Discussion on Acute Myeloid Leukemia (AML)

This discussion between experts addresses unmet needs in the acute myeloid leukemia treatment landscape (AML) and the efficacy and safety of a treatment option for patients with relapsed and refractory AML with isocitrate dehydrogenase 1 (IDH1) mutation.

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Rami S. Komrokji, MD, is the vice chair of the Malignant Hematology Department and the head of the Leukemia and Myelodysplastic Syndrome (MDS) sections at the Moffitt Cancer Center in Tampa, Florida. He is also a senior member of the Malignant Hematology and Experimental Therapeutics Program at the Moffitt Cancer Center and a professor in medicine and oncologic sciences at the University of South Florida’s College of Medicine. Dr Komrokji is an expert in myeloid neoplasms. He has led several clinical trials and lectured worldwide. He has also authored or co-authored more than 325 peer-reviewed manuscripts, 20 book chapters, and more than 700 abstracts in Hematologic Malignancies. Dr Komrokji was previously on the editorial board for the Journal of Clinical Oncology, and he serves as a peer reviewer for several medical journals. He was also a member of the MDS panel of the National Comprehensive Cancer Network. He currently serves on the National Institutes of Health MDS Natural History Study Steering Committee and the Aplastic Anemia and MDS Foundation Board of Directors. 

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Thomas W. LeBlanc, MD, MA, MHS, FAAHPM, FASCO, is an associate professor of medicine with tenure in the Division of Hematologic Malignancies and Cellular Therapy at the Duke University School of Medicine. He is also the founding director of the Cancer Patient Experience Research Program (CPEP) at the Duke Cancer Institute, where he serves as the chief patient experience and safety officer. Dr LeBlanc is board-certified in medical oncology and in hospice and palliative medicine, and his practice focuses on the care of patients with blood cancers, particularly those with acute leukemias and myeloid malignancies. His program of research focuses on palliative care and patient experience issues in hematology. 

Transcript: 

Dr Rami Komrokji (RK): Hi, and welcome to this virtual discussion focusing on acute myeloid leukemia. I'm Rami Komrokji, Vice Chair of Malignant Hematology Department at the Moffitt Cancer Center, and I'm honored to be joined by Dr Thomas LeBlanc, who's Associate Professor at Duke University. Tom, it's so good to see you.  

Dr Thomas LeBlanc (TL): Good to see you as well. I'm happy to be here.  

RK: Thank you. So, we’re going to focus today on AML treatment as the landscape had evolved.  

TL: Yeah, as you know, there are so many challenges that we still face in AML management, despite having many new and more effective therapies. So, as I think about what I'm struggling with often in my clinic and on our inpatient service. It's not always so much achieving remission initially now. We most often can do that with a sizeable proportion of our patients.  

The biggest challenge that I feel like I'm grappling with all the time is the difficulty of relapse and not having enough therapies that are curative or that can give patients deeper, longer remissions, particularly with less toxicity. 

RK: Yeah, absolutely. I totally agree. I think we've made a little bit better progress in ability of achieving remission. However, the relapse remains a challenge short of allogeneic stem cell transplant. I think relapse is inevitable among those patients. 

I think it's important to stress that nowadays it's not one option for patients. So, it's very important at the beginning to get the molecular data and assess the subtype of the ML because the treatment can be tailored accordingly.

So, can you walk us through a little bit about the relapses and what's your experience in your practice? What's the percentage of patients with relapse and how you approach patients when they relapse? 

TL: Yeah, one of the unfortunate realities of AML now is that when people relapse, which a huge proportion of our patients will, outcomes are quite poor universally, particularly if you cannot get them to a transplant, perhaps in a second remission. We can't always achieve a second remission, but whether you think about patients who've received an intensive induction therapy, maybe a novel lower intensity therapy like HMA venetoclax—we're using that regimen a lot—we unfortunately see less than 6-month median overall survival rates really on average across the board after whatever initial therapy people have received if they face a relapse. 

RK: Yeah, absolutely. Obviously historically, we used to say like obviously, what dictates the relapse is the disease risk. So, patients with high-risk disease, almost 80% to 85% of them would relapse, even what we call intermediate risk, more than half of those patients. Even in the new era, obviously, whether we're doing chemotherapy or less intensive therapies, majority of those patients will relapse. Historically, also the timing of the relapse is important, whether patients relapsed early on or later.  The earlier relapses tend to be more refractory, don't respond to the traditional chemotherapy.

I'm sure you get a lot of referrals into your practice and stuff. What would you say is the adaptation for using testing molecular profile for patients at diagnosis and at time of relapse, and how is your experience with the referrals and having those tests being done for patients? 

TL: Yeah. Well, like you were saying earlier, this is one of the most exciting areas and opportunities that we have in AML. We no longer just have 1 or 2 treatments. It's not just 7 +3 or similar intensive induction or single-agent HMA therapies. Now, we have a number of FDA-approved mutationally directed therapies or other targeted therapies that maybe don't even require a mutation, but that work differently and often better than chemotherapy.

But generally, you do have to do the mutational profile testing. It's unfortunately not uncommon that I'll see patients referred in with newly diagnosed or relapsed and refractory disease where they either haven't had complete molecular profiling done or it hasn't been done at the most recent relapse or line of therapy, and we do unfortunately know that clonal evolution is not really the exception. It's the rule in AML, and you not only have to characterize the disease molecularly at diagnosis, but also at each sequential line of therapy. 

So, in that area, FLT3 mutations, IDH1 mutations and IDH2 mutations have become particularly important. There isn't a huge amount of overlap between those 3, so when you add them all together, we end up finding now that upwards of maybe half or so of our patients will have a potential FDA-approved treatment option available for them, a mutationally directed treatment option. 

It isn't always the right thing to do for each patient in each line of therapy. Sometimes, there might not be an approved drug with intensive induction therapy, and that might be the right thing for that person. So, it still gets much more nuanced, but we absolutely need to have everybody doing these tests so that we can have these treatment options available to discuss with our patients and to offer them. 

Since we're gonna be talking a little bit more about IDH1 mutations in our discussion here, I'll say a little bit more about that. We see these in upwards of 5 to 10 or so percent of patients with AML. Unfortunately, we have learned that IDH1 mutations seem to be bad actors compared to what I was taught as a fellow. I remember hearing IDH mutations are good, and they confer a likelihood of responsiveness to chemotherapy and maybe a better chance at cure in particularly normal karyotype AML. 

But more recently, we've come to learn as we do subgroup analyses and stratify these out a little bit more, that it looks like the IDH2 mutations are really probably what's mostly driving the sometimes more favorable prognosis or co-occurring mutations like an NPM1 with an IDH2, but that patients who have an IDH1 seem to have particularly bad outcomes in relapse, where their survivals are clearly well under 6 months. So, we tend to be in trouble here, but what do you see in your practice with IDH1 mutations, particularly those with relapsed or refractory disease?  

RK: Yeah, absolutely. So, first, I cannot emphasize more what you kind of summarized in terms of the necessity of checking molecular testing at diagnosis and at relapse, and at least the targetable mutations or the things that will make a difference in the management, such as the IDH, FLT3, MPM1, maybe P53, and nowadays, I think the technology is widely adopted that you can have access to those. 

As you mentioned, the IDH is a small subset of the AML. The IDH1, particularly, 5% to 10%. They have unique phenotype with being mostly cytopenic; they actually can happen across all the myeloid neoplasms. Historically, those patients have, you know, low chance of response post-first-line therapy, as you alluded to, even originally with the studies looking at like HMA, BCL2 inhibitors upfront. 

Now we know that probably the IDH2 are the ones that drive the more long benefit, that even with those newer treatments that patients relapse, and historically, the chances of response or the survival with traditional chemotherapy had been poor. We actually had even looked in patients with MDS and historically as a cytidine treatment in those patients, and the median survival was 5 months for those patients post-HMA failure. 

So, that even spans outside the scope of AML. Many of those, sometimes, when the relapses happen early on, within the first year of the disease, really the chances of response to the traditional chemotherapy had been very low. I think we are fortunate now that we have more targeted therapies, and we are trying to learn how to optimize their use.  

So, for IDH1, obviously we have IDH1 inhibitors, including olutasidenib. That's a potent inhibitor of the IDH1, more selective for the mutant IDH1 inhibitor. Perhaps maybe you can also summarize to our audience the data that led to the approval.  

TL: Rezlidhia is an oral medication approved by the FDA for the treatment of adult patients with relapsed or refractory AML with a susceptible IDH1 mutation detected by an FDA-approved test. 

There is also a boxed warning for Rezlidhia for differentiation syndrome. Differentiation syndrome can be fatal and can occur with Rezlidhia treatment. Symptoms may include dyspnea, pulmonary infiltrates, pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold Rezlidhia and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution. 

Yeah, it's an interesting story as we've come to learn more about what IDH mutations actually do in the cell. You know, whenever I think about this and talk about it, if I'm teaching our fellows or others, I always laugh a little bit about how we end up having to talk about the Krebs cycle. It's something that, you know, I thought was maybe the way professors haze us in medical school and was never going to have any practical implication. And, you know, here we are talking about the Krebs cycle.  

But what we've learned is that the IDH mutations, whether it's IDH1 or 2, cause this accumulation of 2-hydroxyglutarate, or 2 -HG, which doesn't belong in the cell. It should instead convert to alpha-ketoglutarate, and when you have too much of the 2-HG, you end up getting aberrant methylation, hypermethylation of the DNA and the histones, and that this causes actually a differentiation block. 

So, it causes … it's really a leukemogenic mutation. It causes blasts to accumulate in the marrow. Maybe this is why we don't see IDH mutations a lot in MDS, because once they occur, perhaps there's more rapid progression in blast accumulation that it just becomes AML. We know that this is a big part of the mechanism of disease and proliferation in IDH1-mutated cases. 

So, when we talk about olutasidenib or Rezlidhia, what we find is that in inhibiting that mutated enzyme, you get restoration of the normal alpha-ketoglutarate levels, you get rid of all that extra 2-HG and the aberrant hypermethylation, which probably has turned off tumor suppressor genes and done other things intracellularly that are bad for the patient. 

In the 2102 trial, which is an open-label, single-arm, multicenter trial of just over 150 adults with relapsed or refractory AML who have a confirmed IDH1 mutation, there were some pretty impressive response rates seen. We don't have time to talk in deep detail about all the nuances of the study, but I'll just summarize a couple things. The patients who were treated on this trial received 150 milligrams of olutasidenib twice daily, so that's the standard dose and schedule. It's a continuous treatment, 28-day cycles that patients would get continuously until progression or unacceptable toxicity. 

Looking at the efficacy evaluable population of these patients who are pretty heavily pretreated, older patients, median age of 71 years or so, most had received at least 2 prior treatment regimens. There's a pretty impressive response rate seen overall. So, the composite CR rate was actually nearly 50%. 

Thinking about what we would have expected historically in patients with relapsed or refractory IDH1-mutated disease, there's no control arm in this trial, but certainly, that compares pretty favorably to what we would have expected and what we've seen historically in practice. Other things about this study or therapy that you would want to highlight?  

RK: Yeah, no, I obviously agree with what you said, and I'd like to highlight that again, this was a heavily treated population that was tested. One-third of them were almost refractory, and many of them had more than 2 lines of therapy, as you alluded, and mostly intensive chemotherapy. The relapses in majority of the cases were actually early on, which again, as I mentioned earlier, historically, those patients had a very low chance of response to intensive chemotherapy. 

As you mentioned, more than one-third of those patients achieved a complete response, rapidly, relatively, with the median time to response around 2 months. What was appealing for me from the data is really the durability of the response, that those patients that achieve the CR or CRH, the median duration of response was almost around 26 months, and those patients that had a complete response, the median duration was almost 28 months. 

So really, once patients achieve the response, it is very durable. Also, something important in terms of many of those patients went on the study, transfusion-dependent, and there was also benefit of becoming transfusion-independent among that study, which is an important issue, obviously, for the patients with AML, especially when they are getting those treatments in the outpatient setting. It's also important to put this in the context, and I'll ask you about this, is basically, now, in a lot of cases, many people have used HMA, venetoclax, or BCL2 inhibitor in the upfront setting. That group also has a very poor outcome after failure of this initial therapy. So, can you also allude to the data with olutasidenib, particularly in those patients treated with HMA plus BCL2 inhibitor?  

TL: Yeah, so this is a really challenging and important issue. So, as you were saying, so many patients are receiving first-line, low-intensity, targeted therapy with the novel doublet of venetoclax plus an HMA, either azacitidine or decitabine. This is usually a very effective therapy for significant proportion of patients for a while, but it's not a curative therapy, unfortunately, unless maybe someone goes on to a transplant, and most of these patients are not transplant eligible if they're starting with a low intensity therapy at this point, so we usually need something else for these patients in the second line or beyond.  

If you don't have a targetable mutation, the outcomes are especially abysmal after a failure of venetoclax-based therapy first line. There really isn't a standard of care for these patients, and I struggle a lot with this in practice. Ideally, you get those folks onto a clinical trial, but we're always looking for a targeted therapy option. If you find a FLT3, that's great. You can target that in second line.  

If you find an IDH1 mutation, I'm particularly excited to see that because, you know, olutasidenib gives us a nice option in the second line for these patients where we actually do have some data from this 2102 trial that I was talking about a few moments ago about efficacy in the post-ven failure setting. It's not a huge amount of patients. It's 12 or so. But these patients actually appeared to have a very similar CR rate and composite CR rate as the larger number of patients in the overall parent trial.  

So, in these patients who had relapsed post-venetoclax, the CR rate was about 25 %, and the composite CR rate was about 50%. The median time to CR was about the same, around 2 and a half months, maybe slightly longer in this population, but that's probably not meaningfully different since this is a small number. The median duration of response actually was not reached, and that's a bit surprising.  

We would have expected to see pretty poor outcomes post-ven failure, and most of the patients who achieved a remission with Rezlidhia or olutasidenib post-ven were still in remission at the time of the data cutoff for the analysis that's been reported out so far. So, it's nice to see that and to know that we do have this option post-ven failure in the small proportion of patients who have an IDH1 mutation. So, like you were asking earlier, all the more reason to do the mutational testing so that we can hopefully have a target and not have to resort to less effective, non-targeted therapies. 

RK: Yeah, I absolutely agree that, you know, this post -HMA BCL2 inhibitor failure is really a huge area of unmet need, currently very challenging. When there is a targeted therapy, I think definitely that's the way to go. The data with the olutasidenib looks very encouraging in that population, almost same activity as in patients that had prior intensive chemotherapy. There are even subsets of patients that benefit from this. For example, I think there are some data in patients post-transplant are also the activity of the agent was seen. 

I've had cases in practice where they were on an IDH2 inhibitor, we see failure of treatment, and the escape mechanism is actually evolving an IDH1 inhibitor. So, to keep in mind that, as you mentioned, this is like the clonal evolution and the progression of the disease happens in different flavors and ways. It's important to keep eye on that. So, definitely filling some of the unmet needs in the landscape of acute myeloid leukemia.  

Maybe we turn around a little bit to focus on some of the kind of details of the management; how do you monitor those patients, what do you look for, the safety, what are the things to be on the lookout for in terms of toxicity. So, let's move a little bit to talk about the details of using this treatment, olutasidenib. I always say nowadays whenever I'm prescribing a medication, I pull the package insert, I read the safety because it's very important in how to monitor those patients, especially early on in the treatment. So, can you walk us a little bit into the details of the monitoring, safety, what are the adverse events to be on the look for? 

TL: Yeah, yeah, with all of our novel therapies, we are experiencing new and different toxicity and tolerability issues. That's the case with olutasidenib, as well as with other targeted therapies we've started using in AML. Thankfully, the general theme is that most of the treatment-emergent AEs end up being manageable without having to permanently discontinue treatment. So, if they happen and if they're severe enough, you can usually get by with dose interruptions and reductions.  

Every once in a while, a person may have a serious issue that requires you to discontinue treatment, but usually, that's not what's happening. But if there is a really serious issue with this drug, it's typically going to be either a differentiation syndrome or sometimes hepatic issues. There isn't really significant QT prolongation with this drug, which is nice because it seems like just about everything that I use in AML prolongs the QT, and I'm commonly having patients on 2 to 4 QT-prolonging therapies at the same time, you know, between novel targeted therapies, 5-HT3 drugs, extended-spectrum azoles, etc.  

So, at least we don't have to deal with that issue here with olu. Certainly, there are other symptom and side effect issues though that do come up with this drug that are more so the ones where you would usually use supportive care to manage. So, you know some patients do have nausea or bowel issues. We certainly can see cytopenias, issues like fatigue, febrile neutropenia. 

It's always hard to separate out what's caused by a drug versus what's caused by the disease or by what's happened in the marrow because of the disease too, but certainly, a number of these things probably are directly related to this therapy. So, you have to watch blood counts closely, you have to watch the LFTs particularly, you have to have suspicion for differentiation syndrome. 

I find that to be challenging because DS looks like a whole lot of other things that happen to patients with leukemia. So, if I have a patient on an IDH inhibitor who comes in with a fever, you have to assume that they might have DS, and basically, you put them in the hospital, you empirically put them on steroids and watch them very closely, but you also have to treat for febrile neutropenia. If somebody has sepsis, if they have heart failure, If they have pneumonia, those symptoms all unfortunately, line up quite a bit and overlap with what DS can look like. So, you do end up having to do a lot of empiric treatment there.  

Usually, if you recognize and treat DS early, typically patients do very well with it, but they can die of this if you don't suspect it, if you miss it, if you don't think about it early enough and don't empirically start the steroids early, etc. So, you know, this is a different kind of a therapy. It's a whole new world to deal with. But hopefully, that's a helpful brief overview of the ways that I'm thinking about how to approach this therapy and its toxicity. So, are there other ones that you've seen or that you worry about or other kind of pearls from your practice about how to manage this therapy?  

RK: I totally agree with, you know, your summary, which was very elegantly done. I would say, obviously, I always think of the adverse events in setting of treating of leukemia. There are generic adverse events that we see with most of the treatments, partly because of the nature of the disease. So, as you alluded nicely, most of those patients are mildly suppressed, they are at risk of infection, febrile neutropenia, they are cytopenic. So, there is a lot of complications that can happen even with the treatment.  

But then, I always try also to be on the look for the unique adverse events from a certain treatment. And as you alluded, probably differentiation syndrome is very important with olutasidenib, as well as monitoring the liver function. So, those for me are the 2 things that I'm always on the look for.  

As you said, differentiation syndrome is important. You know, this is like something that we need to act on, and it's very, you know, overlapping. It's very vague sometimes, the presentation: fever, hypotension, hypoxia. I always tell the fellows, if it comes to your mind, if you suspect it, if you are called about somebody who has shortness of breath, you know, before thinking even that this is fluid overload, think in certain circumstances of differentiation syndrome. 

In general, with olutasidenib, the rate of discontinuation because of any adverse event was less than 10%. So that's reassuring. The differentiation syndrome probably occurred in almost 16% of the patients but was manageable. The other thing that sometimes can go hand-by-hand with the differentiation syndrome is really the leukocytosis, and in those patients, if their white blood cell count is going above 10 000, sometimes, I'll introduce some hydrea use, even if they are not having differentiation. 

Obviously, if there is suspicion of differentiation, as you mentioned, we hold the treatment, we treat supportive care, steroids, and when that resolves, then we resume the treatment. So, it's very important. It typically happens before patients are obviously in remission. So, we are on the look in the first few months particularly. 

I usually check blood counts on a weekly basis for the first couple of months and sometimes more if I'm worried about tumor lysis as well or differentiation. Once the patients are in remission after the second month, we ease it to like every other week, and then subsequently, probably once a month once the patients are in steady state. Also, to your point, I also look at liver enzymes and monitor those. If patients have grade 3 or 4 transaminitis, we hold, we dose adjust. I'm always worried more if patients have hyperbilirubinemia and transaminitis as well, and that's true for any treatment.  

I think, to your point, we don't need frequent monitoring or monitoring for QT prolongation because that was not an issue on the study. The interactions with many of the antibiotics and antifungal medications we use are less to worry about or not to worry about with this treatment.  

Tom, thank you very much. This was a comprehensive review focusing mostly on IDH1. As we discussed, I think the landscape is changing. It's exciting time because we have more options to offer our patients, but yet, a lot of challenges. I hope that this was helpful for our audience to specifically also talk about the IDH1 inhibitors in this setting. Anything else you would like to add? 

TL: Well, no, just to say thank you. And yeah, I agree it was a comprehensive discussion. I hope it's useful for the attendees. It's exciting to have some therapies for our AML patients that are improving outcomes.  

RK: Absolutely. Thank you very much. 

TL: Thanks.  

INDICATION  

REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.  

IMPORTANT SAFETY INFORMATION  

WARNING: DIFFERENTIATION SYNDROME  

Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution. 

WARNINGS AND PRECAUTIONS 

Differentiation Syndrome  

REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis.  

If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence.  

Hepatotoxicity  

REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin.  

Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity.  

ADVERSE REACTIONS 

The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.  

DRUG INTERACTIONS 

• Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers.  

• Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs.  

LACTATION 

Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.  

GERIATRIC USE 

No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.  

HEPATIC IMPAIRMENT 

In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome.  

Please see Full Prescribing Information, including Boxed WARNING. 

References: 

1. Saultz JN, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med. 2016;5(3):33. doi:10.3390/jcm5030033 

2. Leotta S, Condorelli A, Sciortino R, et al. Prevention and treatment of acute myeloid leukemia relapse after hematopoietic stem cell transplantation: the state of the art and future perspectives. J Clin Med. 2022;11(1):253. doi:10.3390/jcm11010253 

3. Maiti A, Rausch CR, Cortes JE, et al. Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens. Haematologica. 2021;106(3):894-898. doi:10.3324/haematol.2020.252569 

4. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377. doi:10.1182/blood.2022016867 

5. Abbas S, Lugthart S, Kavelaars FG, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood. 2010;116(12):2122-6. doi:10.1182/blood-2009-11-250878 

6. Chotirat S, Thongnoppakhun W, Promsuwicha O, Boonthimat C, Auewarakul CU. Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients. J Hematol Oncol. 2012;5:5. doi:10.1186/1756-8722-5-5 

7. DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015;90(8):732-6. doi:10.1002/ajh.24072 

8. REZLIDHIA® [package insert], South San Francisco, CA: Rigel Pharmaceuticals, Inc.

9. de Botton S, Fenaux P, Yee K, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv. 2023;7(13):3117-3127. doi:10.1182/bloodadvances.2022009411 

10.  Abaza Y, Winer ES, Murthy GSG, et al. Clinical outcomes of hypomethylating agents plus venetoclax as frontline treatment in patients 75 years and older with acute myeloid leukemia: real-world data from eight US academic centers. Am J Hematol. 2024;99(4):606-614. doi:10.1002/ajh.27231 

11. Cortes J, Jonas BA, Schiller G, et al. Olutasidenib in post-venetoclax patients with mutant isocitrate dehydrogenase 1 (mIDH1) acute myeloid leukemia (AML). Leuk Lymphoma. 2024;65(8):1145-1152. doi:10.1080/10428194.2024.2333451 

12. Gasparovic L, Weiler S, Higi L, Burden AM. Incidence of differentiation syndrome associated with treatment regimens in acute myeloid leukemia: a systematic review of the literature. J Clin Med. 2020;9(10):3342. doi:10.3390/jcm9103342 

13. National Cancer Institute. NCI Dictionary of Cancer Terms. Accessed October 15, 2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/differentiation-syndrome 

Rigel is the sole author and copyright owner of this presentation.

REZ_AML-25006 03/2025