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- [00:02]
A
Welcome to the American Society of Hematology Conversations with Blood Authors podcast hosted by Dr. Laura Michaels. She discusses CPX351 versus donorubicin cytarabine plus gemtuzumab ozogamycin in older adults with non adverse risk NCRIAML18 with Professor Nigel Russell, MD. She then talks with Professor Uwa Platzbecker about his article Azacitidine to treat Measurable Residual Disease in patients with MDS a final long term results of the Relaza 2 trial.
- [00:38]
B
I'm so happy to welcome Professor Nigel Russell of Guy's and St Thomas Foundation Trust in the UK to join us and discuss their study on CPX 351 versus Donna Rubicin Cytarabine and gemtuzumab ozogamycin in older adults with non adverse risk and AML. This is the NCRI AML 18 study. Thank you so much Professor Russell. I wonder if we could start by just giving a little brief overview of the study schema for our listeners and what was the question being asked here?
- [01:15]
C
Thank you very much, Dr. Mohill. The NCRI group have run a sequence of trials over the last 20 years to try to improve the outcome of intensive chemotherapy in older patients over the age of 60 with AML. The first trial which we did on AML 16 showed the addition of GO to DA chemotherapy improved the outcome for older patients. This was just using a single dose of go, but the only benefit was in patients with favorable OR intermediate risk AML, there was no benefit for adverse risk AML. So in AML 18, which started about 10 years ago now, version one of the trial compared a single dose of GO with the same backbone chemotherapy versus a fractionated schedule of just two doses of go, and we found that was well tolerated. The fractionated dose, which we call Dago 2, improved survival compared to the single dose that we'd previously used. But this benefit was really seen in terms of reduction in MRD and it was seen primarily in those patients who proceeded to allograft as consolidation and we thought that was due to the better MRD status of those patients. Version 2 of the trial which we're now talking about AML 18 version 2 is when we randomize patients with the same non adverse risk AML over the age of 60 to CPX or Dago2. And the reason for proceeding to CPX was based upon the results of the trials in secondary aml, which had shown an improvement in survival in patients with secondary acute myeloid leukemia compared to 3,7 da chemotherapy, not including GIO of course, and this benefit was primarily due to reduced toxicity of CPX and also due to an improved outcome in those patients proceeding to allograft. So the question was did this benefit of CPX that have been reported in patients with secondary AML translate to patients with de novo AML without adverse risk cytogenetics and we excluded patients with known secondary aml. We were studying a completely different population to that studied in the pivotal CPX trial.
- [03:38]
B
And what was the most surprising finding that your group is reporting the findings?
- [03:44]
C
Well, firstly, the Dago 2 was associated with a better response rate, improved response following the first cycle of treatment. There was a significantly better CRCRI response response rate in these patients. There was also a superior achievement of MRD negativity in those patients as well and this translated particularly into an improved overall and event free survival in favor of Dago 2 at a three year follow up. And this benefit was particularly seen in patients with de novoaml mutations such as NPM1 mutations. These patients did significantly better with Diego 2, but also in patients with secondary AML mutations. About 50 to 60% of patients in the study had secondary AML mutations not associated with a history of antecedent haematologic disorder. And these patients we thought might do better with CPX, but the benefit was seen with Diego 2 in this population. So unlike the pivotal study, we showed no benefit of CPX in patients with de novo AML or AML with secondary mutations without a history of prior antecedent hematological malignancy.
- [05:10]
B
I know there's still about a third to a little bit more than a third of the patients here went on to transplant in CR1. Was there any reports of VOD in the patients that got fractionated gemtuzumab?
- [05:24]
C
In our studies, we've done a lot of studies with GO over the years and the incidence of VOD has been between 1 and 2%. There was no specific incidence of VOD reported in this study, but that's the overall proportion of patients that develop VOD and it's not significantly different to the population not receiving vgo. So we don't think there's a signal because of the lower doses of GO that we use. We've not seen a VOD signal with these lower doses, one or two doses of go. I would say that the post transplant outcome was good in both arms. The survival was about 60% in both arms for those patients proceeding to transplant.
- [06:11]
B
So this study was conducted between 2019 and 2022 and in the interim between 2022 I think one of the most difficult groups now to design trials for is that fit older patients. Will your group be continuing with intensive cytotoxic inductions or trials that include an ARM for that in the over 60 over 65 fit group or will you be moving into more of a moderated intensity induction in your studies?
- [06:41]
C
We do have a randomized trial proceeding at the moment which is recruiting very well. Patients with NPM1 mutated AML over the age of 60 are randomized to receive a Venn based low intensity VENN and low do cytarabine actually versus Diego 2. So that study's not far off fully recruiting and so we should have results of that in the next year or so, I hope. Beyond that we are interested in looking at the other populations of older patients otherwise intermediate favorable risk disease. The question is we would like to randomize those patients against a VEN based non intensive regimen. Obviously this is an area of active investigation, but these studies have been primarily, as I want to emphasize, in patients with non adverse risk cytogenetics.
- [07:35]
B
That is so interesting. Thank you so much for you and your group for all the work that you've done for patients and for this time today at the podcast.
- [07:43]
C
It's a pleasure.
- [07:44]
B
Welcome Professor Platzbecker, I wonder if you might just tell listeners a little bit about the context in which this trial was designed and outline a little the study schema.
- [07:57]
D
Thank you first of all for having me here at this blood podcast. I think I would get started with the general background of the study, which is the knowledge and I think several groups including MRC have actually nicely shown the prognostic impact of measurable residual disease or MRD in the context of MDs, high risk MDs, but especially AML patients undergoing chemotherapy based regimen and achieving a complete hematologic remission. So in those patients actually maintaining an MRD level or with a kind of increase of MRD during the time course after those patients are at a high risk of developing hematological relapse. So the Relaza 2 trial was a prospective multicenter trial by the study Alliance Leukemia in Germany, which actually had two main questions. Number one, can MRD be effectively targeted and treated with azacytidine and in order to prevent or at least delay the hematological relapse of patients with high risk MDs in the AML? And secondly, and this was actually based on the study design which actually prospectively included patients in complete remission with high risk MDS in the AML to undergo Regular MRD assessments every four weeks over a period of two years after completion of their standard therapy, which could be either chemotherapy based or chemotherapy based followed by allogenic stem cell transplantations. The second objective and question of the trial was what's the natural course of the disease of those patients who are monitored prospectively and actually remain MRD free? And the outcome? Maybe I start with the first objective, with the first question. Patients who became MRD positive. And we relied actually on several MRD markers, some of them being consensus now with npm1 as a very reliable MRD marker. But we also started the study primarily with, with a pilot trial almost 20 years ago in patients after allogenic stem cell transplantation, where at the time of the study design MRD testing was not available. So Christian Tiede from the Dresden University Hospital actually developed a very sensitive, actually as sensitive as a nested PCR CD34 chimerism analysis with enriched CD34 cells in from the peripheral blood, which was actually as reliable as a nested PCR in our days based on those MRD markers. Patients who became MRD positive were treated with standard dose of azacytin. I'm saying this because there have been a lot of clinical trials including maintenance therapy with azacytidine after stem cell transplantation, which used very reduced, sometimes half of the standard dose, sometimes only five instead of seven days. So we relied on the published and available azacytin dose and patients actually received six cycles of full dose azacy. And in patients responding to it, there was actually a de intensification strategy. So it was first reduced to five days, then reduced to every eight weeks, and the maximum period of treatment was actually two years. And to come now to the major conclusion of the trial is that 60% of the patients did not relapse after six months. So the study met the primary endpoint and out of those responders we had 25%. So 1/4 of the responders who never relapsed even after cessation of azacytin. So a quarter of the responders actually also could maintain a treatment free remission. So azacylitin, in contrast to what we know in high risk MDs or sometimes AML, where the drug is considered unstoppable or is continued as long as possible, these patients actually could stop MRD targeted therapy after two years and remained treatment free. So I think this is the, let's say main message from the MRD targeted and relapse prevention part of the trial. The second main message is that those patients who were continuously monitored over two years and some of them even continued the monitoring. There was an exceptional disease free and overall survival exceeding 85%. Also in the context of a prospective study confirming the prognostic importance of MRD in the setting of high risk MDs and AML.
- [12:56]
B
That's just fascinating. So as I understand it, there's a group of patients who become MRD positive and then of those, they're all treated with the azacytidine and some stay positive but don't have hematologic relapse and some go from positive to negative with the azacitine alone. Correct?
- [13:18]
D
Correct.
- [13:19]
B
Okay. And were there markers that say that group is going to progress to frank relapse versus be able to disappear? Did that have to do with the DLIs that were given and did that have to do with the amount of MRD that was detected?
- [13:34]
D
Very good points. So number one, DLI was allowed during the study, but I have to say that only the minority of patients did receive it. And why was that so? Because, and this is also, I think, aligning with our clinical experience that you can actually relapse irrespective of the presence of chronic GbHD. So many patients still had slight amounts of immunosuppression which was then tapered but not like switched off. There was a taper strategy which was allowed, but the majority actually did not have immunosuppression but still had mild signs of gvhd. And again, it was at the discretion of the investigator whether to give or not to give dli. So this was not something we actually recommended or mandated protocol. Actually what you mentioned secondly is very interesting and because we always consider MRD minimal, now it's called measurable, but it was, as you know, it was called minimal. But MRD has a wide range of, let's say, quantity. So patients with a high amount of minimal measurable residual disease actually had a very high likelihood even if the MRD stayed stable to basically relapse at the end of the day. So on a multivariate analysis, we could find that the level of MRD also had a great impact whether the patient was able to clear MRD with azacylidine alone. Secondly, we also made a comparison between patients after allo and non allo. There was also a considerable amount of patients without allo transplant. And actually, in contrast to our previous pilot trial, we could not find a difference in the behavior. So because you may say, well, it's a after allo, it's all about immunology and dli. And so patients actually have a better graft risk leukemia effect. No, this was not the case. There was a numeric difference in favoring this in patients after allo. But in general, also patients after conventional chemotherapy cleared MRD very well and stayed sometimes free of azacylitin.
- [15:41]
B
This is just great work and very interesting, especially when you think about what we do next and sort of what are the next questions to ask. So thank you for this foundational study. Appreciate you joining us.
- [15:53]
D
Thank you.
- [15:57]
A
Thank you for listening to this episode of Conversations with Blood Authors. To read the articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.