, which is focused on Acute Myeloid Leukemia. In today&rsquo;s

presentation, my colleagues and I will review 4 clinical cases. We will discuss an individualized approach to treatment for each patient and will review key trial data that impact our decisions.

I am Dr Naval Daver, associate professor in the Leukemia Department at the [University of Texas] MD Anderson Cancer Center in Houston, Texas.

Dr James McCloskey, chief of the Division of Leukemia and member of the Adult Blood and Marrow Stem Cell Transplantation Program at the John Theurer Cancer Center of Hackensack University Medical Center in Hackensack, New Jersey.

Dr David Rizzieri, professor of medicine, chief of the Section of Hematological Malignancies, and associate director for clinical research in the Division of Hematological Malignancies and Cellular Therapy at Duke Cancer Institute in Durham, North Carolina.

Dr Olga Weinberg, director of hematopathology and flow cytometry in the Department of Pathology and assistant professor of pathology at the Boston Children&rsquo;s Hospital and Brigham and Women&rsquo;s [Hospital] Harvard Medical School in Boston, Massachusetts.

And, Dr Usama Gergis, associate professor of clinical medicine in the Division of Hematology and Medical Oncology at the Weill Cornell Medical Center in New York, New York.

Thank you for joining us. Let&rsquo;s get started with our first case.

Dr McCloskey, if you would like to discuss our first case, which is a

-mutated acute myeloid leukemia, please take it away.

Thank you. Our first case today is a 44-year-old woman who comes in to her primary care physician with flu-like symptoms and fatigue that she says have been present for around 2 weeks. Prior to this,&shy;&shy; she was healthy and had no remarkable past medical history. Upon work-up, the primary care doctor notices that her WBC [white blood cell count] is elevatedit&rsquo;s 65,000 white blood cells&mdash;and they know that there are blasts observed in circulation. The patient is thrombocytopenic with a platelet count of 45,000, anemic with a hemoglobin of 10, and borderline neutropenic with a neutrophil count of 1.1. Her other [laboratory results] are fairly unremarkable. She has normal liver and kidney function, and her cardiac [examination] is also normal, including an echocardiogram that shows an intact ejection fraction.

The patient undergoes a bone marrow biopsy that shows 65% blasts. Her cytogenetics returned and these are normal. Molecular testing is sent and confirms the presence of an

mutation. The patient is also noted to have a

ITD [internal tandem duplication] mutation present at a low level with an allelic burden of .28. In addition to these, mutations are observed in

Case 1: FLT3+ AML

This is a common case that a lot of us will see here: a newly diagnosed

ITD [internal tandem duplication]-mutated acute myeloid leukemia [AML]. It has some other mutations as well

. Basically she&rsquo;s coming to us here for evaluation.

Dr Weinberg, I&rsquo;m sure you receive a lot of cases of this nature. What would be the triage and work flow in the hematopathology and molecular [laboratory tests]?

Every bone marrow, especially for patients with acute myeloid leukemia, would get a morphological evaluationthe aspirate smear. We&rsquo;ll look at the appearance of the blast, we&rsquo;ll look at the background cells, and we&rsquo;ll look for dysplasia. We&rsquo;ll tabulate all those findings, and at the same time we perform cytogenetic analysis

next-generation sequencing [NGS] analysis, sometimes an AML FISH [fluorescence in situ hybridization] panel. When all these tests come back, we can give a full WHO [World Health Organization] classification, which takes into account a presence of some of these cytogenetic abnormalities and mutations, and we show final diagnosis.

Before the cytogenetic tests come back, we can say it&rsquo;s an acute myeloid leukemia. Of course, pending

mutation, we would say it&rsquo;s just AML with

-mutated AML. That&rsquo;s how we work up acute myeloid leukemia.

What&rsquo;s the timeline from when you get the aspirate biopsy sample to issuing an initial diagnosis? Then, in your group in Brigham [and Women&rsquo;s Hospital], what are the main molecular findings that they&rsquo;re looking for, and how quickly are those molecular and cytogenetic analyses becoming available?

We can look at an aspirate within a few hours of its being done, and flow cytometry, of course, is being done at the same time. Within a few hours, we can issue a diagnosis of acute myeloid leukemia. The next-generation sequencing, which at Brigham is called Rapid Heme Panel, comes back within a week, sometimes about 4 to 5 days, because we have a few runs a week. We should have a full diagnosis within a week. Cytogenetic analysis, we can have a read within 24 to 48 hours.

OK. Is it a practice that you&rsquo;re seeing that physicians are waiting for this information, or are they proceeding with treatment and then using the molecular [test results] as the treatment is going on?

Well, it depends. If it&rsquo;s an acute promyelocytic leukemia, some form of therapy will be started. Most of the time our clinicians will wait until next-generation sequencing is back, because that would really determine which trials patients go on. The results of that test are very crucial.

Yes. Anything different we&rsquo;re seeing, Drs Rizzieri or Gergis, in your practice about molecular?

I think you&rsquo;re in a very privileged site. The turnaround you&rsquo;re provided as clinicians is pretty good for NGS. In most of our sites, that takes a couple of weeks, not to run the test, but because of all the data crunching that&rsquo;s required. While we run the NGS panels, we do a separate PCR [polymerase chain reaction] for the targetable upfront lesions, probably what a number of the other clinical sites do. We would search for

with separate orderables for PCR to get that turnaround within the first couple of days. Similar to what was mentioned,

obviously impacts our upfront therapy, and with recent approvals, so would the

, at least on-label. We would look for the same things, but have to get to it a little bit differently to try to get the results in a rapid fashion.

I think we do something a little bit similar, where we do an 8-gene molecular panel, which is a kind of a rapid panel that includes

so the most important&mdash;and then you get the larger panel. We get it in about 9 or 10 days, but that&rsquo;s usually not something we&rsquo;re waiting for in practice. I think looking for secondary, or MRC [myelodysplasia-related changes]-associated features, at least for

, as well as cytogenetics, is important, and this actually impacts our standard of care. What about you, Dr Gergis?

Similarly, we have our in-house panel that turns out

, and then we wait for the rest, and it takes about 4 to 7 days.

before treatment, or are you really using it more for salvage decision?

Depending on the clinical trials that we havecurrently we do not have

upfrontwe&rsquo;ll depend on it in the salvage setting, or with a clinical trial or standard of care.

I&rsquo;m interested in your sense, and maybe James&rsquo;s and Olga&rsquo;s, of the pathology here. With this presentation with a high white count and a

it&rsquo;s always unclear to me how I interpret the allelic burden. In all of these other genetic changes, do we think of that as the driving problem, particularly with this high white count? I don&rsquo;t typically think of

driver leukemias as presenting with such a high white count, necessarily. Maybe that&rsquo;s just my misperception.

-mutated AML does tend to present with a very high white count, so in that sense, it&rsquo;s pretty typical.

by itself can also present with high white count. It&rsquo;s not necessarily unusual. Of course, it probably also depends on how long before the patient was seen.

-mutated patients presenting with high white counts. I think your question is a very good one. How does the allele burden relate to the white count? We have not seen a clear correlation that those who are more highly burdened will come with more leukocytosis, or vice versa. Especially with the data that Dr McCloskey is going to talk about, we don&rsquo;t even know therapeutically if it has an impact. We get the allelic burden, but I think a lot of sites don&rsquo;t even get it. They just say positive or negative, but we don&rsquo;t really do much on it. What do you do, James?

I think that&rsquo;s exactly true, and I think that where we find ourselves right now is in a position where we often have more information than we sometimes know what to do with. I think we haven&rsquo;t yet standardized

testing well enough to know where that allelic burden cutoff should be for high or low. Even if you look at the different guidelines, they often set that cutoff at different places. The different trials have used different cutoffs for allelic burden. It&rsquo;s certainly one of the challenges we face, not only in this example in an upfront setting, but also later and in the context of relapse. How do we determine which driver mutation is really the most important to target?

I would also add that variant allele frequency is very dependent on the kind of testing that you use, and it may not even be reproducible from one NGS panel to another. We recently reported on variant allele frequency in

mutation, which is generally a favorable mutation. Within those patients, it actually seems to subdivide into patients who don&rsquo;t do well, who have a high variant allele frequency. In our study, it did correlate with blast count, so I think there&rsquo;s a lot that we&rsquo;re still learning.

Even between [laboratory tests], you may not have the same variant allele, so that makes it even more complicated.

Right. That makes it even more complicated, and it&rsquo;s hard to draw that conclusion, but it does underline the biology.

One of the other things we&rsquo;re finding, especially as we have, fortunately, new therapeutic options that are available to patients and some of these results become more valuable to us, is that sometimes even the quality of the aspirate itself is so variable. As we start thinking about MRD [minimal residual disease] and all the other molecular tests, if we have a sample that&rsquo;s drawn after 12 other mL have been removed, most of that is really peripheral blood. How does that really translate? Especially in this era where we are making important treatment decisions, I think it&rsquo;s a real challenge for us.

So is it safe to say that allelic burden for

ITD has no bearing in treatment decisions today?

I would say yes. Based on the treatment we&rsquo;re going to discuss, I think if you&rsquo;re positive, you&rsquo;re positive, and negative&hellip;. Should you transplant people who are

allele, which is an emerging research topic? Today I think we would probably treat them, transplant them, give them midostaurin, and then move ahead.

Case 1: Allelic Burden in FLT3+ AML

James, how would you approach this patient for treatment? Let&rsquo;s say you&rsquo;ve got this data, this patient is now sitting in front of you&hellip;. What would you discuss and offer?

We have this patient, a 44-year-old woman with confirmed

-mutated disease. She does have some other concerning mutational abnormalities, most notably the

mutation. Considering all that, this is a patient who&rsquo;s not had therapy before, and this is a patient who we would certainly consider for induction with 7+3 [cytarabine/daunorubicin], plus midostaurin, based on the results of the RATIFY trial.

With these people you would do the midostaurin day 8 to 21 or would you do continuous? People have debated this.

We would do the midostaurin according to the protocols on day 8 through 21. I think the rationale behind that was 2-fold. I think from a molecular standpoint, there was some concept that potentially inhibiting

upfront might reduce the cytotoxic effects of the chemotherapy. Additionally, when we gave the drugs in combination with chemotherapy continuously, there was some concern regarding toxicity, which was much more tolerable when we gave it for a 2-week period following the induction chemotherapy.

We would ideally start it on day 8. I think that when you talk to folks in the community, we already talked about the potential lag behind with molecular results, and then navigating, potentially, that patient&rsquo;s insurance provider. It&rsquo;s unfortunately not unusual that we might be starting midostaurin after day 8, and I think that&rsquo;s not ideal, but given the data we have, I think it makes sense to add it when it&rsquo;s available. So even if that starts on day 11, that would be our standard protocol and I think probably the best approach in the real-world setting.

I think that&rsquo;s important because we get a lot of calls, and I&rsquo;m sure you all do, that I got the results on day 10 or 11, and should I not do the midostaurin because I&rsquo;m not fitting the protocol? I think, there&rsquo;s no data, but we would just do it from day 10 for 2 weeks, because I think adding the TKI [tyrosine kinase inhibitor] is probably more important than doing it on day 8, which is optimal. Dr Rizzieri, what do you think?

I think it highlights the point of working with good pathologists to get the data back quickly, because there really seems to be more and more evidence that earlier addition of

We want to push to get that data as soon as possible.

Yes. Dr Rizzieri, let&rsquo;s have a little bit of a curve ball about something that we get asked in all these symposia. What if this patient had MRC [myelodysplasia-related changes], and this was a younger patientlet&rsquo;s say she&rsquo;s a little bit older, a 66-year-old&mdash;and has a

, which we thought would be very uncommon, but about 20% of the people in the Vyxeos study had it. What would you do for this patient? Would you say, &ldquo;I go for

; the TKI is more important.&rdquo; Would you consider Vyxeos? Would you consider [azacitidine/venetoclax]? There&rsquo;s no right answer, but what do you think?

The short answer is yes. I could see doing any of the 3 scenarios you laid out depending on the patient conversation. That&rsquo;s why I think we&rsquo;re privileged in many of our clinics in academia to still have enough time to sit and have this shared decision making conversation with the patient to try to best understand their goals of care.

If we&rsquo;re initially looking at this as a curative event, then right or wrong, I still feel that aggressive therapy today would be what I&rsquo;m leaning to. In terms of aggressive therapy in the scenario you laid out, then I would choose a CPX-351 and lead to transplant. However, in this particular case, we see the

abnormality as well. That really concerns me. I&rsquo;m not sure we&rsquo;re benefitting these patients with aggressive chemotherapy very much, so I wouldn&rsquo;t feel badly if, in consultation with a patient or another referring physician, they went a different path. A [venetoclax]/hypomethylator combination or something like that, I don&rsquo;t think would be unreasonable in a number of these patients. I think any of those would be on the table in my view. I&rsquo;d be curious as to what my colleagues think.

Anybody else feel differently about this?

I agree. A lot of it, for me, would revolve around age, and what is the AML [acute myeloid leukemia] MRC? Is it just multilineage dysplasia? In that case, I don&rsquo;t find that often as convincing of an argument to pursue Vyxeos. The data there are a little more conflicting, and I think the

mutation is really the most challenging. In a 44-year-old, I completely agree. I&rsquo;m not often excited about the efficacy endpoints in these

-mutated patients. I think we&rsquo;re trying to use [venetoclax] and hypomethylators conservatively, acknowledging that the N [number] in those clinical trials where we are drawing this presumed better response from, is relatively small. If I&rsquo;m on the fence, in an older patient, or maybe in a patient who has some other borderline comorbidities, I&rsquo;m certainly much more inclined to think of that patient as a better candidate for less intensive therapy.

You both brought up some very interesting points for the audience. One is that this fit for [chemotherapy] is no longer purely being based on age. It&rsquo;s really more on biology, because both of you said

and I totally agree with that. A 40-year-old

is not really much better off than a 60-year-old or 65-year-old. I think we&rsquo;re starting to see where people are saying, even for younger ones, is there benefit to giving them [chemotherapy]?

The second thing you said, which we&rsquo;re looking at too at [The University of Texas MD] Anderson [Cancer Center]: is all MRC the same? I think the feeling is that it&rsquo;s not. Some of these softer MRCs may not be the same negative prognostic as the ones with true MDS [myelodysplastic syndrome] or secondary AML, but there&rsquo;s not enough data for that, so we have to look more into that. The third thing is, could you combine these agents, which is something that people are going to look at? Can you add Vyxeos? There are trials ongoing for that, and that could be a good patient for those. There&rsquo;s no right answer. This is where we&rsquo;re privileged, where the right answer 5 years ago was always 3+7 [daunorubicin/cytarabine]. Today, we can have 3 right answers, so that&rsquo;s good.

Case 1: Treatment Recommendations for FLT3+ AML

In the interest of time, we&rsquo;ll move on. Dr McCloskey, if you could give a brief overview of the

I&rsquo;m happy to. As we mentioned, it&rsquo;s been an exciting couple of years in AML [acute myeloid leukemia], but the RATIFY trial looking at the addition of midostaurin to induction in a consolidation chemotherapy in newly diagnosed patients was really the study that resulted in our first FDA approval. Again, this was de novo AML patients between the ages of 18 and 60 with a confirmed

mutation. Patients on this trial were risk-stratified according to their

mutations, but it did accrue patients with TKD [tyrosine kinase domain] mutations, as well as ITD [internal tandem duplication] mutations. They were then further risk-stratified based on allelic burden. In this case, the cutoff for risk for high or low was .7.

This trial was a tremendous effort on the part of many investigators, and over 3000 patients were screened, with eventually 717 patients being randomized in a double-blind fashion to either midostaurin or placebo. Midostaurin was combined with induction cytarabine and daunorubicin, with midostaurin being added on days 8 through 21 at 50 mg twice daily. For any patient who achieved a CR [complete remission], they were then eligible to proceed with a stem cell transplant when that was available. Likewise, until that point, they continued with consolidation with high-dose cytarabine in combination with midostaurin added days 8 through 21 at 50 mg twice daily.

Importantly, I think after this, patients were eligible for a maintenance arm of the study. Patients were not randomized to maintenance. In this context, midostaurin was administered 50 mg twice daily continuously days 1 through 28.

If we look at the breakdown of the characteristics of the patients accruing to this trial, patients had a median age around 47, in keeping with the patient that we just discussed. They were well-stratified, as we discussed, in accordance to their subtype of

whether it be ITD, TKD, or a low or high allelic ratio.

When we broke down responses in those patients, we did not see a difference in CR during the first 60 days. CR rate was just over 50% in both arms. When we expanded to look at CR during induction or consolidation, including patients that subsequently achieved a CR after coming off study, there was a favor. The trial did favor midostaurin with a 66% CR rate compared to 59% in the placebo arm with a

This improved CR rate and the use of midostaurin resulted in improvement in median overall survival to 74 months in the midostaurin arm, compared to 25 months in the placebo arm. Again I think, especially at the time, this was super exciting data. It took us decades to move those curves. Lots of things added to 7+3 [cytarabine/daunorubicin] had failed to separate those curves over the preceding decades.

Many patients treated on the study did proceed to stem cell transplant, and that remains our standard approach for these folks. If we look at outcomes based on those patients who underwent stem cell transplant, we saw that the greatest benefit to stem cell transplant and survival in the midostaurin group was really seen in those patients who went to transplant in CR1 [first complete remission].

This gets at our question about how we approach these patients with

mutations based on the allelic ratio, and midostaurin is a pan-tyrosine kinase receptor. We talked about it inhibiting

, but it actually hits a variety of other receptors, as well, so I think it&rsquo;s particularly relevant to our discussion about thinking about the type of

mutated patients we might select. The bottom line is that all patients on this study really benefited from midostaurin. If we looked at survival based on subgroup, TKD patients benefit, as did patients with a low allelic burden. I think based on that, we really can&rsquo;t yet use allelic burden to decide whether midostaurin should be added to those folks as frontline therapy.

The other thing that was really exciting about this study was that it demonstrated that we could safely add something to 7+3 [cytarabine/daunorubicin] without getting a lot of unexpected toxicities. If we looked at grade 3 and 4 or 5 adverse events, we didn&rsquo;t see a significant increase in infectious complication or myelosuppression. The only thing that fell out of that was an increased risk of rash, which most of us who treat AML feel comfortable with if we&rsquo;re getting an improved efficacy.

With that in mind, we&rsquo;ll touch briefly on another

inhibitor, gilteritinib. Currently, in our commercial use of this drug, it is for patients with relapsed and refractory disease, but I think we&rsquo;re going to continue to see expanding indications for the

inhibitors in both upfront and the relapsed setting.

The ADMIRAL study was a phase III randomized study looking at patients with

mutated AML who were relapsed or refractory. Just over 300 patients accrued to this study, and they were randomized in a 2-to-1 fashion to gilteritinib versus salvage chemotherapy. There were a variety of chemotherapy options for that standard arm. We included low-dose cytarabine, or hypomethylators for patients who were more frail, as well as intensive salvage therapy, including cytarabine-based regimens like FLAG-IDA [fludarabine/cytarabine/G-CSF/idarubicin] or MEK [inhibitors]. &nbsp;

Again, the primary endpoint of interest in this study was CR rate and overall survival. At any point, a patient who had a remission and appropriate donor could proceed to stem cell transplant.

I think this is an interesting model because it raises the potential for us to use a targeted agent in salvage instead of high-dose chemotherapy, and in fact, when we looked at the results in this phase III study, we show that they favored the use of a molecularly targeted therapy. The response rates were almost double for the gilteritinib group compared to salvage chemotherapy. If we look at responses, the CR rate in the gilteritinib group was 21% compared to 11% in the salvage chemotherapy group.

Response rates of CR and CRh [complete response with partial hematologic recovery] were 34% compared to 15%, and more patients treated in the gilteritinib arm were able to proceed to stem cell transplant26% compared to 15%. All of these improved responses translated to an improvement in median overall survival in the gilteritinib group&mdash;9.3 months compared to 5.3 months. Again, I think it&rsquo;s an exciting era where we&rsquo;re talking about a molecularly targeted therapy with a significantly more appealing [adverse] effect profile than chemotherapy.

Case 1: Targeted Therapy in FLT3+ AML

Moving to our next case, we&rsquo;re going to discuss a patient with AML [acute myeloid leukemia] with myelodysplasia-related changes, also called MRC. Dr Rizzieri, could you please do the discussion?

Great. Thank you very much. I&rsquo;m really excited you chose this case because this diagnosis is still somewhat confusing to me, so I&rsquo;ll be really interested in our pathologist&rsquo;s contribution here.

As you see in case 2, this is a 70-year-old gentleman with MDS [myelodysplastic syndrome] diagnosed approximately a year and half before presenting to our center with a very good performance status. The patient previously received decitabine for 6 cycles, and responded, but did not achieve complete transfusion independence. The patient did experience mild depression and fatigue with therapy, but no other serious complications and no infections were noted.

Past medical history was fairly noncontributory and only notable for hypercholesterolemia that was well controlled with lovastatin. White counts at presentation to us were notable for a white count of 1.9 with an ANC [absolute neutrophil count] of .9, so mildly decreased, a hemoglobin of 9.2 with hematocrit of 31. Platelets were markedly decreased at 42,000 with peripheral blasts at 16%. A bone marrow aspirate and biopsy were performed, and as we see, the blast percentage was 65%. Cytogenetics were returned, indicating del [deletion] 5q and a del 7q. Molecular analysis was performed, indicating that

was not mutated, and a 75-gene panel was still pending at the time of evaluation. A diagnosis was made of AML with myelodysplastic-related changes, or AML-MRC.

Thank you very much. Dr Weinberg, we&rsquo;ll start with this patient now, getting the samples to you. What would be the traditional work-up in a patient who you did not know, who, for example, has MRC and this new AML. What FISH [fluorescence in situ hybridization] probes would you use, and what are the other nuances of the diagnosis?

In all cases, we would look at the bone marrow aspirate, and we&rsquo;ll also look for dysplasia in the background. Taking aside the blasts, we would look at neutrophils, erythroid cells, and megakaryocytes and see if they&rsquo;re abnormal.

In a setting of MDS, we would only need 10% of cells to be dysplastic to call it MDS. In the setting of AML, we recognize that the body may be under stress and there might be a lot more dysplasia around, so we would require over 50% of the cells to be dysplastic. If we see more than 50% of cells in each lineage, and we need 2 lineages to be effective, then we would say this case has morphological dysplasia. This is therefore, AML with myelodysplasia-related changes.

This is kind of a confusing entity because you can&rsquo;t see a lot of dysplasia in other types of AML like therapy-related AML. Even AML with recurrent genetic abnormalities can sometimes have that kind of dysplasia, especially things like 6;9 translocation.

Aversion of chromosome 3 or 3q can have a lot of dysplasia in the background. If you see morphological dysplasia, that would lead us to AML MRC. If cytogenetics come back and instead of a normal karyotype, we have abnormalities of chromosome 5 or 7, or we have at least 3 or more unrelated cytogenetic abnormalities, which we often refer to as complex karyotype, that&rsquo;s what we could consider as AML-MRC.

A third way to get into this category is to have a history of a previous myeloid neoplasm like MDS or a mixed MDS/MPN [myeloproliferative neoplasm]. That would also qualify somebody as having AML with myelodysplasia-related changes.

Of course, that could be a little confusing because you could say, why is this not therapy-related AML, if they had therapy? Some of these nuances are just hard, clinically, to sort out, but we would do the same thing that we would usually do. We&rsquo;d do a cytogenetic analysis, in which you grow the cells and you look to see any abnormalities. The problem with FISH probes is that you have limited probes. Most [laboratories] will do probes to chromosome 5, 7, or 20q, and maybe chromosome 11. In cytogenetic analysis, you really want to see the entire range of abnormalities that may be present.

The problem with cytogenetic analysis is that it may not grow. Especially if it&rsquo;s being sent out to a reference laboratory, it may fail, for maybe other sorts of the reasons. That&rsquo;s where FISH can still be really helpful.

Then there&rsquo;s been some reports where some abnormalities that we see on a mutational panel may indicate an underlying MDS. If we see things like

mutations, that may indicate that even if there&rsquo;s no history of MDS, there may be an underlying MDS that was recognized because maybe the patient didn&rsquo;t present for a long time to a clinician, or maybe transferred hospitals and we didn&rsquo;t have a good story of what happened. &nbsp;&nbsp;

I think this is something that&rsquo;s emerging, especially in the hematopathology publications. Are there any mutations that clearly rule you in or out from MRC? You mentioned the

could be suggestive, and then there are some data with

. Let&rsquo;s say somebody has not enough dysplasia to meet the 50% and then you see some of these mutations. Which ones can really say, &ldquo;This person should be MRC,&rdquo; or not?

I think that remains a subject of the study. I don&rsquo;t know that it&rsquo;s very definitive. There&rsquo;s been a publication out of Dana-Farber [Cancer Institute] by Coleman Lindsley [,MD, PhD,] that addressed it. I don&rsquo;t know of any other publications that looked at it, but in that study, they found that things like

mutations were more likely to be associated with de novo AML. We&rsquo;ve all seen in clinical practice

-mutated AML that arises after MDS, or core binding factor leukemias may have that. Outside of that, there are certain mutations that may underlie secondary MDS, like

, but none of these are very specific or definitive.

I would say the most definitive things are morphologic dysplasia and cytogenetic abnormality, especially complex karyotype or abnormalities of chromosome 5 or 7.

That&rsquo;s useful. At this time, I think the 3 groups we could think of are people who have known secondary AML, known chemoradiation, and then known cytogenetics. The molecular [testing] is still in process; we&rsquo;re not sure if we can use that to differentiate people.

Case 2: AML With Myelodysplasia-Related Changes

Dr McCloskey, if you see such a patient, what are the treatment options you&rsquo;re thinking of? This is a 70-year-old man and who has a known diagnosis now of AML-MRC [acute myeloid leukemia with myelodysplasia-related changes].

I think this is a patient who we would certainly easily identify as a high-risk patient. It&rsquo;s an older patient who seems pretty fit, comes to us in adverse cytogenetic abnormalities, and has already received prior hypomethylator. This is a patient who certainly is at high risk from complications from his disease and requires a long conversation about the fact that this is high-risk disease and that even with all of the treatment options at our disposal, his prognosis is poor. What are their priorities? What is important to them from a quality-of-life standpoint? In general, for a patient who&rsquo;s fit, who is eligible and interested in intensive chemotherapy, this is a patient who we would treat with Vyxeos. Again, when I sat down with that patient, my conversation with him would be that we really do have randomized phase III clinical data to support the use of this drug for this particular patient with AML arising from a prior hematologic malignancy like this.

Are you doing this routinely inpatient or outpatient to start the treatment? As you know, people do it differently; what has been your practice? Then also, Drs Gergis and Rizzieri, what do you do?

I think we were very fortunate to be involved with the phase II and III clinical trials with Vyxeos, and in the phase III study we were actually very conservative. We treated all of our patients during induction and consolidation inpatient. The drug is a 90-minute infusion, as we&rsquo;re going to talk about, on days 1, 3 and 5. It immediately raised the possibility that this could be delivered outpatient instead of a continuous IV [intravenous] infusion like we use in 7+3 [cytarabine/daunorubicin].

For us, like many of my colleagues, we&rsquo;re fortunate to have a very large infusion center. We have a large transplant program, so we&rsquo;re able to support our patients outpatient, and we actually had already piloted an early discharge program with 7+3 [cytarabine/daunorubicin]. Once the drug was commercially approved, we put in place a protocol to select the patients who might be eligible for outpatient induction. This included things like living in close proximity to the hospital, having a caregiver, not having certain other comorbidities, and then for us to hold a bed in the hospital that we often share with our transplant teams. We felt we could reliably bypass the [emergency department], and it has been feasible for us.

I would say that most of our patients are still treated inpatient, and that&rsquo;s often their preference because patients are often quite taken aback with this new diagnosis and feel more comfortable being in the hospital. However, it is feasible with great caution and understanding that these patients require a lot of support while they&rsquo;re outside the hospital.

Just like Dr McCloskey mentioned, the initial induction chemotherapy, we&rsquo;d prefer to be inpatient. After all, these patients have a 10% mortality in the first month or so. In the phase III clinical trials, half the patients received the drug in the consultation as an outpatient, so we follow this. My institution is in Manhattan. If this patient lives in the Upper East Side, with an infusion unit that we have open almost 16 hours a day, in the right patients, we can even do the induction. This patient is probably known to us, had this diagnosis, MDS [myelodysplastic syndrome], for a year and a half, so in a few patients, we have done the inductions in outpatient.

Right, in general, inpatient. Anything different, Dave?

I would echo that. I do think with our emerging understanding of the biology and the impact of the things supplementary to the diagnosis in chemotherapy that may impact outcome, I would expect more and more outpatient in the coming decade. As an example, number 1, what is the impact of exercise for the patient&rsquo;s recovery and the impact on disease? That&rsquo;s an emerging area of research that I think may be important. I think the outpatient setting is tougher for our patients. As we know, they have to get up every day and they&rsquo;ve got to get back and forth to the center. That by itself is exercise, and so I think that&rsquo;s important.

The other aspect is the impact in the microbiota of being outpatient versus inpatient. The emerging data on minimizing the protonations in the microbiota may be very important to both response and other toxicities. There may be a significant push in the future, as you understand those factors more, to do more outpatient, when feasible.

Case 2: CPX-351 Treatment for AML With MRC

Vyxeos is an induction-type therapy; it&rsquo;s not low intensity. It has similar intensity to 7+3 [cytarabine/daunorubicin], maybe lower early mortality, but count recovery is long. Is the goal going to beUsama, do you want to address this&mdash;to take him to transplant? What are the things you&rsquo;re going to be looking for after 1 induction or 1 consolidation to consider transplanting this patient?

Basically, this case is a transplanter&rsquo;s dream. What we have is a patient who has 3 main risk factors for very poor outcome without transplant, age being number 1. For a 70-year-old, there is less than 5% survival without transplant long term due to poor cytogenetics and dissident MDS [myelodysplastic syndrome]. Without transplant, this patient is doomed even if he achieves a CR1 [first complete remission]. Meanwhile, he has good performance status, and other than the depression, no real bad comorbidities. The goal is in the hands of the leukemia doctors to put this patient in CR1 and take this patient to transplant as soon as possible. I must add that with the original cytogenetics and all the next-generation sequencing, we actually send typing on this patient. By doing the day 21 or 28 marrow, we have a stem cell graft. In today&rsquo;s age, we have plenty of stem cell grafts, whether it&rsquo;s umbilical cord in my institution, haploidentical, or others. Again, it&rsquo;s a transplanter&rsquo;s dream.

I love your optimism, because it&rsquo;s glass half-full. A lot of transplanters think this is a transplanter&rsquo;s nightmare because he has adverse cytogenetic

, so I hope all the transplanters are listening to your nice commentary that this is their dream.

Just one more question. Let&rsquo;s say, hypothetically, the other big elephant in the room here to think about is HMA/VEN [hypomethylating agent/venetoclax]. This is a younger patient, whereas if this patient were 77, would this change your mind? Would age be the main thing you&rsquo;re looking at, or would you say, &ldquo;No, even if he&rsquo;s 76 or 77, I would consider Vyxeos if he&rsquo;s healthy.&rdquo; What do

you think, Dr Rizzieri? Is age the big thing, or performance status, or others?

I think that&rsquo;s a great question, and while age is important, I don&rsquo;t think these are necessarily the right cutoffs in terms of a biologic impact. There was a fairly large study published in JCO [

] some years ago showing that between 45-year-old and 55-and-above patients, the biology is very different, so above that, I don&rsquo;t know if there&rsquo;s a real cutoff in biology there.

If we&rsquo;re using age as a marker of fitness, I&rsquo;m not a big fan of that. I would rather look at other measures, whether it&rsquo;s SEER [the Surveillance, Epidemiology, and End Results program] or Charlson Comorbidity [Index], strictly. We certainly all have these 78-year-olds who are very fit in our eyes, who we certainly feel comfortable approaching with stem cell transplant. Having said that, have we successfully transplanted an 80-year-old patient? Sure. Is that our goal? No. There are so many other comorbidities that eventually catch up with those patients, probably not always related to transplant, that the delta of improvement there is really minimal. I think that&rsquo;s where you have a long conversation about the goals of care with such patients and really try to delve into what the expected benefit is going to be.

I agree with that. It&rsquo;s not an absolute, it&rsquo;s a continuum, but as you get older, probably, you&rsquo;re moving more and more away from intensive [chemotherapy], of course with exceptions.

Case 2: Selecting a Targeted Therapy for AML With MRC

We&rsquo;ll stop the discussion here and look at some of the data. Dr Rizzieri, if you could walk us through, please?

Sure. You had brought up the issue of CPX-351, so let&rsquo;s look at that with our audience members in a little bit more detail.

This is a cytarabine/daunorubicin liposome using a nanoscale delivery complex. You see the picture of the liposome noted here where it&rsquo;s a 100 nm bilamellar liposome. It&rsquo;s a 5-to-1 molar ratio of cytarabine and daunorubicin, which in preclinical work was felt to be the synergistic ratio. The neat thing with this delivery mechanism is to take advantage of a ratio that is felt to be most synergistic in such a patient and also potentially increase the delivery of the agent to the area of concern, primarily the bone marrow.

You see that 1 unit of CPX-351 is equivalent to 1 mg of cytarabine and .4 mg of daunorubicin. We see the phase I data here, where the ratio was maintained for 24 hours. After the final dose, the drug exposure was maintained for a week, and with that, we found potent anti-leukemia efficacy and it was well-tolerated. That&rsquo;s what led to the phase III study, as indicated here.

This is a phase III prospective randomized study of CPX-351 versus standard induction in older patients with newly diagnosed high-risk secondary AML [acute myeloid leukemia]. We do use a term secondary here, even though it&rsquo;s been stricken from the current WHO [World Health Organization] classification, because at the time this study was conducted, that was still in our vernacular. The primary eligibility was to have patients who were previously untreated for AML, 60 to 75 years of age, and able to tolerate intensive chemotherapy.

Patients were stratified between those who had prior therapy-related AML, AML with a history of MDS [myelodysplastic syndrome] with or without prior HMA [hypomethylating agent] therapy, patients with AML with a history of CMML [chronic myelomonocytic leukemia], and de novo AML patients with MDS karyotype.

There was also an age stratification of 60 to 69 years of age, and 70 to 75. You see that patients could receive up to 2 cycles of induction, those with a remission then went on to receive consolidation therapy, and the primary endpoint was overall survival. You see the dosing as noted here for first induction and reinduction, and fairly standard dosing for 7+3 [cytarabine/daunorubicin], as well.

If we move on to the baseline characteristics, I&rsquo;ll give you a second to look at that, but they are primarily very similar populations, and similar groups of patients by age range and performance status. If you look under the clinical characteristics, we may want to look at those with antecedent MDS with or without prior HMA therapy. This is a group that&rsquo;s of some concern to many of us, and you can see that they were fairly well-balanced. Some had the

positivity in the CPX-351 arm, which is that high-risk group we&rsquo;ve talked about before. Breakdown by white count and platelet count were similar, as well.

The overall response, noted in the next slide, was really encouraging. You see based on CR [complete remission] or Cri [complete remission with incomplete blood count recovery], that incomplete responding group, 37% to 47.7% CR or CRi rate in the CPX-351 group, versus 25.6% to 33.3% in the 7+3 [cytarabine/daunorubicin] group. That&rsquo;s encouraging, but I think the other key here is, is it tolerable? We talked about these patients being primarily older. They may be more infirmed, and you can see in the next slide the early mortality rates6% and 11%, respectively, at day 30, and 14% and 21% by day 60.

If we move to the meat of the primary endpointsurvival&mdash;in the next slide here, we can see patients with CPX-351 have a median survival of 9.56 months versus 5.95 months in those receiving 7+3 [cytarabine/daunorubicin]. That&rsquo;s a statistically significant difference at .005. Importantly, when you look at those curves and the difference, I think that&rsquo;s a clinically meaningful difference for our patients, as well.

Now, if you look at a Kaplan-Meier curve for overall survival and for those landmarked at the point of stem cell transplant, ITT [intention-to-treat] analysis population is noted here. The median survival of CPX-351 patients was not reached, and for those with 7+3 [cytarabine/daunorubicin], was 10.25 months, also with a clinically and statistically significant difference. This is as presented by Jeff Lancet [MD] at ASCO [the American Society of Clinical Oncology meeting] a couple of years ago.

Here&rsquo;s a phase III prospective randomized study showing a survival difference, and I think we have very few of those in our specific field, so that&rsquo;s very encouraging, but what cost does it come at? What are the [adverse] effects and toxicity? The next slide shows the febrile neutropenia, fatigue, pneumonia, bacteremia and sepsis issues that we follow. I think it&rsquo;s very comparable in these objective measures for [adverse] effects in these 2 groups.

If we move to the next slide, in terms of count recovery, this is one of main differences that we&rsquo;ve all noticed as we roll out CPX-351. It takes about an extra week to recover your counts. We really want to preach patience for these patients. Notably, if you&rsquo;re used to doing a nadir marrow at day 14, you probably want to delay that as we did on study to day 21 or so. These patients will recover, but it&rsquo;s just about a week delayed.

The conclusion from the phase III study of CPX-351 versus 7+3 [cytarabine/daunorubicin] is that older patients with high-risk secondary AML have longer overall survivals with CPX-351 than 7+3 [cytarabine/daunorubicin], and longer overall survival when even landmarked from patients undergoing transplant.

The post hoc analysis showed a greater proportion of patients with CPX-351 achieving a CR or CRi, that&rsquo;s 47% versus 36%, and more of those patients underwent transplant. Patients receiving consolidation following successful induction also had longer survival with CPX-351 versus 7+3 [cytarabine/daunorubicin].

The last 2 slides of this looked at the safety of combination. It&rsquo;s a fairly busy slide, and I&rsquo;ll give you a minute to look at that. There really isn&rsquo;t anything, when you look at all grades of toxicity, that jumps out at me as different in this particular presentation. I&rsquo;ll be interested in my colleagues&rsquo; views of this, because all of us have a sense from treating a lot of these patients that it is better-tolerated. We&rsquo;re talking about a lot more outpatient home therapy and, not for nothing, my patients love not losing their hair. Maybe that&rsquo;s why they feel better when they look in the mirror, and that&rsquo;s not a bad thing.

Case 2: CPX-351 Trial Data in AML

In the last slide, we look at another alternative beyond this combination therapy. We look at something that has newly hit the bricks here, which is venetoclax. It&rsquo;s almost good for what ails you, it seems, in so many heme malignancies. This is a phase I/II study of venetoclax plus low-dose cytarabine, and the low dose in Dr Andrew Wei, MBBS, PhD&rsquo;s, abstract was 20 mg daily for 10 days, I believe. Correct me if I&rsquo;m wrong on that.

This was for patients with untreated AML [acute myeloid leukemia] who were older. They had a reasonable performance status and adequate organ function. You see the most common grade 3 or greater AEs [adverse events], as was expected, would have been cytopenias and febrile neutropenia. There was some evidence of tumor lysis syndrome, as we do see with this agent, though.

The table on the right is really telling. With this combination of therapy, there were CRs [complete remissions] or CRis [complete remissions with incomplete blood count recovery] in 54% of patients, which is very encouraging for this combination. The duration of a full remission was 14.8 months for those with a CR, and you can see down the line, for variations of the types of CR, somewhat less.

One of the most interesting things to me, which relates to the prior case that was presented, is the impact on patients with what we consider high-risk genetics and lower responsivity to traditional chemotherapy. We have patients in this small study with

mutation. They had 3 out of 10 with a remission. Patients with an

had a 44% CR rate, and those with PM1, even higher, nearly 90%.

All of this relates to a median months of survival of about 10 months in all comers. Estimated 2-year survival is 27%, which is certainly higher than what we&rsquo;d expect in an elderly group of patients with AML. I think this is encouraging as we see the emerging data on applying some of the new targeted therapies to such patients.

Well, thank you very much, and to summarize, I&rsquo;ve heard a lot of different approaches to the Vyxeos data, or thoughts to it. What&rsquo;s really interesting is that the quality of neutropenia is different with different agents. If we said to anybody 10 years ago, &ldquo;I&rsquo;m going to prolong your neutrophil recovery by a week,&rdquo; we would all be upset and say, &ldquo;This is definitely going to cause increased induction mortality.&rdquo; This did prolong it a week, and it was half the induction mortality.

I think there are other factors, like you saidmucositis, gastrointestinal [GI] toxicities&mdash;that probably have an important impact that we overlook. These are good data, and I think the FDA did a very good job in getting this approved.

The other thing we heard initially when the data came out was that people said, &ldquo;Well, you know, CR/CRi rate of 47% seems lower than I can get with 7+3 [cytarabine/daunorubicin].&rdquo; Actually, if you go back and you look at true patients with MRC [myelodysplasia-related changes], which almost none of the older publications really separate because it was not identified, then you really do see 35% or 38%. Comparatively, the 47% or 50% CR/CRi is actually quite meaningful. I think all-in-all, very nice data. It will be very interesting to see how we can combine this with other agents, and of course, there will be dose reductions, etcetera, but we have a lot of nice options in this population.

Case 2: Novel Therapies for AML With MRC

-mutated acute myeloid leukemia [AML], and I&rsquo;m going to ask Dr Gergis to discuss the case, please.

Thank you very much. I think it&rsquo;s very timely to discuss

and acute myeloid leukemia. Our case today is a 65-year-old woman who presented with some bruising and fatigue, and she&rsquo;s very fitmuch better than most of us around the table. She walks 3 miles every day. She has a past medical history of hypercholesterolemia that is controlled. She presents with pancytopenia, white [blood] count [WBC] of 2.8, hemoglobin of 9, and platelets of 40,000. She now is diagnosed with acute myeloid leukemia&mdash;blast percentage 48%, cytogenetics are diploid, next-generation sequencing mutations in

She was appropriately treated with 7+3 [cytarabine/daunorubicin]. Treatment course was complicated, as expected, by mucositis and febrile neutropenia. After resolution of her complications, she received 2 cycles of high dose Ara-C consolidation. In the midst of her consolidation 6 months after initial diagnosis, she presented with fatigue, body ache, and gum bleeding. She was pancytopenicWBC 1.8, hemoglobin 8, and platelets 28,000&mdash;and she had circulating myeloblasts. The bone marrow biopsy was hypercellular with 80% blasts and normal cytogenetics. Next-generation sequencing was done again on relapse, and she has the same

Well, thank you very much. We&rsquo;re moving now more into the pure targeted therapies and salvage, which is where a lot of these drugs are initially getting approval. For

, we have gilteritinib, recently, and others in review like quizartinib. Dr Weinberg, for the molecular testing, are you routinely seeing people check this in the relapsed setting? If they are, are they asking for targeted panels or are you repeating the whole panel? What do you do?

It is approved in a relapse setting. It&rsquo;s not approved in a day 30 kind of setting, so we don&rsquo;t use it there.

Our panel is not really meant to be a minimal residual disease [MRD] panel. There are other panels that you can use for that, but we don&rsquo;t run those.

Since you brought it up, minimal residual disease, now we&rsquo;re going to stop for 1 hour and discuss this. I&rsquo;m not going to do that, but I would just like to ask, clinically, does anybody use MRD in treatment decision-making today? At what time point do you use it and for what? James?

I think we use MRD mostly for risk stratification. We do MRD testing at the time of first remission. We do MRD testing before they proceed to transplant and then subsequently every 3 months from the peripheral blood. I think that everyone will probably comment on this. There are a lot of variables right now in terms of how we measure MRD and how we reliably interpret it even as 1 patient might have different results, depending on the laboratory or depending on the particular aspirate that we send. There&rsquo;s a lot of variability, and in general, we do not alter treatment based on the MRD response at this time. I do think it adds something in terms of risk stratification and it is incorporated into some of our clinical trials.

Anything different, Dr Rizzieri, that you do with MRD?

I do it so I can understand if it&rsquo;s going to interrupt my sleep pattern at night, like you said. We know when to worry. It doesn&rsquo;t necessarily mean that I&rsquo;m going to jump and offer an allotransplant sooner rather than later, though I&rsquo;m inclined to have that discussion concerning that issue. You can see if Usama agrees.

What do you think? You use it at transplant?

Let&rsquo;s say somebody is low MRD-positive. What is your discussion, as a leukemia doctor?

It&rsquo;s a tough discussion because a patient like this, at 65 years old, should come to transplant in CR1 [first complete remission]. Now, with the decision tree, we prefer if she&rsquo;s MRD-negative. If it&rsquo;s MRD-positive coming to transplant, the survival rate is in the range of 20%. That doubles if she&rsquo;s MRD-negative. Transplant does not offer that much for MRD-positive patients. We talk to our leukemia colleagues, and you can only do too much, and sometimes your patient&rsquo;s still MRD-positive after 2, 3, 4 cycles of chemotherapy. Then we have to bite the bullet and transplant, and be more vigilant with MRD monitoring after transplant. How does that really help? You reduce immune suppressive agents and cause more graft versus host disease. You get into another black hole.

Acute Myeloid Leukemia

Case 1: FLT3+ AML

Case 1: Allelic Burden in FLT3+ AML

Case 1: Treatment Recommendations for FLT3+ AML

Case 1: Targeted Therapy in FLT3+ AML

Case 2: AML With Myelodysplasia-Related Changes

Case 2: CPX-351 Treatment for AML With MRC

Case 2: Selecting a Targeted Therapy for AML With MRC

Case 2: CPX-351 Trial Data in AML

Case 2: Novel Therapies for AML With MRC

Case 3: IDH2-Mutated AML

Case 3: Targeting IDH in AML

Case 3: IDH Inhibitors for the Treatment of AML

Case 4: High-Risk de novo AML

Case 4: Treating AML With HMA/Venetoclax

Case 4: Observations of HMA/Venetoclax in Trials

Case 4: Additional Considerations in High-Risk de novo AML