James K. McCloskey II, MD, is the interim chief in the Division of Leukemia at Hackensack Meridian John Theurer Cancer Center in Hackensack, New Jersey.

For patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), the advent of oral decitabine-cedazuridine (Inqovi) represents a significant advancement in treatment. This oral formulation provides a bioequivalent and far more convenient alternative to intravenous (IV) decitabine (Dacogen), empowering patients to maintain their quality of life while receiving effective therapy in the comfort of their home.

As a physician dedicated to helping patients live longer and better, I’ve witnessed firsthand the burden that frequent hospital visits for IV infusions place on patients battling these diseases. Although oral decitabine-cedazuridine may appear simply as a biosimilar on paper, its impact on a patient’s daily life is transformative.

Long-term data from the phase 3 ASCERTAIN trial (NCT03306264), recently published in The Lancet Haematology, confirm the safety and efficacy of this oral formulation.1 The study demonstrated that the toxicities observed with oral decitabine-cedazuridine are consistent with those of IV decitabine. Critically, the primary end point of total drug exposure was met, with the oral formulation achieving 98.93% (90% CI, 92.66%-105.60%) of the IV decitabine exposure, establishing pharmacokinetic equivalence.

This equivalence translates to real-world benefits for patients. For example, one of my patients participated in ASCERTAIN for over 2.5 years. Imagine the cumulative time this individual would have spent in a clinic chair receiving IV infusions, time that was reclaimed thanks to the oral formulation.

Although the benefits are clear, some considerations warrant attention. Patients with compromised gastrointestinal absorption, such as those who have undergone gastric bypass surgery, may not be ideal candidates for oral decitabine-cedazuridine. Close monitoring is also essential, particularly during the initial treatment cycles.

The availability of oral decitabine-cedazuridine has already shifted the treatment paradigm for patients with MDS and CMML. Many of my patients have transitioned from IV to oral therapy, experiencing improved convenience without compromising efficacy. Furthermore, this oral formulation has opened doors for novel combination strategies. The National Comprehensive Cancer Network guidelines now recognize oral decitabine-cedazuridine as a potential partner for venetoclax (Venclexta) in patients with higher-risk MDS or acute myeloid leukemia.

The success of oral decitabine/ cedazuridine has spurred further research in this area. A phase 2/3 study (NCT04256317) evaluating oral azacitidine (Vidaza) in combination with cedazuridine recently completed its phase 2 portion, and we eagerly await results from the expansion cohort. This is just the beginning of the story of oral hypomethylating agents.

Recent challenges in drug development for high-risk MDS highlight the critical importance of continued clinical trial enrollment. Collaboration among academic and community oncologists is crucial to advancing research and providing patients access to promising new therapies. At Hackensack Meridian Health, we are committed to fostering these partnerships to improve outcomes for all patients.

Garcia-Manero G, McCloskey J, Griffiths EA, et al. Oral decitabine-cedazuridine vs intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study. Lancet Haematol. 2024;11(1):e15-e26. doi:10.1016/S2352-3026(23)00338-1

Articles

Oral decitabine-cedazuridine (Inqovi) offers a significant advancement for patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), providing a bioequivalent and convenient alternative to intravenous decitabine. The phase 3 ASCERTAIN trial confirmed its safety and efficacy, showing pharmacokinetic equivalence to IV decitabine. This oral formulation enhances patient quality of life by reducing clinic visits and enabling home treatment. However, patients with compromised gastrointestinal absorption may not be ideal candidates. The formulation also facilitates novel combination strategies and highlights the importance of continued clinical trial enrollment.

The oral formulation of decitabine-cedazuridine helps empower patients with MDS or CMML to maintain their quality of life from the comfort of their home.

Oral Decitabine-Cedazuridine Is a Game Changer for MDS and CMML Treatment

 So…we’ve talked a lot about myelofibrosis, the mechanism and all of the drugs that are currently approved to treat it. What do you think about the future of myelofibrosis treatment, Dr McCloskey?

 I agree, this has been a lot of information. I hope everyone found that as interesting as I did. But I think that the future is even more exciting in this disease, and I think…at Hackensack [University Medical Center], I’ve been the director of the leukemia program now there for 3 or 4 years, I guess, but I really started as the director of the myeloproliferative neoplasm division and…I think that the disease space is just changing so quickly. We have more offers and clinical trial proposals every day than we could possibly ever do. We are declining them despite the fact that our myelofibrosis patient population has grown faster than the other areas of our division, and so there are so many exciting drugs coming, I think. To highlight a few, I think the BET inhibitors are a very exciting class of drugs. The one we’ve been hearing the most about was pelabresib, and that is likely to be the drug probably to make it to commercial use first, I imagine. We saw updated data [at] ASH [the American Society of Hematology meeting] looking at the MANIFEST-2 trial [NCT04603495], which … had several arms. But what we saw [at] ASH was the combination arm up front, so pelabresib or BET inhibitor plus ruxolitinib, where we saw spleen volume responses that were…60% at week 48. So as you recall that…pretty robust numbers. Granted this is phase 2. It’s small, but even more importantly this response was maintained in 80% or more of patients. So, it seems to be a durable response. There are some issues with this drug, in my opinion. I think that it does have some cytopenias that could be problematic.

There are other drugs in development behind pelabresib that don’t have as much of an anemia impact. We are going to have one of those Hackensack. So we’re really excited about that. We also saw updated data on a PI3 kinase inhibitor parsaclisib, which we also had this study at Hackensack. This is a PI3 kinase inhibitor that was looked at as an add-on to ruxolitinib. So this looked at patients who had an inadequate response or did not respond to ruxolitinib and were then continued on ruxolitinib with the addition of this drug, parsaclisib. And we did see at week 24 a 19% reduction in spleen volume. And we also saw their median symptom score decreased by 44%. So this was significant response rates. In that same group of higher-risk patients, and possibly disease-modifying drugs, is navitoclax. This is the BCL-2 inhibitor in development. The randomized phase 3 up-front trial has completed accrual, where we looked at ruxolitinib alone versus ruxolitinib plus navitoclax. Again, we saw some updated data [from] ASH where we saw significant rates of bone marrow fibrosis reproduction. Which, for better or worse…is something that does hint, I think, at least at disease modification.

In that same area like with disease modification and reduction in bone marrow fibrosis and we’ve previously seen data on … that we think that’s a drug that is probably going to come to us both in MDS [myelodysplastic syndrome] and myelofibrosis in the future. And luspatercept. So that’s a drug that we know affects the NF kappa-beta pathway. It has been shown in MDS now to be effective [in] low-risk disease of improving anemias, and we are studying it now in myelofibrosis, where we have seen improvements in anemia. And I think that while it’s not maybe as super exciting and cutting-edge as some of these other new drugs…added to ruxolitinib in the frontline setting, as we’ve been talking about all this time, where anemia limits our ability to treat patients, it may also have the ability to be more disease-modifying by allowing us to maintain ruxolitinib dosing. So we do have the clinical trial in myelofibrosis with ruxolitinib or any JAK inhibitor, in fact. And luspatercept that Hackensack [is accruing] now. So lots of exciting options and I think a very bright future of this disease where we haven’t had new options in so long. So, with that…I wondered if anyone had any final thoughts. Anything else you’d like to share?

 I think…after talking about all of this…we all can agree that it’s so important up front to properly…risk-stratify our patients, careful assessment and response. We have other options now, so if they’re not responding appropriately, I think now is the time that we have to switch to a different agent to see if we can get a better response for that patient and therefore improve their quality of life. And I also think, again, as I said before, just talking about transplant and prognosis up front, I think it’s so important to get these patients in with the right people just to see what their options are down the road and move forward with that.

 I think for me, it’s…an exciting time that we get to discuss 3 different JAK inhibitors…2 of which were approved, and that’s just [the] past few years for the treatment of myelofibrosis, and hopefully more…that will be approved soon. And really with the increasing number of these agents that are available, I think it’s important to really recognize the differences in the toxicity profile between these agents and really try to prevent adverse events with appropriate monitoring and medications if possible and probably treat those [adverse] effects that we see for a safe and effective use of these medications. And I think manufacturers’ prescribing information is always a great resource to just know about adverse events, dose adjustment, and various drug/drug interactions. They do get updated as more data [are] collected over time. So…for our colleagues, I would highly recommend really utilizing those resources as questions come up when seeing these patients on the medications.

 I agree with all that…. The future is really exciting…but the present is really exciting. I think all these drugs being available to us, it’s really going to help our patients. I think the other thing that we…touched upon though is the value of collaboration. I think that I would highlight that. Most of the patients with myelofibrosis who see us at Hackensack, they also have a local oncologist. And I think that there are other myelofibrosis nerds out there, probably in your backyard, who would love to help work with you if you’re a local oncologist. I think that these patients really benefit from seeing a physician at a tertiary center, but then also really benefit from continuing their care with their local oncologist because it’s not easy to get around in New Jersey. Traffic here is not so fun all the time. And…honestly, driving 20 miles could take you half the day sometimes.

So there’s not always a need for that, but I think that patients and providers really benefit from that relationship, collaborating on the care of the patients initially and then the bridging to transplant, but then also, as we mentioned, the clinical trial aspect because…this is such a rare disease that if we’re going to continue to make progress, we have to do clinical research, and by meeting a physician at another center early, it…gets on our radar. It allows us to check in maybe once a year, so we’re getting more patients onto trial, and I think that’s something that…we want and our patients want. So…I think that just to wrap up, I’d really like to thank Danielle and Geeny for contributing. You know they are incredible team members. They make my life better and our patients’ life better. I thank you, the audience, for joining us today and listening. We certainly hope that you found this episode of own 

 program to be useful and valuable in the management of your patients with myelofibrosis. Thanks a lot.

Transcript is AI-generated and edited for clarity and readability.

Videos

Closing out their discussion on myelofibrosis management, experts from the John Theurer Cancer Center consider novel therapies under investigation and the future treatment paradigm. 

Evolving Treatment Landscape of Myelofibrosis 

 So, thinking about these drugs that we use in less cytopenic patients. Geeny, could you talk to us maybe about the—I know we touched upon some of this, but, really, the safety profiles for ruxolitinib and fedratinib?

 Ruxolitinib and fedratinib do have some overlapping [adverse] effects, but they also do have some unique toxicities. So to go over each, some [adverse] effects of ruxolitinib include cytopenias. I think we mentioned it before about thrombocytopenia, anemia, and neutropenia. So, for these, really depending on the degree of cytopenias, we may have to reduce the dose or even hold the treatment. And ruxolitinib has also shown to increase risk of various infections. So we do want to monitor patients closely for any signs and symptoms of infections and treat promptly if they do develop any. And, lastly, again, Dr McCloskey alluded to this earlier, but if we do discontinue ruxolitinib abruptly, patients can develop a form of withdrawal syndrome or exacerbation of symptoms. So it’s really important to also counsel patients about not stopping treatment on their own. And if we are planning to discontinue treatment with ruxolitinib in a patient, like Dr McCloskey said, we do want to gradually taper them off rather than stopping abruptly.

And as for fedratinib, we can also see some cytopenias, especially anemia and thrombocytopenia. Again, depending on the degree of cytopenias, we may also have to interrupt and adjust the dose. And something that’s a little bit different with this medication is at the most common nonhematologic toxicity that we see with this medication is GI [gastrointestinal] toxicity that manifest as diarrhea and nausea and vomiting. So for nausea and vomiting, we can actually prevent with prophylactic antiemetic with something like 5-HT3 antagonist. And for diarrhea, it’s important to counsel patients to monitor closely. And we can also treat with anti-diarrheal medication like loperamide. But if we are seeing severe GI toxicity that does not respond to supportive care within 48 hours, we do have to hold treatment until resolution and reduce the dose. There’s also a risk of hepatotoxicity and amylase and lipase elevation. So we do want to monitor these labs at baseline and then periodically thereafter. And the last adverse event that I want to highlight, which also Dr McCloskey alluded to earlier, is encephalopathy, including Wernicke’s, which is a box warning for this medication. And in the clinical trials, this was a rare occurrence, but it can be severe. So, we want to obtain a thiamine level at baseline and monitor periodically throughout treatment. And if patient does have low thiamine level at baseline, we should definitely replete prior to starting them on fedratinib. So, with everything said, Danielle would you be able to highlight which patient population we may choose to use ruxolitinib versus pacritinib versus fedratinib?

 I think when the patient comes in, every patient is so different. So if someone is coming into the office and their counts, they have these really robust counts, I think Jakafi would be a great drug for that person. You’re not worried so much about the cytopenias. I think Dr McCloskey had mentioned earlier, fedratinib. We don’t use it so much, but I think that it does have its place for more of the proliferative disease. And there is pacritinib too. So that’s classically, I think, even when we first started using it, it was that classic pacritinib patient with very low platelets, this is a great drug for them. I think even more so now, we’re using pacritinib in patients even with a very good platelet count whose primary problem is the anemia to spare them from some of the [adverse] effects from something [like] Jakafi. So, I think again, each patient is very unique, and I think these drugs each all have their spot in the different types of myelofibrosis patient.

 Right. I agree with that totally, Danielle. I think that…to highlight what Danielle is saying, pacritinib obviously was approved based on the data from these studies looking at thrombocytopenic patients and that, as people might be aware of, the FDA approved indication—I think Geeny mentioned this earlier—is for patients with platelets counts less than 50,000. Obviously, we understand that that FDA assigned that label based on the data that they’ve been provided. However, many of us, including the panel at the NCCN [National Comprehensive Cancer Network] recognized that…the data [were] primarily in these patients with … thrombocytopenia. But we still have these patients who have an unmet need that they’re not responding to ruxolitinib or…maybe they are so anemic, I can’t give those drugs. And so, the NCCN has added it now as a treatment option that’s endorsed by the expert panel there…, again, as frontline [treatment for patients] with platelets less than 50,000 but for any patient in the second line irrespective of platelet count. I think that that’s why…Danielle is mentioning we have many patients who are deriving benefits from this therapy despite not being profoundly thrombocytopenic.

Panelists consider the patient and disease factors that might indicate use of a specific JAK inhibitor when managing patients with myelofibrosis.

Factors Informing Selection and Use of JAK Inhibitors in Myelofibrosis 

 So, Danielle, we’ve talked a lot about drugs. I know I’ve been tossing around a lot of numbers here. Can you talk…about how this comes into the clinic, how it comes to life? How do we decide on a treatment and what are some of the challenges that we face…? And also…when would you consider a clinical trial?

 So I think, typically, when we’re seeing patients, we kind of always have clinical trial in the back of our mind, even upon initial diagnosis, progression. We’re constantly screening these patients to see if we have a good option for them. When choosing therapy, specifically, I think you’re looking [at, is] that patient, more of that, cytopenic, myelofibrosis, are they more proliferative, depending on their counts, can we give them Jakafi without causing major cytopenias, or did they come to us already very cytopenic and may benefit from [a] more pacritinib-type drug? And I think it’s really important to assess [a] patient’s symptoms because…I think there’s such a wide variety of symptoms with myelofibrosis patients. They may come and not really have many symptoms, and then other people are coming, and they have absolutely every symptom. So I think it’s important to talk to the patient and figure out what drug kind of fits them best. As far as transplant goes, I think it’s so important to get that conversation started in the very beginning when we’re meeting them, because so often we’re seeing patients and you have a window to transplant a patient, and sometimes by the time we’re seeing them in our office, they are getting too sick for transplant or too old for transplant. So, I think it’s really important to at least work them up, especially if they’re an intermediate-2 or high-risk patient. Get them hooked up with your transplant team, see what their options are, because transplant can’t happen overnight. This takes many months to plan. And knowing what our options are up front can help us definitely best manage that patient and then get them over to transplant if appropriate. Dr McCloskey, how do you approach sequencing therapies for patients with myelofibrosis with our currently approved agents?

 I think the first thing and most important thing is that we’re thinking about sequencing. I think we are finding that many times we’re…stuck in a rut because we’ve gone so long with just the same tools and the tool basket that there can be a tendency to really forget about the other options or maybe not appreciate the value of controlling some of these parameters we talked about. So the first thing is that we are constantly looking for treatment failure. It is incredibly important that you examine your patients every time they’re there, that you palpate the spleen. We have now routinely implemented [that all patients get] an ultrasound at least once a year. And I guess for me, I think the first thing that I do, and I say this all the time, is I determine—we’re talking about ruxolitinib first line—what I expect that drug to do for me. If it’s supposed to be controlling symptoms, then I’m monitoring the symptoms while I’m watching for the spleen. If I am trying to control the spleen volume, [and] if it’s not doing for that for me, then I know I need to change.

Additionally, if I cannot keep the patient on an adequate dose, then I need to switch. Because with ruxolitinib, we know that spleen volume reduction is a dose-related phenomenon. And so I think that the first step is just recognizing we have those other options. And I think Danielle mentioned one of the… things that drives us, particularly in our clinic, is that we have all these trials. So we’re always trying to put patients on a trial. But I think that for me, I often am looking at that spleen volume reduction, and I often if I’m in a meeting and I am sitting in a room full of people, I have colleagues that will cite the value of spleen volume reduction in those patients, and the fact that, hey, if we can control the spleen volume, we improve survival. And I have colleagues who will [say], well, that is selection bias. And I totally agree. If we’re writing a paper, if we’re talking about our next clinical trial, yes, it is selective bias. But the fact is that we take care of a lot of patients. Danielle and I see many patients during the week, and it’s our response to care for them. And when that patient, when SM is in front of me, I don’t know whether or not she’ll be a responder. So I think it’s my job to offer her that opportunity to have a response. So that’s why we really think it’s so important to stay on top of the spleen, so we intervene early and sequence early when there’s treatment failure.

When we’re switching between agents, then it can be challenging. Remember that these patients can have a ruxolitinib withdrawal independent of which agent we’re talking about. So, usually I try to taper the ruxolitinib down and switch over to one of these other agents. If I’m having a patient who is particularly symptomatic, I may send that patient… home with some steroids to have on hand in case we see ruxolitinib withdrawal. I think, going back to momelotinib, that trial require[s] a washout, and I can remember patients who in fact didn’t make it on study because they just couldn’t be off the ruxolitinib. And so that’s the one thing I would say is important. Otherwise, I tend to switch between all these agents pretty quickly once I’ve tapered them down and watch them closely. I think as you switch over, keep in mind these drugs could have different behaviors for your patients. If you have an elderly frail patient, give them a call, check on them to make sure that they’re doing OK and [that] they’re not withdrawing at all.

Broader perspectives on the optimal selection and sequencing of systemic therapy in patients diagnosed with myelofibrosis.

Optimal Selection and Sequencing of Therapy in Patients With Myelofibrosis  

 Danielle, could you talk more about any other biomarker testing that’s important to these patients?

 We’re typically doing biomarker testing during diagnosis initially for a baseline, and that can help us with further treatment planning. Again, we usually do this at diagnosis. And then if we’re ever concerned about progression of disease, we would again do these to see if we were coming up with different biomarkers that weren’t there initially, if something had gone away … We continuously monitor our patients and decide on a case-by-case basis when to do them, but certainly [doing them] at initial diagnosis or any point of progression is really important. And I think we usually are telling our patients that these will help us determine more about their disease. Patients always want to know what their prognosis is. Is this good or is this bad? And I think this helps us to have that conversation with them and give them more information about how we think their disease will behave.

 Absolutely. And I think in addition to that, like Danielle mentioned [with] these biomarkers, something else we’re often doing as well is monitoring allele frequency. While I would say that this is … ahead of the curve in terms of its current use in day-to-day clinical practice, it is something that we watch. We have shown that changes in variant allele frequency are associated with both response to the therapies that we use in these patients, but also increase in allele frequency associated with the risk of progression. So that’s something we’re monitoring as well. I think that Danielle mentioned that initial approach. I think important one to keep a lookout for is 

. When you see this on your next-gen panel, this is always a worrisome mutation, particularly in other patients who might be negative for the 3 classic mutations that we see in myelofibrosis [MF]. Which you all know includes primarily 

. These are important mutations. But when we see the 

, that always confers a more adverse prognosis. And 

 as well … These tend to be bad actors, just like we see in other disease diseases in the myeloid space, especially if there’s a high 

 Dr McCloskey, can you tell us about the different types of myelofibrosis?

 We talked about … the molecular heterogeneity of the disease. And I think that in the average clinic, this is a disease that oncologists probably aren’t seeing every single day. At Hackensack, we see this every day, and we probably have multiple patients each day that we see. And [although] we tell everyone they have myelofibrosis, in reality many of these patients have different diseases. And I think we are making strides and improving our understanding of this just like we have in AML [acute myeloid leukemia] and MDS [myelodysplastic syndromes]. A lot of this starts with understanding what’s going on at a molecular level. And clearly we understand that, molecularly, not all diseases are the same. I think that we all have those patients who are triple negative for those classic 3 mutations that I mentioned. And clearly, they probably have a different disease than a patient who might be more commonly seen with a high 

 allele burden as the solitary abnormality.

And so, there’s a variety of ways we can kind of look at these patients. One discussion we’re having right now is … separating patients into proliferative and cytopenic myelofibrosis. And it’s important to understand that patients may start proliferative and can progress later to be cytopenic. But [patients with] cytopenic myelofibrosis tend to be patients who, as the term would imply, have cytopenias. At a molecular level, this disease tends to be signified by being 

 negative or having a low allele burden, and additionally will often come to us with other mutations. So [it means] having more complexity from a molecular standpoint with mutations being seen in epigenetic modifiers, in the spliceosome genes. And not surprisingly, these patients tend to have disease that behaves more poorly. That’s why in the DIPSS calculator, cytopenias are one of the factors that weigh heavily into your risk stratification. These patients with cytopenic MF tend to have disease that is more progressive. And also, as we’re going to see, they have disease that can be more difficult to manage because the therapies that we’ve had until recently often worsened those cytopenias.

And when we see these patients, I think the other thing that can be difficult is that it can be hard to decide … We start a JAK inhibitor and then their counts are a lot lower. Is that disease related or is it drug related? And sometimes it’s … impossible to tell. At some level, in my opinion, it’s always disease related. So if we can’t treat them on adequate doses of the drugs that we have because of cytopenias, it really just indicates us now that we need to switch to other options. But historically, this has been a big problem for us is because the treatments we’ve had [for] cytopenias often limit dosing of drugs that otherwise [might be] really effective.

Expert panelists consider key molecular markers that guide the classification and management of myelofibrosis, along with other important subsets of disease.

Molecular Markers and Subsets of Myelofibrosis 

James K. McCloskey II, MD, medical oncologist, Division of Leukemia and the Adult Blood and Marrow Stem Cell Transplantation Program, John Theurer Cancer Center, discusses the results of the phase III ASCERTAIN trial in myelodysplastic syndrome (MDS). 

Prior data showed that the oral combination of decitabine and a DNA methyltransferase inhibitor could prolong the exposure to decitabine, similar to when decitabine is given intravenously in patients with MDS. Therefore, the trial evaluated the use of a fixed-dose combination of cedazuridine and decitabine, known as ASTX727, in

patients with intermediate- and high-risk disease. Patients were randomized to receive decitabine intravenously in cycle 1 or 2 of therapy, followed by ASTX727 for the remainder of treatment, says McCloskey.

The results showed that the exposure to decitabine was the same, whether patients received decitabine orally or intravenously. These data will move treatment to the outpatient setting, making it easier for patients to receive therapy, says McCloskey. Moreover, these data have established a precedent for examining additional oral therapy combinations in lieu of intravenous therapy.

James K. McCloskey II, MD, discusses the results of the phase III ASCERTAIN trial in myelodysplastic syndrome.

Dr. McCloskey on the Results of the ASCERTAIN Trial in MDS

James K. McCloskey II, MD, medical oncologist, Division of Leukemia and the Adult Blood and Marrow Stem Cell Transplantation Program, John Theurer Cancer Center, discusses IDH inhibitors in acute lymphoblastic leukemia (AML).

Over the last 6 months, there have been several drugs that have come to market in a field that had previously not seen a drug approved in decades, explains McCloskey. The use of IDH inhibitors in 

-mutated patients with AML continues to excite physicians, McCloskey adds.

A quarter of patients with AML will have a mutation with 

. Currently, there are 2 drugs to target these mutations. For 

-mutated AML, the drug enasidenib (AG-221) has recently come to market. There is phase II data demonstrating that 89% of patients with relapsed/refractory 

-mutated AML had stable disease by day 90 with enasidenib. These patients could survive for a period of time with stable disease and might later have a response, explains McCloskey.

In those patients, one quarter went on to have a response and therefore had an improvement in the risk of death from AML. Stable disease might be a more important endpoint for molecular therapy than it is when using chemotherapy agents, says McCloskey.

Dr. McCloskey Discusses IDH Inhibitors in AML

James K. McCloskey II, MD, medical oncologist, Division of Leukemia and the Adult Blood and Marrow Stem Cell Transplantation Program, John Theurer Cancer Center, discusses targeting CD19 in patients with acute lymphocytic leukemia (ALL).

CD19 is an ideal target in B-cell ALL, says McCloskey, as it is expressed on the surface of the cells of these patients.

The antibody-drug conjugate loncastuximab tesirine (ADCT-402), which is designed to target CD19, is currently being evaluated in patients with relapsed or refractory B-cell ALL.

James K. McCloskey II, MD, medical oncologist, Division of Leukemia and the Adult Blood and Marrow Stem Cell Transplantation Program, John Theurer Cancer Center, discusses targeting CD19 in patients with acute lymphocytic leukemia.
 

Dr. McCloskey Discusses Targeting CD19 in B-Cell ALL

Patients with myelofibrosis, a rare myeloproliferative neoplasm associated with a high mortality in intermediate- and high-risk disease states, have few options for treatment. Allogeneic stem cell transplantation is the only potentially curative option. Ruxolitinib is a JAK1/2 inhibitor that has been shown to improve quality of life and reduce spleen size, but it is associated with significant hematologic toxicity precluding its use in patients with significant thrombocytopenia.

Here at the John Theurer Cancer Center (JTCC), we treat a large number of patients with myelofibrosis. Although we perform allogeneic stem cell transplantation in appropriately selected patients, we are investigating new treatment options.

Pacritinib, a JAK2/FLT3 inhibitor, is among the most promising of those emerging options. The agent has significantly reduced spleen size and was associated with improved symptom control in early clinical trials. Treatment with pacritinib was associated with an improvement in platelet count and anemia among participants, with 25% of transfusion-dependent patients becoming transfusion independent.

Because of the rarity of the disease and lack of acceptable standard treatment, we encourage oncologists to reach out to experienced cancer centers early in the disease course to explore clinical trial options that aid in the development of novel therapies such as pacritinib. The PERSIST-2 study, currently enrolling patients at JTCC and more than 100 other locations in the United States and Europe, is one of the few randomized phase III studies focusing on patients with myelofibrosis and thrombocytopenia.

Myelofibrosis is a primary bone marrow malignancy that belongs to the myeloproliferative neoplasm category. This heterogeneous group of diseases includes chronic myelogenous leukemia, essential thrombocythemia (ET), polycythemia vera (PV), systemic mastocytosis, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Patients may present with primary myelofibrosis (PMF) or may evolve to a myelofibrotic state from preexisting ET or PV.

Both primary and secondary myelofibrosis share a similar pathophysiology. Initial stages of the disease are characterized by aberrant clonal stem cell proliferation with increased CD34-positive cells in the marrow and abnormal cytokine expression. This results in reactive bone marrow fibrosis and worsening anemia and thrombocytopenia. In later forms of the disease, patients exhibit significant hepatosplenomegaly as these organs become sites for hematopoiesis.

The clinical manifestations of myelofibrosis include constitutional symptoms, splenomegaly, anemia, thrombocytopenia, bone pain, pruritus, and splenic infarct. Severe fatigue, bone pain, and gastrointestinal symptoms related to splenomegaly can dramatically impact the quality of life for patients with myelofibrosis.1 This burden is often compounded by comorbid conditions and advanced age. Many patients will die from the disease, and approximately 20% eventually evolving to acute leukemia.

Multiple prognostic models exist for risk stratification at the time of diagnosis (IPSS), after diagnosis (DIPSS), and based on molecular and cytogenetic features (DIPSS-plus). Age greater than 65 years, hemoglobin >10 g/dL, leukocyte count >25,000/μL, platelet count <100,000/μL, circulating blasts ≥1%, constitutional symptoms, and high-risk cytogenetics, are associated with inferior outcome.

 have also been linked with poor clinical outcome.

Myelofibrosis has been closely linked to dysregulation of the JAK2/STAT pathway. Mutations in 

 V617F, exon 9 of calreticulin (CALR), and exon 10 of the thrombopoetin receptor gene (

) all lead to dysregulation of the JAK2/ STAT pathway and are observed in 58%, 25%, and 8% of PMF patients, respectively.

 JAK2 is an intracellular tyrosine kinase that regulates the STAT pathway. The STAT pathway is responsible for regulating crucial aspects of hematopoiesis.

 V617F mutation results in impaired auto-inhibition of JAK2, resulting in constitutive activation of the JAK2 cascade.

In addition to aiding in diagnosis, these molecular phenotypes have been observed to have some prognostic value. Patients with mutated CALR as the only abnormality have a more indolent course. The 9% of patients with a triple- negative phenotype have a poor prognosis. 8 The discovery of the role of JAK2 signaling in PMF, ET, and PV led to the synthesis of molecules targeting the JAK2 receptor. Ruxolitinib is a JAK1/2 inhibitor that was studied in two randomized phase III clinical trials, COMFORT-I and COMFORT-II. Both trials showed that ruxolitinib decreased spleen size and constitutional symptoms, and was associated with an improved quality of life. These benefits were seen irrespective of the 

 mutational status. Neither study demonstrated a significant survival benefit.

Ruxolitinib was generally well tolerated but associated with anemia (90%) and thrombocytopenia (70%). The anemia associated with ruxolitinib was worse during the first 2 months of therapy with an overall improvement thereafter. Thrombocytopenia did not improve and as a result, ruxolitinib dosing needs to be reduced in patients with platelet counts <200,000/μL and must be withheld for patients with platelet counts <50,000/μL.

Pacritinib, formerly called SB1518, is a novel inhibitor of JAK2 and FLT3. Unlike ruxolitinib, it has no JAK1 activity. In preclinical studies, it exhibited potent JAK2 inhibition independent of mutational status.

		Table. Reduction in Spleen Volumea With Pacritinib Versus Best Available Therapy, According to Baseline Cytopenia Level

		BAT indicates best available therapy; ITT, intent to treat.

Spleen volume reduction defined as ≥35% from baseline to week 24.

ITT population indicates primary analysis included all patients randomized. Patients who missed MRI or CT scans at baseline or at week 24 were counted as nonresponders.

Evaluable population analysis included patients who had assessment at both baseline and at week 24.

Early clinical trials showed promising results in patients with myeloid malignancies including PMF. The results of the phase III PERSIST-1 trial were presented by Ruben A. Mesa, MD, at the 2015 ASCO Annual Meeting in June.

 In this study, 327 patients with PMF, post-PV myelofibrosis, or post-ET myelofibrosis were randomized in a 2:1 fashion to pacritinib versus best available therapy (BAT). Patients previously treated with ruxolitinib were excluded. Best standard of care options included erythropoietin- stimulating agents, immunomodulatory drugs such as thalidomide and lenalidomide, and hydroxyurea. The primary endpoint was the proportion of patients achieving ≥ 35% spleen volume reduction (SVR) at week 24.14 Of the 327 patients enrolled, 220 were randomized to the pacritinib arm and 107 to BAT.

Median time to diagnosis was 1.12 years. Patients with thrombocytopenia were not excluded; 32% and 15% of patients had platelet counts of <100,000/μL or <50,000/ μL, respectively. A significant proportion (75%) were 

— positive. The median duration of treatment was 16.2 months on pacritinib versus 5.9 months on BAT. The SVR rates at week 24 were 19.1% for pacrtinib versus 4.7% for BAT (

 = .0003) in the intent-to-treat population and 25% versus 5.9% (

 = .0001) in the evaluable population (Table). Subgroup analysis showed that patients with significant thrombocytopenia also experienced SVR. In fact, the greatest difference in the treatment arms was observed in evaluable patients with the lowest platelet counts. In patients with <50,000/μL platelets, 33.3 % versus 0% met the primary endpoint (

 = .037). These patients also experienced a 35% increase in platelet counts from baseline compared with BAT (35%; 

= .003). In the subgroup of red blood cell—dependent patients, 25.7% of patients receiving pacritinib became transfusion independent. None of the BAT patients experienced this benefit.

As seen in phase II studies, the most common grade 3 serious adverse events were diarrhea, nausea, and vomiting. Hematologic adverse events were uncommon. Despite some reported gastrointestinal toxicities, patients treated with pacritinib experienced a significant improvement in symptoms. Patients on study completed a daily electronic diary of symptoms including the Myeloproliferative Neoplasm Symptom Assessment Form. Patients treated with pacritinib experienced greater improvement in their symptoms when compared with BAT (40.9% vs 9.9% among evaluable patients, 

 As a result of these findings, the PERSIST-2 study has been launched.

 The trial is enrolling patients with platelet counts ≤100,000/ μL. The primary objective of PERSIST-2 is to compare the efficacy of two dose-schedule arms of pacritinib with that of BAT in this patient population.

The efficacy co-endpoints consist of the proportion of patients achieving a ≥35% reduction in spleen volume from baseline to week 24 (measured by MRI or CT) and the proportion of patients achieving a ≥50% reduction in total symptom score from baseline to week 24. Patients are randomized 1:1:1 to one of three treatment arms including pacritinib 400 mg orally daily, pacritinib 200 orally twice daily, and BAT.

			Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia. 

			Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. 

			Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. 

			Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). 

			Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. 

			Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations- based molecular prognostication in primary myelofibrosis: an international study of 570 patients. 

			Guglielmelli P, Lasho TL, Rotunno G, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. 

			Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. 

			Dawson MA, Bannister AJ, Göttgens B, et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. 

			Vainchenker W, Constantinescu S. JAK/STAT signaling in hematological malignancies. 

			Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo- controlled trial of ruxolitinib for myelofibrosis. 

			Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. 

			William AD, Lee AC, Blanchard S, et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[ 19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21, 23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. 

			Mesa RA, Egyed M, Szoke A, et al. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PETMF). 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov website. Identifier: NCT02055781.

Pacritinib, a JAK2/FLT3 inhibitor, is among
the most promising of those emerging options for patients with myelofibrosis.

James K. McCloskey II, MD