In this exclusive session, leading experts Amer Zeidan, MBBS, MHS, John Mascarenhas, MD, Jan Bewersdorf, MD & Rory Shallis, MD, discuss and debate the special considerations for managing patients with hematological malignancies in the COVID-19 era.
The topics discussed follow from the recommendations made in a recent publication the speakers co-authored in Lancet Haematology: reducing nosocomial COVID-19 infections and resource allocation, clinical trial participation and treating patients with ALL, CML, MPNs, MDS and AML.
Reducing Nosocomial COVID-19 Infections and Resource Allocation
“With hematologic malignancies and also solid oncology patients, currently data from China showed that there was a up to three to four-fold increased mortality of those patients. And so, what we tried to do is we tried to conserve resources, trying to really protect our cancer patients, both hematologic and solid malignancies, from the COVID floors to prevent the nosocomial spread of the infection.”
– Jan Bewersdorf
Clinical Trial Participation
“In our institution we were allowed, with written justification to the institution, to maintain patients on clinical trials in which there were no alternative best care options that they could receive locally. And we limited the visits to those that ensured safety. We eliminated efficacy evaluations, like MRIs or bone marrow biopsies, that wouldn’t change the course of their care, unnecessarily.”
– John Mascarenhas
Treating Patients with ALL, CML, MPNs, MDS and AML
“Generally with curative intent therapy, while you are trying to reduce the risk of the myelosuppression and the risk of infection for patients, at the same time, you don’t want to alter a regimen that has been associated with a chance of cure.”
– Amer Zeidan
Amer Zeidan: Hi, everyone. My name is Amer Zeidan. Welcome to VJ HemOnc, where we are talking today about the management of hematologic malignancy during the COVID era.
Amer Zeidan: My name is Amer Zeidan. I'm an Associate Professor of Medicine at Yale University and the Director of Early Hematology Therapeutics research and I'm joined here by my colleagues, Dr. John Mascarenhas, Dr. Jan Bewersdorf, and Dr. Rory Shallis for discussion of our paper that has been published in the Lancet Haematology journal, where we cover different aspects of management, and general considerations, and then go into the disease specifications.
Amer Zeidan: I will start with Dr. Mascarenhas.
John Mascarenhas: Thanks, Amer, and thanks for inviting me to be a part of this. My name is John Mascarenhas. I'm an Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai, and I lead the Adult Leukemia Program there, and have a focus in MPN clinical research.
Rory Shallis: Hi. Thanks for the invitation again. My name is Rory Shallis, Assistant Professor at Yale. My clinical focus is acute leukemias and myeloid malignancies. Thanks again.
Jan Bewersdorf: Good morning, everyone. I'm Jan Bewersdorf. I'm a medical resident at Yale. I've been working with Amer, and my main focus is on hematologic myeloid malignancies. And during the COVID pandemic, I also, as part of my residency training, took care of COVID patients without hematologic malignancies in the ICU setting, and I'm hoping to share some of those experiences today.
Amer Zeidan: Maybe we can start with John. How was it like to be in the middle of this, with really very little evidence on how to direct management of patients, especially as being in charge of the leukemia group in your institution, and having very little evidence to go by?
John Mascarenhas: I would say in one word: Overwhelming. So it was an overwhelming experience, and as many institutions have or are now currently experiencing, it was a rapid rise in admissions, both to the hematologic malignancy group but also obviously the rest of the medicine floor. Within a very short amount of time, I would say within several weeks, our entire hospital was essentially converted to a COVID hospital, in which only a very small fraction of patients without COVID were being cared for. Additional beds were built in the main hospital floor, as well as a group built a tent in Central Park across from our hospital, where patients were also diverted, and then patients were sent either to the Javits Convention Center or to a US medical ship that was in the harbor that was also taking patients. So it was overwhelming, the pace was rapid, and there was unfortunately very little evidence driving many of our decisions at that time.
John Mascarenhas: As you and I have discussed previously, fortunately, even in the short amount of time since the paper's been developed and published, there is evolving literature that helps perhaps guide us more effectively today than it did in April and May, when we first started experiencing the pandemic.
Amer Zeidan: I think some of the main considerations that we were dealing with in hematologic malignancies, I think two parts: one related to the nosocomial spread of the infection, and how do you handle the whole situation of having potentially asymptomatic patients or asymptomatic providers? And the concern about spreading that within the hospital, which was, of course, compounded by the fact that many of our patients are immunocompromised and they are probably more susceptible to the infection, based on the published experience at that time. And the management of the blood transfusion, which got complicated, I think, by this pandemic.
Amer Zeidan: I will let Jan, as someone who really has been on the front lines on the medicine front, where a lot of those issues are also very important, talk about the experience and how this has been going on.
Jan Bewersdorf: Thanks, Amer. As you already mentioned, with hematologic malignancies and also solid oncology patients, currently data from China showed that there was a up to three to four-fold increased mortality of those patients. And so, what we tried to do is we tried to conserve resources, trying to really protect our cancer patients, both hematologic and solid malignancies, from the COVID floors to prevent the nosocomial spread of the infection.
Jan Bewersdorf: If I can give you the example of what we did here at Yale: We converted regular units to dedicated COVID floors. We did some engineering adjustments to divert the airflow, creating negative pressure units for COVID patients, while the hematology patients were on a dedicated unit with positive pressure. And what was also essential is to have dedicated staff. So one provider is only assigned to either a dedicated COVID floor or a dedicated non-COVID floor. And I think that has been an experience that other places have also implemented.
Jan Bewersdorf: And what is essential there is that you need to know a patient's COVID status. So when I started, my first COVID patient was back in March, and at that point, the turnaround time for the COVID testing was probably five to seven days, which makes it really difficult to allocate the patients to the appropriate floor. But then over time, the testing capacities increased, the testing turnaround time decreased significantly, and nowadays at Yale, all patients get tested in the emergency department already when they come in, and we have the results in probably two to maybe four hours, which is essential that we can really assign patients to the appropriate unit.
Jan Bewersdorf: And this is an experience that, as Dr. Mascarenhas pointed out, there's a lot of progress being made in just a few weeks to months.
Amer Zeidan: That's a very great perspective. I think one of the challenges, talking to many of my colleagues across the country, especially in areas where they were hit really hard basically, that this idea of trying to geographically cluster patients on different floors, or even to have providers who are only seeing patients who are COVID positive or negative is probably not as feasible everywhere because of the limitations on geography and the limitations in the number of the providers.
Amer Zeidan: What has your experience been, John, in this, I think, important logistical issue of where to triage the patients and how to handle the staffing?
John Mascarenhas: As Jan pointed out, we also over time adopted a policy in which certain floors were relegated to COVID patients only, and we desperately tried to keep our hem-malignancy patients, particularly our transplant patients, segregated, and that meant nursing staff and physician staff would attend to those, and eventually not also concurrently see COVID positive patients. So we were able to follow a similar approach, and as Jan pointed out, as the pandemic progressed and our capabilities improved, our turnaround time for testing improved, and our ability to effectively implement this segregated approach was obvious. And I do think that we saw a significant decrease in what probably was nosocomial transmission of the disease initially, which we weren't necessarily appreciating.
John Mascarenhas: We adopted a policy that's still in place: any patient that's being admitted for therapy or for an elective admission, needs within 48 hours to have negative COVID testing by a PCR nasal swab, and in some cases we even repeat it twice to make sure that it's truly negative.
John Mascarenhas: And what we've seen is that we've been effectively able to, in July 2020, reduce our COVID admission rates significantly, so most patients that are being admitted are documented to be COVID negative. It's actually rare right now in New York City to have a COVID positive admission. We do get patients that come in for various reasons, perhaps non-hematologic malignancy patients, that have an incidental COVID test that's positive, but right now, thankfully the rate of actual COVID admissions is quite low.
Amer Zeidan: I think, John, you bring up an important point in terms of the rapidly changing nature of this epidemic in terms of geography. So you are going into phases in which the systems are almost close to being overrun, where you had so many patients initially in New York and Connecticut, and then things got much better, where we are seeing very few patients in the inpatient or the outpatient units. But then your resource allocation and staffing and procedures then have to adapt, and all of that changed.
Amer Zeidan: I think that brings me to talking a little bit more about resource allocation. Maybe Rory can tell us more about some of the experience that people in areas that are being hit hard right now, whether in the south of the US, or other countries like Brazil, or other areas, in terms of how could they help or benefit from that experience.
Rory Shallis: Obviously, quite recent resource allocation efforts, particularly for some centers with an increased burden, like at least our center a few months ago, fortunately, we're in a better spot, and most definitely John's center down at Sinai, had at least, for quite some time, prioritized the care, as Jan had kind of mentioned, for patients with COVID-19.
Rory Shallis: Difficulties are likely to arise in centers that are kind of already stretched thin, with regards to infrastructure, other material resources, and unfortunately, finances. These issues are likely to affect the care of patients with other medical conditions, including those that are serious, like those with hematological malignancies. And similar to patients on clinical trial, which I think we can talk about in a little bit, these patients are likely to have delays in timely lab testing, and of course, delays, interruptions, abbreviations, and even in some cases, discontinuation of treatments like chemotherapy, as well as surgical, and in some cases, radiation planning and administration. This can altogether unfortunately affect long-term outcomes, and potentially that also includes the likelihood of cure in some patients, unfortunately.
Rory Shallis: With regards to how to approach this, the overarching goal is, of course, if the patient's in the best position to achieve these long-term outcomes and cure. With regards to resource allocation, one of the unfortunately highlighted points more recently has been, forgive the term, but the rationing of interventions, some of which can be life-saving. Connecticut, New York ... obviously in a better spot it looks like these days, but in some cases, standard of care options. Or, I guess we'll talk about it a little bit, optimal clinical trial options for some patients with, say an older patient, with poor disease characteristics, that otherwise has exhausted any further disease-directed care might be in a rougher spot, and some providers might consider that more of a futile situation, unfortunately.
Rory Shallis: So again, a lot of moving parts, and I guess the overarching message is it has to be individualized, even though a lot of centers do have protocols that dictate the mechanisms by which patients receive some of these fragments of care. And I think Jan's going to, at some point, touch on the general ethical considerations and then more day-to-day stuff, like blood product transfusion considerations or protocols that each center might kind of implement.
Amer Zeidan: Sure. Before we expand more on clinical trial and blood transfusion, I just want to stick a little bit with the resource allocation. I think one of the things that helped in managing this pandemic and trying to reduce the chance of our patients being infected, but also to try to maintain some care, is the wider use of telemedicine.
Amer Zeidan: Telemedicine is great, in the sense that it allows the patient to be evaluated without necessarily being able to come to the center, but in contrast to other specialties where the patient needs could be probably managed remotely, I think in our specialty, dealing with patients with hematologic malignancies, even if you do telemedicine, there are a lot of things, such as blood transfusions, chemotherapy administration, management of complications, that would still require the patient to come in. And also the logistical front of having to set up all these changes in logistical, regulatory processes, and even things like billing and things like that; to go to a virtual format has been quite difficult and a very, I think, sharp learning curve.
Amer Zeidan: Maybe, John, you can tell us about your experience of that switch to telemedicine, and some of that resource allocation, how that worked out for you in your center?
John Mascarenhas: Yeah, I think that's a very important point. Prior to the pandemic, I had never really engaged in telemedicine. And then, rapidly during the pandemic, we adopted a strategy in which patients typically with chronic myeloid leukemias, whether it was CML, essential thrombocythemia, polycythemia vera, in some cases, myelofibrosis and even myelodysplastic syndrome patients were seen through telehealth visits, and then were directed either to a local laboratory for their blood counts and/or had home testing arranged by certain agencies so that we could try to limit the exposure of the patient to the cancer center, but also vice versa, the exposure of the cancer center to patients coming in and out, and no family members.
John Mascarenhas: We adopted a strict policy also of only the patient was allowed to come up to the cancer units. Unfortunately, loved ones were not, unless it was a dire necessity to have a spouse or a loved one to accompany the patient. The same was true on the inpatient side. In fact, many of the consult services, such as hematology consults and infectious disease consults, were done through telehealth visits, so they could also reduce the exposure in and out of the patient's room.
John Mascarenhas: So there was a clear shift, which actually still persists today, to some extent, in care of the patients, which I firmly believe will outlast this pandemic. I think there has been a realization or an acceptance that to some degree, a certain degree of care that we provide our patients does not necessarily require them to be physically in the cancer center for each visit. But it's not true across the board, so obviously for our patients with acute leukemia, in which the care often requires point of care, in person management, whether it's transfusional support, or injection of growth factor, or whatever else, or evaluation of neutropenic fever, there are patients that can be seen through a telehealth modality, and then perhaps less frequently, in order to reduce travel, exposure to mass transit, and exposure in the cancer center.
John Mascarenhas: That is something that was new to our group. In fact, we are embarking with several institutions, including Memorial Sloan Kettering, University of Texas at San Antonio, and perhaps Cleveland Clinic in a multicenter, randomized, Phase III study evaluating telehealth interventions in patients with chronic diseases like myeloproliferative neoplasms, with a control arm which is standard of care, to look at outcome measures of interest such as stress, by stress thermometers that are validated, and outcomes, such as infection, hospitalization rate, change in therapy, et cetera.
John Mascarenhas: I think the world in which we have lived previously with in-person care is going to change to some extent. And I think, as you all probably anticipate, even though we are fortunate right now that New York and Connecticut has a low rate, the assumption is that with time it will increase again, until there's effective prevention or vaccination. So we are preparing that this will continue, or where other pandemics may arise, and that there will be a shift in the oncology care model going forward in which there will be less emphasis on in-person care.
Amer Zeidan: Our hope is, of course, that some of the regulatory resilience and accommodation that happened because of the pandemic that I think facilitated a lot of the aspects related to telemedicine hopefully will persist, because there were a lot of exceptions made by the states and federal government and CMS, and I suspect the same happened across the world, that I think will be important to kind of retain in some capacity after the epidemic passes, basically, to be able to continue to do virtual medicine on a larger scale.
Amer Zeidan: So Jan, one of the aspects that cannot be done really virtually by telemedicine is blood transfusions or blood product transfusions, which are essential for the management of patients with hematologic malignancies, whether on the inpatient and the outpatient front, and not really only for patients with hematologic malignancies, but many patients with surgery, trauma, medical conditions.
Amer Zeidan: Maybe you can give us some insights into how the blood banks and transfusion services have tried to manage some of the challenges that were brought up by this pandemic, in terms of blood transfusions.
Jan Bewersdorf: As you already mentioned, doing induction chemotherapy or bone marrow transplant without transfusion support is virtually impossible, given the profound cytopenias that are caused by chemotherapy, or even the underlying disease on top of it.
Jan Bewersdorf: I think it's important to keep in mind that this has two aspects. One is the recipient of the blood product, and the other one is the safety of the donor. One of the struggles in the beginning, and probably in other parts of the world right now still, is that we want to protect the donor from the exposure to the healthcare system, and they have to come in to a transfusion center, they get exposed to other donors, they get exposed to the staff. They have to be there for a certain period of time, and the travel to that center. And then on the other hand, it was unclear, and still is somewhat unclear, if the SARS-CoV-2 virus can be transmitted via blood. So far there have been no reported cases of bloodborne transmission, so that seems to be less of a pertinent issue.
Jan Bewersdorf: Strategies that have been adopted here in the United States has been related to donor deferral, and that have been in place in the past: if you had traveled, if you had HIV, hepatitis C. So some regulations in that regard have changed ... men who have sex with men ... some of those policies have changed to increase the donor pool. That's for the donor front.
Jan Bewersdorf: And then on the other hand, the recipient side, what we've been trying to adopt here, and what we've been discussing in the paper, and we should always preface with saying that this is crisis standard of care, which should be adapted to the local situation at hand.
Jan Bewersdorf: There's clear data that show that the hemoglobin goal of seven to maybe eight for some patients, especially with underlying cardiovascular disease, is sufficient, and overtransfusion can actually be harmful. So we've been advocating for keeping those strict transfusion guidelines, and maybe considering, as John pointed out, to maybe reduce the frequency of clinic visits by giving growth factor support, ESA, and that maybe at one point giving two units rather than one, and trying to spread out the frequency of transfusion intervals.
Jan Bewersdorf: Another especially important point are platelet transfusions, because platelets have a much shorter shelf life, only three to four days until they need to be transfused, so those have been more of an issue rather than the red cell supply. And there is some consideration to really reduce the need for prophylactic platelet transfusion, and if the supply is really short, to transition to more of a as-needed transfusion strategy - if someone is bleeding or is requiring an interventional procedure.
Amer Zeidan: All of these are great points, Jan, and I have to again emphasize, we keep emphasizing at every juncture of this talk that a lot of these factors are really different based on geographic locations. I actually heard from some of our colleagues in Europe while we were working on this consensus paper that some of the countries did not experience shortages in blood transfusions, and one of the explanations that was given in some of the countries that have complete lockdown is that one of the exceptions in which you can leave your home was if you were going to donate blood, so that might have provided some incentive for additional blood donations.
Amer Zeidan: I do think that this is something that people have to think about, in terms of, do you adjust your blood transfusion practices if your blood supply is short? Some of those decisions about when to use prophylactic or not to use prophylactic transfusions and all of that should be taken, of course, in the context of the blood shortage supply, and in coordination with the blood bank and the institutional policies, and all of that.
Amer Zeidan: Rory, another aspect that you hinted on earlier, and I think was affected very significantly during this pandemic in general, but also for patients with hematologic malignancies, is the clinical trial participation. Maybe you can give us more from your insight about how clinical trial participation has been affected, and what are the factors that should be considered when centers are opening, and what type of trials they should be focusing on?
Rory Shallis: Sure. You nailed it. The operations of trials have, I'd say, undoubtedly been disrupted due to a multitude of factors, not only work from home orders, other social distancing orders instituted by many centers, which a lot of these centers that have pretty robust clinical trial portfolios are in areas that were pretty heavily hit. But in addition, a lot of the laboratories that are really necessary for interval, for PK studies or correlative studies, that have instituted similar mitigation efforts were, and in some cases are, still closed. Further and unsurprisingly, actually, active trial patients can unfortunately contract the virus and develop COVID-19, severe cases which can just, of course, further upset or disrupt trial events, and even standards of care. So you kind of alluded to it, but ultimately many trials were suspended to enrollment.
Rory Shallis: In this new era, which I'd say maybe again we can only speak to really Connecticut and New York a bit more faithfully, the key emphasis, and appropriately so, has been on patient safety. The FDA, and Health Canada, and I think a few of the bodies in Europe have offered sort of published guidelines in this regard, essentially describing the mechanisms of safe trial conduct. But then, as you just said, fortunately some centers, like our own, in light of available data suggesting that these mitigation strategies can be effective, are reopening, opening to accrual, many trials within the portfolio.
Rory Shallis: You had asked, what considerations have to be heeded with regards to how to navigate at this juncture? I would say the perceived disease space priority is one, and of course infrastructure. I think many providers would agree that the population most likely to benefit, at least in the immediate term, of course fingers crossed, Are those patients with relapsed refractory disease, for whom there are essentially not a lot of favorable options at that point in their disease course, as opposed to a trial that by chance could randomly assign a patient to get standard of care therapy, but now also has to accept not only the inconvenience but also the theoretical risks of having increased blood draws, trial events, and just as John had said, overall healthcare exposure, which of course as we know can, at this point, increase your risk of contracting the infection.
Rory Shallis: Our center is starting to reopen many of the trials that, of course, had to go through a process of discussions about which ones have more priority in this case. It sounds like John and Sinai are doing the same. So this is evolving, and I believe for the better, and maybe someone else can kind of provide more insight. But I do think this is improving over time.
Amer Zeidan: Great points. I don't know if John, do you want to talk more about your experience, in terms of ... ? I anticipate that some of your trials, or all of them have been shut down at one point, and how did you go about the process of choosing which trials, thinking about different diseases, thinking about Phase III versus Phase I, versus a lot of visits, versus control arms? What were your thinking and strategies to prioritize trials?
John Mascarenhas: At one point, the institution was directing what was allowed from a clinical research perspective, and I suspect oncology was treated differently than some of our other colleagues, in which perhaps the consequences of the disease were not as significant, and therefore the intervention was not considered as necessary.
John Mascarenhas: In our institution we were allowed, with written justification to the institution, to maintain patients on clinical trials in which there were no alternative best care options that they could receive locally. And we limited the visits to those that ensured safety. We eliminated efficacy evaluations, like MRIs or bone marrow biopsies, that wouldn't change the course of their care, unnecessarily. So it was really a pared down version of how the trials were originally written, and of course, there was agreement from the sponsors and the FDA. This was all coordinated, actually I thought, quite effectively.
John Mascarenhas: For example, if it was an early phase study, we were not subjecting patients to multiple PK draws throughout the day. That would have been inappropriate. We would just get whatever safety information was needed, dispense the medication.
John Mascarenhas: For some studies in which the patients had been enrolled for quite some time and were stabilized, assessed by the investigators, we were allowed to actually send medication, which we normally are never allowed to do, oral medication that is, to the patient, and conduct telehealth visits, and get local laboratory evaluation. That enabled us to maintain patients on studies.
John Mascarenhas: And then ultimately, we prioritized the way in which we now open studies and have approached our studies. If they are randomized phase III studies in which there is a control arm which is standard of care, those studies are not prioritized over studies, for example, that are for, as pointed out previously, relapsed/refractory patients in which there is no viable commercial option for those patients. So those patients are deemed more at risk from their disease, and therefore more likely to benefit from an intervention like a clinical trial, and were allowed to enroll. Again, trying to minimize interventions or visits that really didn't contribute to their safety.
John Mascarenhas: And that has revolutionized the way we've approached, historically, clinical trials. We're slowly rolling that back now, but how that will play out over the next three months, six months, or a year is not quite clear, because even things that we all take for granted, like sponsor-directed monitoring visits, in which a clinical trial CRO would come to your institution and evaluate your regulatory documents and your medical record, now is all done remotely. So there are many different changes in the clinical trial world that I think, actually, have been quite effective.
John Mascarenhas: And again, I think it also exposes something, that we now realize that there are things that we had done previously that probably are not essential to the care of patients on clinical trials, and could be done remotely, and could be done in different ways. So I do think this experience has taught us, from a research perspective, how to adapt to changing times, and that will probably endure, is my guess.
John Mascarenhas: We are now in the process of opening up our full clinical trial portfolio, and we are keeping vigilant to how the pandemic may change, and then perhaps we would have to go back to closing certain studies and prioritizing again.
Amer Zeidan: Maybe I will add that some of what are agents that we work with in HemOnc in general actually might have potential to help in COVID, and some of those agents have been repurposed, actually, to try to be used basically in COVID patients. I think that also has been an interesting aspect of how things have gone.
Amer Zeidan: I think in the last 10 minutes or so, I will try to focus a little bit on the specific diseases, and I think two general points here, after discussing all those general aspects, is again that all of those discussions that we make in the paper and recommendations, basically should be individualized according to the specific epidemiological nature in the specific area. As we mentioned, there's a lot of variation that goes in the number of the cases, and adjustments have to be made.
Amer Zeidan: And I think the second point that was pointed out at the beginning is that all of those are based on experience and theoretical considerations from, I would say, highly experienced providers who work with these diseases on a routine basis, but without a lot of evidence to direct these recommendations. So some of those probably will change over time as more evidence comes across. Our hope, of course, is that this whole virus we are going to have some curative therapy, and hopefully all these discussions become more of a historical points for the future, although they could be helpful if a new virus evolves, but I think these are important things to think about.
Amer Zeidan: I'll start with acute lymphoblastic leukemia, and again, just some high level alterations. This is not meant to discuss in any kind of depth, but some of the considerations that the providers can think about when they have a patient with acute lymphoblastic leukemia.
Amer Zeidan: Maybe Rory, you want to chip in?
Rory Shallis: Sure. Just to keep it high level, maybe just to lump patients that have acute leukemia in general, just to spare some of the specifics of the AML patients, but generally again, this, as Jan and everyone seems to be saying, it's really predicated upon the level of crisis in a certain area. That, if possible, and if the multitude of factors otherwise align all right, we do recommend the consideration for the delaying of therapy if it is otherwise possible.
Rory Shallis: However, if the patient is intended to be treated, I know it's the case at our center, it's protocolized, and I would imagine at many other centers it's the same. We recommend testing pretty much all patients, even if asymptomatic, for the virus prior to treatment initiation. A negative result, great. The testing is RT-PCR, mean sensitivity rate as low as 70%, but upwards of 98%, which is why sometimes more than one test is otherwise recommended.
Rory Shallis: If the result is positive, then generally we delay for 14 days, which is, I guess, kind of two-fold. One, it's sufficient time to allow reasonable recovery from non-severe illness, but also a quarantine. We have seen patients with prolonged positive results, for which we just really again, recommend delaying, if still possible.
Rory Shallis: There are, I'd say, two general exceptions. One, not to get too specific, but intrathecal therapy for which there's really no risk of inducing deep and protracted cytopenias, and of course, patients that otherwise can't wait, that can't have their treatment delayed.
Rory Shallis: So just keeping it high level, a lot of the age and fitness related kind of considerations, with regards to dose reductions such as anthracyclines for ALL patients, or pegaspargase, an essential compound for the treatment of ALL, these still apply. I guess some of the other high level considerations that we do touch upon in the publication are the use of anti-CD20 monoclonal antibodies, which just to, I'd say again, this is sort of a priori, really avoid any additional immunosuppression that could be induced by these therapies for a disease that is CD20 positive. And I guess with regards to ALL, it's really essentially how much therapy can you get away with, but still maintaining a good depth of response.
Rory Shallis: A lot of this is really centered around measurable residual disease, or MRD. How many cycles of chemotherapy can you really get by with? Is two enough? How much consolidation or intensification is necessary? In some cases ... and again this is all individualized ... I'd say we do recommend, if the patient is MRD negative and can sort of move forward with the maintenance phase of disease, which can last up to 2.5 years, for an older patient and maybe a dose-reducing steroid or avoiding vincristine altogether, those are some of the considerations we do touch upon specifically, even though I know the use of corticosteroids, this is sort of changing. Early data suggests that this might even be worse for patients that are older with the disease, but now, as we're aware, there is some benefit in severely ill patients that are hospitalized, and ventilated, or require oxygen.
Rory Shallis: So I'd say those are some of the higher level considerations, not even getting into the role for transplant, which I think most would still say for patients that have ALL and have relapsed/refractory disease, getting them to transplant when they're in remission and avoiding delay is still probably the best option for these patients.
Amer Zeidan: All of those are great considerations. I think some of the basic principles that we generally have again to stick in, is that generally you think about patients as curative intent therapy or non-curative intent therapy, and generally with curative intent therapy, while you are trying to reduce the risk of the myelosuppression and the risk of infection for patients, at the same time, you don't want to alter in a regimen that has been associated with a chance of cure. So I think that has to be taken into the context of what's the goal of their treatment. I think some alterations in those regimens, in situations where you are going for non-curative therapy are easier than when you are going for curative therapy.
Amer Zeidan: One of the things I think that you could also, and you touched on this, is allogenic bone marrow transplant in many institutions, because of the resources, because of the needs of those patients have been delayed in some patients, and I think continuing, for example, if somebody's getting Hyper-CVAD, continuing to be on two cycles, four cycles to try to give the patient an additional two, three months of therapy until things settle down and you can get to transplant is another thing.
Amer Zeidan: I think the use of growth factors is an area that we had a very robust debate within our group, not only within ALL but in general. I think for G-CSF, for use of basically the granulocyte stimulating factor, there are some concern that this might potentiate or increase the impact of COVID in some patients, if they do contract it. However, the advantage of course is shortening the duration of neutropenia and infections. And I think this is an unresolved area. It presents, I think, a very good place in which we really need more evidence, but I think the general approach is not to minimize therapy except in situations where it's really there's a significant issue.
Amer Zeidan: And the second point is to try to closely counsel these patients about some of those changes and try to minimize, I think, interventions or disruptions of interventions, such as delaying bone marrow transplant, as much as possible.
Amer Zeidan: A lot of these apply to AML as well, in terms of the issue of delaying therapy. For example, I think we realize more with time that you can delay therapy in some patients with AML, but of course not in all patients, and the same applies for the ALL. So there are patients who you are going to need to start treatment, even on the same day or the next day, because the clinical situation calls for it.
Amer Zeidan: We still don't really know what is COVID course in a patient who happens to have it if they receive induction therapy. And I think out of abundance of caution, our recommendation, and those are in lines. I have to point here that there are actually great resources from the American Society of Hematology on their website about some of those recommendations. And there have been several papers, aside from our paper, presenting some of these recommendations.
Amer Zeidan: I think there is a general sense that it's better to delay therapy, if you can, if the clinical situation allows it, if the patient recovers from a COVID infection, although we still don't know if the patient had the infection whether things would worsen, but our assumption, that would be the case.
Amer Zeidan: John, do you have any opinion to add on the management of acute leukemia patients in this setting?
John Mascarenhas: No. I think I totally agree with what's been said, and we also took a risk-adapted approach. For example, if you were an elderly unfit patient with AML, we would try to delay therapy or manage with a hypomethylating agent. If you were a fit person with ALL, for example Th-positive ALL, we resorted to using steroids and TKI to try to induce a remission and minimize the amount of myelosuppression, in which maybe historically we wouldn't have tried that approach. So we adapted our approach, as you pointed out.
John Mascarenhas: I think this is quite different than, for example, the chronic myeloid malignancies that we see that are typically outpatient. For patients, for example, with essential thrombocytopenia, polycythemia vera, I really try to delay their return to the cancer center unless it was imminent, and used telehealth visits. In some cases we allowed for a little bit more flexibility with the goal hematocrit for polycythemia vera patients, or increased the cytoreductive therapy, like hydroxyurea to try to control the counts better during this period. We rarely initiated new therapies during the pandemic, and we advised patients who are on chronic therapies not to discontinue therapies.
John Mascarenhas: I think there are some particularly interesting considerations, as it relates to MPNs, and what you brought up about repurposing drugs. First, I'll mention that many of our patients also take interferon alpha, which is, if anything, a proinflammatory drug, so that posed some concern that could exacerbate the outcome of patients who have COVID, which we now realize and appreciate is a quite hyperinflammatory syndrome that drives the pulmonary compromise and the multi-organ dysfunction, driven by cytokines that are proinflammatory, such as IL-1, IL-6, TNF-alpha, and others. And many of these are also part of the pathogenesis of myeloid malignancies, particularly MPNs, and the focus of therapeutic intervention.
John Mascarenhas: So we used ruxolitinib and now fedratinib in the US to address patients with higher risk myelofibrosis or refractory polycythemia vera. It's used frequently now in the setting of transplant to mitigate graft versus host disease. And what we appreciate with these drugs for now a number of years is that they're very potent anti-inflammatory drugs that down regulate the inflammatory milieu that drives a lot of the complications surrounding MPNs.
John Mascarenhas: A report out of China, out of multiple centers in a randomized fashion that was not blinded, comparing ruxolitinib to a placebo vitamin C pill and keeping standard of care in place in patients with severe COVID in China, suggested that there was, in fact, some efficacy in terms of limiting the amount of complications or progression to ventilatory support, and reducing biomarkers of inflammation, such as CRP and ferritin, that are highly upregulated in patients who are quite sick with the disease. And this is translated now into a randomized Phase III study in patients with severe COVID infection with ruxolitinib and also perhaps interestingly, the PREVENT study, which is a randomized Phase III study, a global study, using pacritinib, which is a novel but unapproved JAK2 inhibitor that also inhibits IL-1 receptor associated kinase, and would reduce the inflammasome component that again is contributing to the hyperinflammatory state that leads to this pulmonary compromise that we see.
John Mascarenhas: Importantly, a topic that we didn't really address, is the fact that there seems to be an intersection between inflammation and thrombosis that occurs. There's now multiple reports of both microvascular and macrovascular thrombotic events, in terms of deep venous thrombosis, pulmonary embolism, and even strokes, particularly in patients you would not expect, in like younger patients. And for that reason, in our institution too, we have approached the care of these patients that meet certain parameters of severe disease with prophylactic low-molecular-weight heparin, either 30 or 40 milligrams twice a day of Lovenax. There are studies that would suggest that may reduce the complications surrounding thrombosis, which again, I think is intimately linked to inflammation.
John Mascarenhas: So we still have a lot to learn, but if you look at clinicaltrials.gov, you will see increasingly the use of or re-appropriation of drugs that we use in our field, actually, for the treatment and prevention of COVID.
Amer Zeidan: I think this brings up some of the challenges again that we have with hematologic malignancy, that issue of the thrombosis and the use of anticoagulation that you brought up, which I think many institutions are using either prophylactic or full doses in many of those patients.
Amer Zeidan: And of course, many of our patients with hematologic malignancies, especially acute leukemias, have very low platelets. And we struggled with this question, bascially, when the patient is very thrombocytopenic and they had a severe COVID infection, what do you do in terms of anticoagulation? So I think that's another area that I think requires some significant research.
Amer Zeidan: I think we covered the acute leukemias and the chronic leukemias in general, and I would add a little bit about myelodysplastic syndromes here, where, as we know, myelodysplastic syndromes are generally divided into higher risk and lower risk. With the lower risk myelodysplastic syndromes, the goal of therapy generally is on quality of life and minimization of complications, so trying to distance those patients from the care centers, I think, has been important.
Amer Zeidan: Some of the aspects we've been trying to do, along the lines of what was mentioned, is to try to space out the blood transfusions, as long as it's safe. Some institution use a hemoglobin of eight or seven, so consideration of using more stringent hemoglobin level, as long as the patient doesn't have significant cardiac risks or other factors that would necessitate more frequent transfusions. Trying to use two units of blood transfusion rather than one. Considerations in the use of prophylactic platelet transfusions. The use of erythropoiesis-stimulating agents to try to improve the anemia and minimize the need to come for transfusions. And also, probably in some patients who don't have severe cytopenias, more consideration to delaying therapy because many of those patients, if their cytopenias are not severe, they can potentially be delayed and have blood work remotely, without coming to the bigger centers where they might be at more risk of contracting the infections.
Amer Zeidan: For higher risk patients, they are generally treated in many ways aggressively, like AML, in which a treatment is generally, we try not to delay it for a long time. We do the same practice of trying to check for COVID carriers, basically before we start treatment, and ideally if the patient happens to have a positive PCR, then delay the treatment by a couple of weeks or until clearance, if possible.
Amer Zeidan: Generally with those patients, the treatment with hypomethylating agents is outpatient, so those patients generally don't need to be hospitalized. The same considerations about blood transfusions and minimizing those to the extent that is possible it can be done without compromising their safety, as well as trying to, for example, the approval of some new agents.
Amer Zeidan: We have an oral decitabine now that's available, so that could spare some of the visits of the patients that come right now five to seven days to get injectable hypomethylating agents, whether I say is azacitidine or decitabine.
Amer Zeidan: I think another consideration in patients who are already in complete remission and doing well is to try to space out the cycles from every four weeks to every five or six weeks, although I would not go beyond six weeks because we have very limited data, but in our clinical practice, I have actually extended to six weeks in patients who are doing very well and in CR for multiple months. So I think it's reasonable to do that in the setting of COVID situation to minimize the visits to the clinic.
Amer Zeidan: Patients who are stable, we have been trying to do telemedicine visits as well with them, if they don't have any other specific need to come in. Some of the new consults as well, that we had as a second opinion, also we try to do remotely for those patients, and discussing of the clinical trial options. Many of those have been on hold anyways, so I think that minimized the chance of the patient interacting with the larger healthcare facilities, where there could be an opportunity of catching the infection.
Amer Zeidan: I think this learning curve has improved a lot now. Many of the institutions, including ours and I'm sure in New York, basically have stringent visitor policies. Most of the visitors are being screened basically for any symptoms, any fever. Many of the institutions are testing their providers on a regular basis and implement a lot of those procedures, such as social distancing within the workspace, limiting the number of providers, and many institutions are mandating the use of masks basically in the facilities. So I think all of these things are helping to reduce the chance of nosocomial infections, which I think will be very important for the patients to feel comfortable, in terms of coming back to resume leukemia care.
Amer Zeidan: There has been a lot of concern that there would be some delays because many patients were not coming, and there has been already some data about increased incidents of cardiac deaths and strokes because the patients are afraid to come to the big facilities. And there have been some concerns that the same thing might happen with cancer, where we have delayed diagnoses.
Amer Zeidan: So given that the COVID situation is probably going to be with us for probably a long period, at least a year or two I would think, until some effective therapy or a vaccine becomes available, I think some of those strategies will be important to implement so that the patients will feel safe to come to the institutions where they can receive the best care possible.
Amer Zeidan: I think here we covered most of those areas. I encourage everybody to go back to the paper in Lancet Haematology and to use resources that are out there. Many societies, including the American Society of Hematology, have published guidelines for specific malignancies, in terms of guidance for the providers.
Amer Zeidan: And I would end here with any final words from you. Maybe start with John?
John Mascarenhas: No, I appreciate being included. I think we covered the breadth of the paper, and, as I think you pointed out and we all pointed out, at the end of the day, the approach needs to be individualized within the context of the environment in which the practitioner is providing care. I still think that, as you pointed out, we're not done with the pandemic and that we still have a lot to learn. But also I think as a medical community, we will see the lingering effects of this pandemic, in terms of how we provide care going forward, how we approach clinical trials, and our mentality towards patient care and the spread of nosocomial infections.
John Mascarenhas: Thanks for including me.
Amer Zeidan: Thanks. Jan?
Jan Bewersdorf: Thanks for being invited to this discussion. I think what this paper highlights as well is the international collaboration. We had 52 co-authors on this manuscript, and that really highlights that this is a global problem, and that there is no one size fits all solution, and everything needs to be individualized. And we are learning every single day from others, and adopting those best practices that we touched on today. I think that will be one of the hopefully more long-lasting positive endpoints of the COVID pandemic, and a lot of things may change in the future as well.
Amer Zeidan: Rory?
Rory Shallis: I'll echo John and Jan's comments and sentiment, that the invitation is appreciated. The conversation was great, and I will also say that even more focal collaboration, I think, is not only recommended but also it's quite good, just to involve infectious disease, our pharmacy colleagues for patients that are otherwise complex. This was a good talk.
Amer Zeidan: I'd like to thank my colleagues and thank VJHemOnc for organizing this presentation, and I'm sure if any questions come up, any of us will be happy to respond after the program. Thank you so much.
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