapse_after_HSCT.png" width="400" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span style="font-variant-east-asian: normal; font-variant-numeric: normal; text-align: left; vertical-align: baseline; white-space: pre-wrap;">Figure show survival without relapse. Red curves are MRD negative patients and green curves are MRD positive patients. Time is days since HSCT. Source: </span><span style="font-variant-east-asian: normal; font-variant-numeric: normal; text-align: left; vertical-align: baseline; white-space: pre-wrap;"><a href="https://journals.lww.com/hemasphere/Fulltext/2022/06003/S167__PREDICTION_OF_RELAPSE_AFTER_ALLOGENEIC_STEM.68.aspx" rel="nofollow">Hemasphere 2022;6(S3):68-69</a>.</span></td></tr></tbody></table></span></span></span><p style="text-align: left;"><span style="font-family: georgia;"><span><span style="background-color: white; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span style="background-color: transparent;">This result indicate, that survival clearly depends on MRD status of the patient as measured by ddPCR in blood or bone marrow samples.</span></span></span></span></p></div><div><span style="font-family: georgia;"><span><span style="background-color: white; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span style="background-color: transparent;"><br /></span></span></span></span></div><div><span style="font-family: georgia;"><span><span style="background-color: white; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span style="background-color: transparent;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjifuU9p2MfpplBPZ5NRTFmvs7YrOiWI8MH5DFQvx2F8-mycMpjbniReKfnseukyUgNEqiumeJv14WDsAe2PJJH202hQ-1lQC3QON3CXzcF-W7_zYoiyfvp_TjcJa-jTJncOc1N47OJj12h3iEctCrHFA-AeqRGtANj4T2WpISWOtdFIYPnBgk/s512/2022_Nordic_mainly_MRD_negative_without_relapse_after_HSCT.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="317" data-original-width="512" height="248" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjifuU9p2MfpplBPZ5NRTFmvs7YrOiWI8MH5DFQvx2F8-mycMpjbniReKfnseukyUgNEqiumeJv14WDsAe2PJJH202hQ-1lQC3QON3CXzcF-W7_zYoiyfvp_TjcJa-jTJncOc1N47OJj12h3iEctCrHFA-AeqRGtANj4T2WpISWOtdFIYPnBgk/w400-h248/2022_Nordic_mainly_MRD_negative_without_relapse_after_HSCT.png" width="400" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span style="font-family: georgia; text-align: left;"><span><span style="white-space: pre-wrap;">Figure show the 137 transplanted patients without signs of disease</span></span></span><span style="font-family: georgia; text-align: left;">. Patient without relapse are mainly MRD negative plus some borderline or converted from positive to negative. Source: NMDSG14B</span></td></tr></tbody></table></span></span></span></span></div><div><span style="font-family: georgia;"><span><span style="white-space: pre-wrap;"><br /></span></span></span></div><div><span style="font-family: georgia;"><span><span style="white-space: pre-wrap;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgL-a1JR_u94OgxT4dO1aoLJxgeEBiZWPAhT-J7OOr3JFqi2HMmW3hAFZcftu_jqLC3ia_G-l31rgcXqa5mxj3fUMP2nR8S43V-vUkdJnQ3_3NOpaU-hxVspnVxPQgtxp6ShZ61IU_S_GBr0UeaqxmwjsRPrcndLedz6oQYNBfdYykf25zoZpg/s512/2022_Nordic_mainly_MRD_positive_relapse_after_HSCT.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="317" data-original-width="512" height="248" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgL-a1JR_u94OgxT4dO1aoLJxgeEBiZWPAhT-J7OOr3JFqi2HMmW3hAFZcftu_jqLC3ia_G-l31rgcXqa5mxj3fUMP2nR8S43V-vUkdJnQ3_3NOpaU-hxVspnVxPQgtxp6ShZ61IU_S_GBr0UeaqxmwjsRPrcndLedz6oQYNBfdYykf25zoZpg/w400-h248/2022_Nordic_mainly_MRD_positive_relapse_after_HSCT.png" width="400" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span style="text-align: left;">Figure show the 53 transplanted patient with relapse. Patients with relapse are mainly MRD positive. Source: NMDSG14B.</span></td></tr></tbody></table></span></span></span></div><p style="text-align: left;"><span style="font-family: georgia;">Notice, that the treating physician was not informed about the MRD status during this first part of the NMDSG14B study.</span></p><p style="text-align: left;"><span style="font-family: georgia;">Another question phase 1 of the NMDSG14B study attempted to answer was if bone marrow biopsy was better than blood samples at predicting relapse.</span></p><div><span style="font-family: georgia;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhH13umBdaj3LDUZA_kczp_SrTTtgozCioiNRfYoSHpb7TdaFndml_hiSWjZVZFVTMU4ywo_CregoY1slivS5xOhmUGNMV9KbrH83jTN2XPad_kcoX58PSh4OBkc1XznCNMQR5MuEA4cORCoWUkjXWD53fTDVDnsiIqhdSbo4Kajwr8Geb2Gj0/s512/2022_Nordic_blood_or_bone_marrow_for_relapse_prediction.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="317" data-original-width="512" height="248" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhH13umBdaj3LDUZA_kczp_SrTTtgozCioiNRfYoSHpb7TdaFndml_hiSWjZVZFVTMU4ywo_CregoY1slivS5xOhmUGNMV9KbrH83jTN2XPad_kcoX58PSh4OBkc1XznCNMQR5MuEA4cORCoWUkjXWD53fTDVDnsiIqhdSbo4Kajwr8Geb2Gj0/w400-h248/2022_Nordic_blood_or_bone_marrow_for_relapse_prediction.png" width="400" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span style="text-align: left;">Figure shows in which samples relapse were detected. Only 27 of the 53 relapsed patients had the necessary data for this analysis. In 12 of these detection was at the same time from bone marrow biopsy and blood samples. In 9 the bone marrow biopsy result appeared before the blood sample result, and in 6 patients the relapse was only detected in the bone marrow. Source: NMDSG14B.</span></td></tr></tbody></table></span><p style="text-align: left;"><span style="font-family: georgia;">I doubt these data are sufficient to conclude what type of test should be preferred for detecting relapse. At least it would be informative to know if there is a lag time between relapse detection in the bone marrow and in the blood. </span></p></div><p style="text-align: left;"><span style="font-family: georgia;"><span id="docs-internal-guid-4cb6e346-7fff-36ec-4b95-4a0ebf4633c7"><span style="background-color: white; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">Thus phase 1 of the NMDSG14B study showed that individualized MRD measurement with ddPCR are possible, that MRD positive samples predict relapse, that patients change from being MRD positive to MDR negative due to a GVL effect, and that further investigation is needed on whether both blood samples and bone marrow biopsy are needed. </span></span></span><span style="background-color: white; font-family: georgia; white-space: pre-wrap;">And the answer to the question in the section heading is: Yes, you can.</span></p><div><h3 style="text-align: left;"><span><span style="font-family: arial;">What next?</span></span></h3></div><p style="text-align: left;"><span style="background-color: white; font-family: georgia; text-align: justify; white-space: pre-wrap;">So phase 1 of NMDSG14B has been completed successfully and the results presented at one of the major hematology congresses, so everyone should be ready to start phase 2 of the study, where the attending physician receives feedback on his patient's MRD status, and thus the opportunity to intervene with measures that may change the process to something positive for the patient. There is just one small problem that many have probably already heard about: Nurses are not exactly queuing up to fill vacant positions at the hospitals. Phase 2 of NMDSG14B requires the employment of a project nurse who is interested in being part of the exciting environment surrounding allogeneic stem cell transplantation of MDS patients. If you know someone like that, then I know a doctor who would love to talk to that person!</span></p><div><span id="docs-internal-guid-0431b941-7fff-ae1c-af65-3b4ce9ba9eaa"><div><span style="font-family: georgia;"><span><span style="background-color: white; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">A final note: </span></span></span><a href="https://www.astctjournal.org/article/S1083-8791(20)30095-1/fulltext" style="font-family: georgia; text-decoration-line: none;"><span style="color: #1155cc; font-variant-east-asian: normal; font-variant-numeric: normal; text-decoration-line: underline; text-decoration-skip-ink: none; vertical-align: baseline; white-space: pre-wrap;">Eileen Wedge</span></a><span style="font-family: georgia; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"> shows that with pretreatment with FluTreo before HSCT, only about 15% of MDS patients experience relapse after HSCT treatment, and not as Dr. Magnus Tobiasson told the EHA 2022 Congress in Vienna 30%. The latter must have been a typo.</span></div><h3 style="text-align: left;"><span style="font-family: arial; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;">A Cure with a Caveat</span></h3><div><span style="font-family: georgia;"><span style="white-space: pre-wrap;">I think it is fair to say doctors are getting better at HSCT of MDS patients, but there is still room for improvements and the very important one of preventing relapse is being worked on. But if you talk with MDS patients, who have had an HSCT, then you will know, that although HSCT is called the only cure for MDS, it is a cure, which come with life long often daily medication.</span></span></div></span></div><br /><div style="text-align: center;"><span style="font-family: georgia;"><span id="docs-internal-guid-c68799eb-7fff-3fa8-3109-e8ae840b5e4c"><span style="background-color: white; font-family: Arial; font-size: 12pt; font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span style="border: none; display: inline-block; height: 172px; overflow: hidden; width: 319px;"></span></span></span></span></div><div><span><span><span style="font-variant-east-asian: normal; font-variant-numeric: normal; vertical-align: baseline; white-space: pre-wrap;"><span style="font-family: georgia;"><br /></span></span></span></span></div></div>Niels Jensenhttp://www.blogger.com/profile/14071035070040472470noreply@blogger.com0tag:blogger.com,1999:blog-9471278.post-8502029513561876592022-07-17T13:08:00.001+02:002022-08-17T13:24:12.733+02:00Is it still ethical to give MDS IPSS-r intermediate patients AZA?<p>At EHA virtual in 2020 during the first year of the pandemic <a href="https://www.linkedin.com/in/ioannis-kotsianidis-6aa79a27/?originalSubdomain=gr">Professor Ioannis Kotsianidis</a> presented a poster with analysis of survival and time to leukemia evolution in MDS patients, who where intermediate based on <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425443/">IPSS-r</a>. It showed no statistical difference in both survival and leukemia evolution between patients receiving azacytidine and those that did not. So the only effect of azacitidine for this subgroup of MDS patients appear to be the side effects of the treatment, such as nausea, vomiting, diarrhea, constipation, hemorrhoids, heartburn, stomach pain or sores on mouth or tongue. Currently this analysis is only based on 357 MDS patients with IPSS-r intermediate disease from the Hellenic National Registry of Myelodysplastic and Hypoplastic Syndromes, but if these findings are confirmed by studies of other European MDS registries, such as the <a href="https://clinicaltrials.gov/ct2/show/NCT00600860?term=Registry&cond=MDS&cntry=NL&draw=2&rank=1" target="_blank">Dutch</a>, <a href="https://clinicaltrials.gov/ct2/show/NCT02808858" target="_blank">Italian</a> or Spanish, then I think it would be unethical to continue treating this subgroup of MDS patients with azacitidine. Until such studies done, one should at least when talking about azacitidine treatment also take into account the IPSS (see results under poster picture). Below is a picture of the poster and you can access the poster at the <a href="https://library.ehaweb.org/eha/2020/eha25th/294741/ioannis.kotsianidis.effect.of.azacytidine.on.survival.and.leukemia.evolution.html?f=menu%3D14%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D2%2Aspeaker%3D94165" target="_blank">EHA Open Access Library</a>.</p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiGs2vvMRObI1yHojr4bym7iGkfccLE17oVlnFqkh28Do9ox3hUvfhhvap8Xi5w4PeG_zIYaugZXqdH1Pp-CSWmx7BhG9egQGBZwiZhcubwEr6j7iWXzAVloe9qk9CQFFAw8vITTUHXbP90sdDJ5DGApOhrzEfZ7WG6T0H_UoY4-btcfcQ-x6E/s1899/Screenshot_20220717_113406.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="945" data-original-width="1899" height="317" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiGs2vvMRObI1yHojr4bym7iGkfccLE17oVlnFqkh28Do9ox3hUvfhhvap8Xi5w4PeG_zIYaugZXqdH1Pp-CSWmx7BhG9egQGBZwiZhcubwEr6j7iWXzAVloe9qk9CQFFAw8vITTUHXbP90sdDJ5DGApOhrzEfZ7WG6T0H_UoY4-btcfcQ-x6E/w638-h317/Screenshot_20220717_113406.png" width="638" /></a></div>The analysis performed by Kotsianidis et.al showed the following results<div><ul style="text-align: left;"><li>Among the 357 intermediate IPSS-r MDS patients the overall survival and leukemia free survival was respectively 33 months and 28 months.</li><li>Among the 64 patients receiving azacitidine 21 patients had HR-MDS according to IPSS, and also higher bone marrow blast count and higher blood transfusion requirements.</li><li>Patients receiving azacitidine had similar survival rates as patients who did not receive azacitidine.</li><li>Intermediate IPSS-r patients with intermediær-2/high IPPS were more than three times as likely to respond to azacitidine as those with intermediær-1/low IPSS.</li><li>Low <a href="https://www.kidney.org/atoz/content/gfr" target="_blank">eGFR</a>, high <a href="https://ecog-acrin.org/resources/ecog-performance-status/" target="_blank">ECOG</a> status, high <a href="https://bmccancer.biomedcentral.com/articles/10.1186/s12885-020-07317-y" target="_blank">EASIX</a> and high circulating blasts were indicative of inferior overall survival.</li></ul>The authors conclude that in the IPSS-r intermediate subgroup of MDS patients treatment with azacitidine appear not to effect overall survival, and that the results should be confirmed on an independent cohort. So in my view the answer to the title question is "Yes, with informing the patient about the results of this study prior to starting treatment with azacitidine". </div>Niels Jensenhttp://www.blogger.com/profile/14071035070040472470noreply@blogger.com0tag:blogger.com,1999:blog-9471278.post-81214378491756798032022-03-07T13:04:00.002+01:002022-04-27T12:08:50.242+02:00How will we distinguish MDS and AML going forward - molecular genetics?<p style="text-align: justify;">If you are an MDS patient you properly have been told by your doctor, that your MDS disease may progress to AML. According to <a href="https://ashpublications.org/blood/article/127/20/2391/35255/The-2016-revision-to-the-World-Health-Organization" target="_blank">the WHO 2016 classifications of myeloid neoplasm</a> your disease is considered MDS if you bone marrow blast are less than 20%, and considered AML if your blast are above 20%. However, bone marrow blast is measured by counting cell in a microscope. If you are a scientist you might think that measurement must have some uncertainty. Uncertainty in science means, that if you take a sample of the liquid in the bone marrow and have two different technicians determine the blast percentage in this sample, they are very unlikely to get the same result. In November 2018 my hemoglobin was measured twice on the same same sample. One result was 7.6 mmol/L and the other 8.0 mmol/L, and my doctor remarked, that gives a good idea of the analysis uncertainty. At several occasions my doctor and I have discussed the problem of basing the MDS diagnosis on blood smear and the counting of the percentage of dysplastic cell in the different blood cell lineages. My doctor actually at at one time tested the reliability of blood smear to decide if a patient has MDS, by having three different technicians evaluate the same smear. The result was not encouraging.</p><p style="text-align: justify;">A measurement of blast percentage is actually a counting process while looking in microscope. The technician count two things: the number of cells observed and the number of blast cells, and the ratio of these number multiplied by 100 is the blast percentage. Naturally both counts are uncertain and the division actually increase the uncertainty. So I would ascertain, that it is difficult to know if the blast percentage is 19% or 21% needed to tell you if your MDS is still considered MDS or has progressed to AML. Naturally you disease don't change drastically just as the measurement cross the 20% cut of point. However, what do change is what approved treatments your doctor may offer you and what trials you are eligible for. </p><p style="text-align: justify;">Dr. Michael Heuser from Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation at the Hannover Medical School in Hannover, Germany in the spring of 2019 wrote a guest editorial in MDS News titled "<a href="https://mds-foundation.web-maintenance-request.com/wp-content/uploads/sites/4/formidable/6/2-High-Risk-MDS-and-AML-One-or-Two-Diseases-Heuser.pdf" rel="nofollow" target="_blank">High-Risk MDS and AML: One or Two Diseases?</a>" which compared how high-risk MDS and low blast count AML are defined and also compared genetics and prognosis in these diseases.</p><p style="text-align: justify;">Dr. Michael Heuser points out that blast count is the most important value for increased risk disease in MDS, and hence that the disease develops into a form of AML. Contrary to this blast count is not a major risk factor in AML. He also reported that <a href="https://ashpublications.org/blood/article/122/22/3616/32001/Clinical-and-biological-implications-of-driver" rel="nofollow" target="_blank">Papaemmanuil et.al</a> found that blast count correlated positively with mutations in WT1, IDH2, STAG2 and NRAS as well as complex karyotype, but negatively with SF3B1 mutations. To me this alone indicate, that one cannot diagnose MDS and give a prognosis without a gene sequencing. Luckily most leading MDS clinics are already doing that.</p><p style="text-align: justify;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgixSyhQVQP5P_TtcPHq9ZhRDLpc8s3P1a-yoopeIirqITAepaiIXZtcRowEIo8dHqfHJ6OG-nop2ki1Dxk8D7hjzVMm9mazn1OfqnGGU-kzTQwQGMlu3LcGoyfGNQuA0uLQXlNESCIdjDbxmzEyuTroEDzOOzu1CxFwxYCI222iBWZjEWQNpY=s1833" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="1057" data-original-width="1833" height="185" src="https://blogger.googleusercontent.com/img/a/AVvXsEgixSyhQVQP5P_TtcPHq9ZhRDLpc8s3P1a-yoopeIirqITAepaiIXZtcRowEIo8dHqfHJ6OG-nop2ki1Dxk8D7hjzVMm9mazn1OfqnGGU-kzTQwQGMlu3LcGoyfGNQuA0uLQXlNESCIdjDbxmzEyuTroEDzOOzu1CxFwxYCI222iBWZjEWQNpY=s320" width="320" /></a></div><div style="text-align: justify;">Dr. Heuser then points to a study by <a href="https://www.nature.com/articles/leu201180" rel="nofollow" target="_blank">Bacher et.al</a> who showed that for a group of 90 HR-MDS patients and 180 low blast count AML patients blast count had no effect on overall survival. A larger study by <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486407/" rel="nofollow" target="_blank">DiNardo et.al</a> involving 163 HR-MDS patients, 230 patient with low blast count AML and 1159 AML patient with blast count above 30% also showed identical survival for HR-MDS and low blast AML patients, while survival was a median of 2.5 months worse for high blast AML patients. Dr. Heuser conclude that marrow blasts are prognostic in MDS (I guess with respect to development of AML), but not when comparing HR-MDS to low blast count AML. He further state that HR-MDS is genetically distinct from de novo AML. Based on these observation I think it would make sense to define a disease with between 10% and 30% bone marrow blast as MDS/AML Overlap disease, which would be similar to the overlap between PNH and MDS, and also allow mutations to define from which end your disease comes, as described in the above figure from Dr. Heuser's editorial in MDS News. As you will discover if reading on, that is exactly with Estey et.al propose in recently published perspective in Blood.</div><p></p><p style="text-align: justify;">The chart is also in agreement with what I read in the records of a now dead MDS patient I met at <a href="https://www.medscape.com/viewcollection/32263" rel="nofollow" target="_blank">ASH 2011</a> in San Diego during the Photo Galla Exhibition featuring elderly patients with MDS. This MDS patient due to his religion did not receive blood transfusion, but his doctors in Chicago tried every substance in their arsenal on him, and depending on the effect of the latest drug his blast percentage changed from below 10 to above 25.</p><div style="text-align: justify;">Dr. Heuser in the editorial goes on to state thar HR-MDS and low blast count AML patients share genetic characteristics including response to treatment. This leads to a suggestion of using cytogenetic characteristics and mutations to define MDS and AML, as seen in the figure here borrowed from the editorial. </div><div style="text-align: justify;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEiln4CdCOBglmzUB7GLRcrChSTm3kn6uNUNGs4CCELAN69HGHQLhtkCXlc0rlDuTMr4pTA8zVK4ikTNjH9lTJhBKwDMriWi9zdW3muR15LMKbCVY-EI_Z5bVRr-cjAj1dSxo0tAyj-NsdN-EkpTMrlTehv-Jy0JrRj_yfUHlHqLXYwc5dUdvWE=s1833" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="1057" data-original-width="1833" height="185" src="https://blogger.googleusercontent.com/img/a/AVvXsEiln4CdCOBglmzUB7GLRcrChSTm3kn6uNUNGs4CCELAN69HGHQLhtkCXlc0rlDuTMr4pTA8zVK4ikTNjH9lTJhBKwDMriWi9zdW3muR15LMKbCVY-EI_Z5bVRr-cjAj1dSxo0tAyj-NsdN-EkpTMrlTehv-Jy0JrRj_yfUHlHqLXYwc5dUdvWE=s320" width="320" /></a></div>This defines HR-MDS and AML without using the rather uncertain bone marrow blast percentage measurement with a cut off point of 20% blast. That was 3 years ago. </div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">However, earlier this year Dr. Elihu Estey et.al published a perspective titled "<a href="https://ashpublications.org/blood/article/139/3/323/476130/Distinguishing-AML-from-MDS-a-fixed-blast" rel="nofollow" target="_blank">Distinguishing AML from MDS: a fixed blast percentage may no longer be optimal</a>" in Blood, which discuss a very similar idea based on data from among other places the Fred Hutchinson Cancer Research Center. Unfortunately Dr. Estey died suddenly last November, so was unable to see the effect of his perspective hopefully will have on the 20% blast percentage cut point. Dr. Elihu Estey was a leukemia specialist at the Division of Hematology at the University of Washington and at the Fred Hutchinson Cancer Research Center where he routinely challenged the validity of widely accepted medical practices, such as e.g. cooked versus normal diet in people receiving intensive remission induction chemotherapy for AML (See <a href="https://cancerletter.com/obituary/20211105_3/" rel="nofollow" target="_blank">obituary by Roland B. Walter, Andreas Hochhaus and Robert Peter Gale</a> in The Cancer Letter). </div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">Estey et.al start by discussing the uncertainty of determining blast count by observing that if 500 cells are counted in a sample blood sample indicating 19% blast, then the 95% confidence interval is 16%-23%, and similarly for a blood sample indicating 21% blast the 95% confidence interval is 18%-25%. Hence there is significant overlap of the confidence interval leading to Estey et.al concluding that 20% limit for a disease being AML in the WHO 2001, 2008 and 2016 classifications is as problematic as the 30% limit in the older FAB classification. </div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">After presenting extensive clinical data Estey et.al state that the biologic data presented in the article provide no reason to determine eligibility for either an AML or MDS trail based solely on a 20% blast cut point. I am not qualified to discuss the data presented by Estey et.al, so I will leave that for others.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">However, even though WHO already in the 2001 Classification stated that bone marrow blast percentage alone should not determine what treatment a patient is given many eligibility criteria in HR-MDS or AML trials are based on the 20% cut point. This according to Estey et.al prevents patients from participating in trials which based on their disease biology could potentially be beneficial.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">They goes on to recommend that patients with NPM1, FLT3 or TP53 mutations should be eligible for AML trials regardless of blast count. And further propose that HR-MDS and AML patients with 10% to 30% blasts be routinely eligible for both MDS and AML trials, which would allow formal testing of the effect of blast percentage on trial outcome. They also recognize that the 10% blast lower limit and 30% blast upper limits should be subject to verification based on results from clinical trials, and state that in principle the lower limit could be as low 5%.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">Finally Estey et.al express hope that a uniform genetic evaluation of the current MDS, MPN and AML designations might allow harmonization of trials and comparison across diseases. I think the work of Papaemmanuil et.al presented at EHA 2021 Virtual is a step in the creation of the database necessary to further this idea of uniform genetic evaluation across hematologic neoplasms.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">In my view Estey et.al in their perspective propose a new disease category of MDS / AML overlap of patients with between 10% and 30% bone marrow blasts, much like Dr. Heuser proposed in his editorial in MDS News 3 years earlier.</div><div style="text-align: justify;"><br /></div><div style="text-align: justify;">I hope the work of Papaemmanuil et.al, Estey et.al and Dr. Heuser will influence the next revision of the WHO Classification of Myeloid Neoplasms and help move disease classification from using look, i.e. blood smears, and arbitrary cut points to using molecular genetics. The benefit would be that patients in the future don't find they are ineligible from a trial based on an arbitrary cut point and an uncertain measurement.</div>Niels Jensenhttp://www.blogger.com/profile/14071035070040472470noreply@blogger.com0tag:blogger.com,1999:blog-9471278.post-85389075119993768132022-03-03T13:22:00.006+01:002022-04-27T12:10:05.572+02:00Have we forgotten how the past progress in hematology was achieved?<p style="text-align: justify;">Yesterday the <a href="https://www.sciencedirect.com/journal/european-journal-of-cancer" rel="nofollow" target="_blank">European Journal of Cancer published</a> an editorial by two researchers from Canada and India titled "<a href="https://www.sciencedirect.com/science/article/pii/S095980492200048X?dgcid=author" rel="nofollow" style="font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif;" target="_blank">Contemporary clinical trials in hematologic cancer: Have we forgotten where we came from?</a><span style="font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;">" about the decline in randomized clinical trials in general and specifically in hematology. And the worrying change from trial endpoints such as overall survival (OS) and quality of life (QoL) to surrogate endpoints such as progression free survival or relapse free survival. The editorial is based on an article by Wesson et.al titled "</span><span style="font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; text-align: left;">Characteristics of clinical trials for hematological malignancies from 2015-2020: a systematic review", which is yet to be published.</span></p><p style="text-align: justify;"><span style="text-align: left;"><span style="font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;"></span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="text-align: left;"><span style="font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEiPBR52tLrVBL5SgY0jE35VPZxPe9VW1wDPiXOSXMKf1cvAFaX8HdA07mcDV9h99mBs4LPnZO-1POmSlrl1cTkED7U7PbzU3qarCGB9B0ndtFX7Vzsc5rjuMmY-BlAjXrAtsBlhINOzLokPS0uD95CjgMoNPxEg3GFP4EESKnlLePyEgZL61TU=s2400" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="Clinical trials by Nick Youngson CC BY-SA 3.0 Pix4free" border="0" data-original-height="1600" data-original-width="2400" height="213" src="https://blogger.googleusercontent.com/img/a/AVvXsEiPBR52tLrVBL5SgY0jE35VPZxPe9VW1wDPiXOSXMKf1cvAFaX8HdA07mcDV9h99mBs4LPnZO-1POmSlrl1cTkED7U7PbzU3qarCGB9B0ndtFX7Vzsc5rjuMmY-BlAjXrAtsBlhINOzLokPS0uD95CjgMoNPxEg3GFP4EESKnlLePyEgZL61TU=w320-h213" title="Clinical trials by Nick Youngson CC BY-SA 3.0 Pix4free" width="320" /></a></span></span></div><span style="text-align: left;"><span style="font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;">The editorial viewpoint made me think about the drug Glivec (Gleevec in USA) developed by Novartis and <a href="https://www.ema.europa.eu/en/medicines/human/EPAR/glivec" rel="nofollow" target="_blank">approved by EMA for use in CML in Europe</a> in November 2001 just a few months after <a href="https://www.cancernetwork.com/view/fda-gives-fast-approval-gleevec-treatment-cml" rel="nofollow" target="_blank">Gleevec was approved in USA</a>. The active substance in the drug is imatinib. I personally know one of the first CML patient in Denmark who got this drug, and more than 15 years later was one of the first to stop taking the drug. That CML patient is still alive and very active. At the time this patient stopped taking imatinib the survival curves for CML patients could no longer be distinguished for the similar curves for the general population. That in my view is true progress in treatment of hematological cancers.</span></span><p></p><p style="text-align: justify;"><span style="text-align: left;"><span style="font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;">Compare this to the approval of Vidaza developed by Celgene and approved by EMA in late 2008. In the randomized trial that was the basis for approval Vidaza with the active substance azacitidine showed OS improve from 15 months to 24 months for high risk MDS patients. Later real life experience was unable to active the OS reported in the trial, and for many patients the drug did not work or suddenly stopped working. That is disappointing. However, in the editorial Sengar et.al state that since the 1970's the randomized clinical trials in oncology have been getting larger and the observed benefit in oncology trials been a mosted median gain of 3-4 months in OS. So trial burden for patients has increased, but not the benefits.</span></span></p><p style="text-align: justify;"><span style="text-align: left;"><span style="font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;">According to Sengar and Booth the article by Wesson et.al only 21% of trials registrered on <a href="https://www.clinicaltrials.gov">clinicaltrials.gov</a> during 2015-2020 were randomized, and among these only 15% of trials used OS or OoL as the primary endpoint. In fact between 2009 and 2013 only 35% of cancer medicines approved by EMA had evidence of improved OS. I think if you ask patients, then their focus will be on OS and QoL. After all what is PFS worth if you have to deal with poor QoL due to the side effects of a drug?</span></span></p><p style="text-align: justify;"><span style="text-align: left;"><span style="font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;">But the choice of endpoint is not the only thing Sengar and Booth find worrisome. Apparently a large proportion of single arm phase I/II trials is not just a stepping stone to a randomized phase III trial, but are uncontrolled trials designed for regulatory approval. It is also my experience, that there is a huge pressure on regulators for the approval of new treatments with modest or no benefits in OS or QoL. Finally the financing of clinical trials have shifted to more than 80% being financed by pharma companies.</span></span></p><p style="text-align: justify;"><span style="text-align: left;"><span style="font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;">The editorial by Sengar and Booth and the review paper by Wesson et.al are clear calls that clinical trials should get on a patient centric track. And when you get sick your focus is generally: <u>To be cured, and get back to a normal life as soon as possible</u>.</span></span></p><p style="text-align: justify;"><span style="text-align: left;"><span style="font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;"><br /></span></span></p>Niels Jensenhttp://www.blogger.com/profile/14071035070040472470noreply@blogger.com03550 Slangerup, Danmark55.845994 12.16976727.535760163821152 -22.986483 84.156227836178843 47.326017tag:blogger.com,1999:blog-9471278.post-27493463115241956762022-03-02T09:38:00.001+01:002022-03-02T12:03:08.120+01:00About me<p> I am an myelodysplastic syndrome patient living in a small town in Denmark. On my 23rd wedding anniversary a hematologist at <a href="https://www.nordsjaellandshospital.dk/" rel="nofollow" target="_blank">Nordsjællands Hospital</a> in Hillerød about 40 km northwest of Copenhagen told me that I had a chronic disease called Myelodysplastic Syndrome. My wife, who was with me at the hospital, told me that he also told the type of MDS was refractory cytopenia with multilineage dysplasia. I was started on treatment with EPO (the Aranesp version), my wife was instructed in the waiting room on how to give me the injections, and then we went on to celebrate our anniversary first with an afternoon in Helsingør and later with a dinner at restaurant Jan Hurtigkarl in Aalsgaarde. I still remember it as a very lovely evening, where from our window table in the restaurant we could see the royal yacht sail north from Øresund into Kattegat. That was July 8th, 2005.</p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgthWgHW9GNYMUwjXWeLPfOppX9aUhj1hIqGgkIU1psBi99UBox698IzlNXQ-vPnrPZud4h4RnKikLZE1ZxhCS1i3qdTRslFv_M35veLcAdcawFT1mIUOFf8isUXJbFnRuRFmje1KcJ3kJ7QU01J-IuTIHVCq8VEmvl0ji8YFxEmhZ-jOeAgvc=s1874" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="891" data-original-width="1874" height="152" src="https://blogger.googleusercontent.com/img/a/AVvXsEgthWgHW9GNYMUwjXWeLPfOppX9aUhj1hIqGgkIU1psBi99UBox698IzlNXQ-vPnrPZud4h4RnKikLZE1ZxhCS1i3qdTRslFv_M35veLcAdcawFT1mIUOFf8isUXJbFnRuRFmje1KcJ3kJ7QU01J-IuTIHVCq8VEmvl0ji8YFxEmhZ-jOeAgvc=s320" width="320" /></a></div>Today is March 2nd, 2022, and I am still alive, although back in 2005 my wife thought she would loose me within a year and hence our good friends from our six years in Sarnia, Canada visited Denmark that fall to comfort her. During that visit our friends treated us and our children to dinner at our local thai place Restaurant Bangkok. Another enjoyable evening.<p></p><p>Around 2011 after having accessed the MDS Foundation website many times I wrote to the foundation, and basically told them, that their website looked like something from the early days of the internet. That resulted in call with their chairman of their board and their director at the time. The outcome of the talk was that they contacted some local people in USA to upgrade their website. Later i was invited to a meeting in Edinburgh were local MDS patient organisations were discussed, and were I met Sophie Wintrich - the current director of MDS Patient Support Group UK. A result of the meeting in Edinburgh was an invitation to Partners for Progress in a small town outside Munich. Partners for Progress was a two day event hosted by Celgene to dialog with patient organisations. At a later Partners for Progress event I had the opportunity to meet the CEO of Celgene and discuss with him how patients could get influence both on pharma companies and on European politicians in Bruxelles.</p><p>Over the past 10 years I have learned a lot about MDS especially since the small Danish MDS patient support group I started at the end of 2013 was merged into LyLe - a Danish support group, which now support lymphoma, leukemia and MDS patients and has over 1000 members and over 100 MDS patients in their facebook group for MDS patients and caregivers. Thanks to LyLe I was able to attend EHA in Copenhagen in 2016 and EHA in Stockholm in 2018 as well as recent virtual conferences both in Europe and USA.</p><p>In this blog I will write about anything related to MDS and my life with MDS. As a Canadian doctor said at the first meeting for MDS patient in Denmark: Most MDS patients don't die because of their disease, but with the disease.</p>Niels Jensenhttp://www.blogger.com/profile/14071035070040472470noreply@blogger.com0