Targeted Oncology

 Would you say that based on the findings of this trial, but also the REACH1 trial and your experience itself, that ruxolitinib has become the standard of care for steroid-refractory acute GVHD [graft vs host disease] for your patients?

 Being approved for this indication and having promising results in a large study like this, it’s hard to deny your patients this drug when you want to get them off steroids. I have been reaching out to use ruxolitinib, and initially, depending on what their blood counts are, I feel comfortable starting even at a low dose of 5 mg twice a day and escalating that if need be depending on how they tolerate it.

 Dr Chao, in North Carolina, has ruxolitinib become fairly standard treatment for steroid-refractory acute graft vs host disease?

 It has. As long as there’s not a competing clinical trial, we have and used ruxolitinib. Even before this trial and before the final results.

 How has your anecdotal overall experience been in this setting?

 It’s been close. It’s not the easiest drug to use in these patients because, 25 after an anecdotal transplant, the counts are pretty fragile. You have to be careful with the play counts but sometimes with their neutrophil count as well.

 To add to that, when we’re also treating leukemia patients, thinking about how we prevent relapse and if you want to start them on ruxolitinib dose, all that also impacts your ability to treat them effectively if they have cytopenia in addition to this.

 All of us would agree that while the REACH2 results are impressive, and we applaud the investigators for conducting a phase 3 randomized trial in that setting—which is quite rare—there’s still room for improvement. What we showed was that while there’s a compelling overall response rate, the durable response rate at 8 weeks out remains in the minority of patients. Dr Chao, what do you think the unmet needs are going forward for steroid-refractory acute GVHD? Do we need better drugs, better trials, better ways to prevent, or all of those things? What do you think we most need to focus on?

 We need better drugs. I agree with you. If you look at the durability, it’s better than some things we’ve had, but the overall response and the length of response are probably not as good as we would like. The trial design people have complained about the special alternative therapy with 10 choices. That’s reality, but limiting to some of the other choices would have made it cleaner. It’s always true that your results can look better because your drug is better or because the controls are worse. Sometimes it’s hard to tell. There are still a lot of unmet needs.

 Dr Munshi, what are your thoughts on that?

 I agree because we still have nonresponders, even to this combination. What happens to those patients? How do we get them off steroids? To Dr Chao’s initial comment, do we need steroids at all? Can we use something else steroid sparing as frontline therapy? We don’t have answers to that.

 The next few years will hopefully be exciting in graft vs host disease research in general. There’s been more interest, and we have more clinical trials. We’ve all seen that and participated. We’re all hopeful that we can make some more progress even beyond this to ultimately improve the outcomes for our patients.

 Dr Munshi, there are several agents under investigation. Are there any that you or your center are most excited about?

 I’d be happy to hear your thoughts on the alpha-1 antitrypsin drug that was used in the first line after steroid-refractory acute GVHD. Bortezomib is a friendly fire around here. It’s easily available, and there was a phase 2 randomized trial that looked at bortezomib with TAC [docetaxel, doxorubicin hydrochloride, cyclophosphamide] methotrexate and then with TAC sirolimus. They’re not robust data. It looked like the combination with sirolimus had about a 15% incidence of grade 2 to 4 acute GVHD compared with the standard TAC methotrexate, which happens to be 30% to 40% incidents of acute GVHD. Maybe in some cases, you could use bortezomib. But when you look at the data closely, there weren’t impressive responses in grade 3 or 4 acute GVHD. It’s something that’s readily available. You can see in the data that was the other JAK1 inhibitor didn’t pan out when used with TAC [docetaxel, doxorubicin hydrochloride, cyclophosphamide] methotrexate for profile access. It didn’t show a lot of difference. I haven’t been using any other monoclonal antibodies or things like that, but I’d be interested to know what you and Dr Chao do in your practices.

 There were impressive data from using alpha-1 antitrypsin necessarily refractory setting from both Michigan and Seattle, and it’s being tested in the up-front setting for clinical high-risk graft vs host disease in a trial run by the CTN [Clinical Trials Network]. Here in Boston, in addition to ruxolitinib, when patients have steroid-refractory lower GI acute graft vs host disease, we’ve been pursuing 2 other modalities of therapy. One is the monoclonal antibody, vedolizumab, which is approved for inflammatory bowel disease and targets a mediator of lymphocyte trafficking to the intestine. I’ve conducted clinical trials using that agent, and we’ve seen some responses to it, but it also does not appear to be a home run. Earlier use is better than using it in the very steroid-refractory setting.

The other avenue we’ve looked at is the role of the microbiome in transplantation, meaning the diversity of the bacterial colony in one’s intestines. A lot of associative studies done by Dr Chao’s colleagues, also done by investigators at [Memorial] Sloan Kettering [Cancer Center] and other sites, have shown that patients with dysbiosis or restricted microbiome diversity predict a higher incidence of graft vs host disease. That’s led some of us to pursue the role of trying to restore diversity as a treatment for acute graft vs host disease. We’ve done third-party fecal microbiota transplants right after transplant empirically to prevent graft vs host disease. We’ll have an upcoming trial to treat steroid-refractory acute GVHD. There have been anecdotal series around the world that have used fecal microbiota transplantation with some success to treat graft vs host diseases as well. It’s something that bears watching. It is an interesting world that requires us to think about what is a drug and how to manufacture it and then to be sure of the contents of something as we’re doing it. Dr Chao, because your center has done some work on the microbiome, what are your thoughts on the future of that?

 That’s promising. The correlation is clear. We need to prove causality, and then if that’s the case, fecal transplants work quite well for 

. It works well for difficult-to-treat diseases like that.

This transcript has been edited for clarity.

Videos

The panelists discuss the role of ruxolitinib steroid-refractory acute GVHD and comment on unmet needs in treating this patient population, including fecal transplants.

Case 1: The Role of Ruxolitinib in Steroid-Refractory Acute GVHD

Dr Munshi, you had mentioned that when patients are first admitted to the hospital, you engage other services to help patients with acute GVHD [graft vs host disease]. Can you describe when a patient is in the hospital with GI [gastrointestinal] GVHD? Dr Chao had mentioned the long road to recovery. We’re familiar that this patient has weeks ahead in the hospital to slowly recover. What other supportive care is engaged for this patient to recover?

These patients don’t feel the brunt of the steroids and the first week that they get such high doses, but it’s very quick. It all catches up: They get myopathy, and they get very weak and debilitated. I’m quick to engage physical therapy and occupational therapy up front for these patients to prevent disability and long-term disability. Somebody who’s having this degree of the area is depleted of protein and calories; they get malnourished quickly. As much as we want to maintain enteral feeding, in an acute setting gut rest is warranted to prevent the extra absorption and output. I put them on clear liquids and start them on TPN [total parenteral nutrition] for a short time to give them a little break.

 A team approach is needed to help the patient recover from this type of complication. There is literature on this, as we treat patients who had an initial endoscopy to get a biopsy. Dr Chao, does your center do serial endoscopy in these patients to help assess the response or figure out what’s going on?

 We will do a second biopsy sometimes when patients are not getting better, just to be sure we’re not missing something like CMV [cytomegalovirus]. It’s not to see if they start GVH but to be sure there aren’t other reasons for their diarrhea.

 There’s some literature, mostly pediatric, that when you look at these biopsies in patients who have steroid-refractory acute graft vs host disease being tested, oftentimes when you focus on mucositis, you may see that a good amount of these patients have thrombotic microangiopathy localized in the GI tract. There’s some literature that the endothelium itself is a target organ of acute graft vs host disease. Do you look for that in your patients, Dr Chao? How does that play into what options you can select from management?

We’ve been slow to come around to realizing the endothelium as a target for a lot of what we do in terms of damage. Encephalitis has been mostly understood in the COVID-19 era, but we do the same thing with the PrEP [pre-exposure prophylaxis] regimens that we use with the TBI [total body radiation]. That synthesizes a lot of the toxicity between GVHD, VOD [veno-occlusive disease], SOS [sinusoidal obstruction syndrome], and TMA [thrombotic microangiopathy]. For microangiopathy, in many ways it could be a spectrum of endothelial injury and attempts to recover. We do look at TMA for adults; we’re way behind the pediatricians. They’re more attuned to it, and we don’t pay as much attention as we should.

 I agree. It’s good to see some research starting in this area. The next few years will shed more light on this to help us understand. We should mention that for this indication of steroid-refractory acute graft vs host disease, the FDA in May 2019 approved the agent ruxolitinib for adult patients who started with refractory acute graft vs host disease. This becomes 1 additional option. As far as the case goes, the patient herself was then started on ruxolitinib at 5 mg twice a day and subsequently increased the dose to 10 mg twice a day when it was apparent she was tolerating the drug quite well. The NCCN [National Comprehensive Cancer Network] has had recently formed a panel for transplant and transplant complications. The consensus panel thought it was reasonable to treat steroid-refractory acute graft vs host disease. Dr Munshi, does this list look comprehensive to you as agents that you or your group think about when contemplating treatment for such patients?

 This is quite a large list but not something unknown to us all. At any given time we’ve tried several of these agents, not quite in this order, but whatever anyone’s comfortable using in this room. Everyone has their preferences. ECP [external counterpulsation] is commonly used depending on if it’s available at peoples’ centers and infliximab if it’s lower GI GVHD. Some of my colleagues use ruxolitinib quite frequently as well as ATG [anti-thymocyte globulin]. There’s a whole variety of choices, but the response rates are similar. I’m not enthusiastic about 1 vs another. We’ll look at the data to come for ruxolitinib. Maybe that might be game changing.

 Do you mind going through the data for the REACH2 trial that validated ruxolitinib as a standard of care in this setting?

 This was a phase 3 study done outside the US. It was in patients with steroid-refractory acute GVHD who were randomized 1:1 to receive ruxolitinib 10 mg twice a day with steroids, with or without a calcineurin inhibitor, vs best-supportive therapy with steroids with or without calcineurin inhibitor. The best-supportive therapy was chosen based on these 9 agents that are commonly used in Europe based on their guidelines and all of which we have used as well in the United States. These patients were allowed an optional crossover, and the primary end point was the overall response rate at day 28. The secondary end points were to look at the durability of responses on day 56. Other key secondary end points were also failure-free survival, event-free survival, and nonrelapse mortality. The population did include pediatric patients as well. The age limit started with 12 years and above, including the adult population, and patients had to have myeloablative and naturally were excluded if they had an active infection or severe organ failure.

Looking at the primary end point of overall responses at day 28, ruxolitinib had an overall response rate of 62% with 34% complete responses, compared with the control arm, which had an overall response rate of 29% and about 19% complete responses. This seems to be a big difference when you look at quick responses to something that’s refractory to steroids. In the secondary end point, looking at the durability of these overall responses at day 56, you can see that ruxolitinib had a 40% durable overall response at day 56 with about 27% of these patients having incomplete responses and about 22% overall having durable responses in the control group. Those patients who were in CR [complete remission] seemed to have maintained these responses even at day 56. What is nice about these data is that several patients were able to come off their steroids by day 56, achieving these responses. At least about 21% of these patients were able to discontinue their steroids by day 56 in the ruxolitinib arm.

If you look at the response duration, it looks at the loss of responses at 6 months as part of the secondary end point. It was about 10% in the ruxolitinib arm compared with 39% in the control arm. These data weren’t statistically significant, but when you look at the survival curves, they do separate. In terms of failure-free survival, which was another secondary end point for this trial, designed to compare survival outcomes. The data weren’t statistically significant, but if you look at that the curves do separate on the median failure-free survival 5 months in the ruxolitinib arm compared with 1 month in the control-arm. The failure-free survival means that these were patients, who from randomization to the first relapse, at the time of needing more therapy in addition to steroids, or death due to nonrelapse or nondisease causes constituted failure-free survival. When looking at the adverse events—none of which is unknown to us—we’re familiar with all of them. Most patients on ruxolitinib really had thrombocytopenia, anemia, and CMV infections, more in the ruxolitinib arm compared with the control group. All these seem to be managed well, and there were some stopping rules. If patients couldn’t be supported with low platelet counts, then they could come off the ruxolitinib or both could receive platelet transfusions.

This transcript has been edited for quality.

Understanding the importance of having a multidisciplinary team in the treatment of acute GVHD, panelists discuss the NCCN Guidelines and REACH2 trial.

Case 1: Ruxolitinib and the REACH2 Trial

 Why don’t you tell us a bit more how this patient did?

 The patient was started on Hydrea 500 mg twice a day and titrated to 2 g a day, in addition to phlebotomy and the baby aspirin. He came back 5 months later complaining of fever, extreme fatigue, and worsening itching, both in terms of severity and the area of skin affected. His spleen is now 3 cm, blood pressure is still good, white blood cell count is about unchanged at 22.3 per mm3, platelets are about the same 780 per mm3, and hematocrit is much worse at this point at 60%. The ferritin is 7 µg/L, and EPO [erythropoietin] is still less than 3 mU/mL.

 This is clearly a very aggressive case of polycythemia vera. There’s splenomegaly clearly even on Hydrea, significant erythrocytosis, and difficult symptoms. Stephen, do you think this represents formally hydroxyurea resistance?

 I think it does. I don’t know if it’s specified how long the patient had been on hydroxyurea at the 2-g dose, but let’s say it’s been at least a few months. That does meet the criteria of hydroxyurea resistance. Obviously, this patient’s counts all remain high or even worse despite this very high hydroxyurea dose. That alone would indicate that the patient does meet criteria for hydroxyurea resistance.

 I definitely agree. Although I would say that more patients tend to fail Hydrea because of intolerance, hydroxyurea resistance is out there as well. At a very solid dose, this individual is clearly not meeting the goals. Jamile, what might be the treatment options for this individual?

 I agree with you, Ruben. I was going to say that assuming compliance—assuming he’s taking the 2 g that he’s been prescribed—he’s obviously not responding well. The counts are high, he’s still unoptimized, and everything is low. Even if you phlebotomize him more, he still has high white blood cell counts. You have to move on to the only other available therapeutic action at this point for patients who have met either Hydrea resistance or intolerance. I would be discussing ruxolitinib in this patient.

 That’s an important consideration and a great segue. I share with my colleagues that 1 of the unmet needs in polycythemia vera is that there is frequently reluctance to begin individuals on cytoreduction early enough. Prithviraj took us through those NCCN [National Comprehensive Cancer Network] Guidelines. People are typically a little too slow getting them on cytoreduction, and then sometimes a little too slow recognizing that the initial cytoreduction was suboptimal and then moving them on to second-line therapy with ruxolitinib. Prithviraj, why don’t you take us through a bit of the data regarding Hydrea resistance and what we know about the treatment options?

 Sure. I will quickly go over the formal ELN [European LeukemiaNet] criteria for hydroxyurea resistance and intolerance to serve as a framework for our discussion. As was being discussed, you’re resistant when you’ve done a good dose for a decent duration, which is defined as 2 g a day or as much as the patient can tolerate for at least 3 months. When you’ve done that and you’re still needing phlebotomy or platelets and the white blood cell counts are still high, the spleen has not shrunk enough, and the spleen symptoms are still there, that’s resistance.

Intolerance is a bit more intuitive and, as Ruben pointed out, common. There you can see nonhematologic toxicities like leg ulcers, mouth ulcers, etc. You can also see cytopenias at the lowest dose that you need to get that hematocrit under control. If you are causing other cytopenias, that’s a problem. Why is this important? Hydroxyurea resistance actually correlates with worse survival and higher risk of leukemia transformation. Ruben, as you showed several years ago, it also correlates with symptoms. In a large study with 1334 patients, it was consistently seen that symptoms were worse in the patients on hydroxyurea, suggesting this burden as a whole is higher in those patients.

Dr Prithviraj Bose reviews treatment options in the setting of hydroxyurea failure in patients with polycythemia vera.

Case 1: Treatment Options after Hydroxyurea Failure in P. Vera

 Why don’t you share with us a bit more about your case?

 Going back to where we left off after the diagnosis, the patient was started on phlebotomy, 250 mm every other day to a target of less than 45%, and a baby aspirin daily. The hematocrit target of less than 45% was achieved within the first month. It was stable for 2 more months. At 3 months, he reported that the headaches were better and the dizziness was gone. The early satiety and pruritus were still there but had not gotten any worse. The plethora was still there, blood pressure was good, and the spleen was still at 2 cm below the left costal margin. The blood counts were still fairly similar, except the hematocrit was better at 49%—so still not at goal. White blood cell count was 22 per mm3 and platelets were 774 per mm3, so you see pancytosis, which is a signature of PV. Ferritin was only 9 µg/L, presumably from all the phlebotomy. EPO [erythropoietin] was very low, at less than 3 mU/mL.

 Stephen, what are your thoughts about this case? It sounds like a fairly aggressive case. Is this individual doing well with initial therapy?

 There appears to have been some response to the treatment regimen thus far, but certainly not optimal. For instance, the hematocrit, as correctly pointed out, has not been brought down to below 45%, which is probably the most important treatment goal with this approach. Then you have the issue that this patient has an ongoing leukocytosis and some degree of thrombocytosis, which is less of an issue and can be quite complicated in this setting because there can be some degree of reactive thrombocytosis from the iron deficiency induced by the phlebotomies. That part is secondary, but we haven’t even achieved adequate hematocrit control with fairly frequent phlebotomies. In addition, though some of the patient’s symptoms have improved, his relatively mild splenomegaly has not changed, which you wouldn’t expect anyway with phlebotomy. I believe he still has some early satiety related to that. There are a number of things indicating that we don’t have optimal control of this patient’s disease at this point.

 Jamile, is this someone that you would start on cytoreduction? What might you pick if that’s the case?

 If someone is continuing to have symptoms, then hydroxyurea would be the go-to.

 Prithviraj, do you think this individual with a little splenomegaly needs any additional staging? Would you repeat the bone marrow? Does a screen change your decision for starting frontline therapy?

 I don’t think so, Ruben. They’ve been on phlebotomy only, and as Stephen mentioned, that’s not going to shrink the spleen or make the early satiety better. It doesn’t make me want to repeat a marrow, restage, or question anything. It just goes along with the fact that this patient needs some cytoreductive therapy.

Experts in polycythemia vera discuss decision-making around when to initiate cytoreductive therapy in patients with low risk polycythemia vera.

Targeted Oncology | Authors

Articles

Case 1: The Role of Ruxolitinib in Steroid-Refractory Acute GVHD

Case 1: Ruxolitinib and the REACH2 Trial

Case 1: Treatment Options after Hydroxyurea Failure in P. Vera

Case 1: Considerations for Cytoreductive Therapy in P. Vera