Transplant Considerations in Hematologic Malignancies in Light of COVID-19

Naval G. Daver, MD

In light of the COVID-19 pandemic, transplant-eligible patients with cancer are undergoing careful assessment to determine whether they should proceed with the procedure or receive additional consolidation therapy to buy time, according to Naval G. Daver, MD.

For patients with hematologic malignancies such as acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) in the frontline setting, most allogeneic stem cell transplants are being conducted as planned, said Daver, although patients will be tested for the virus to ensure they are not infected prior to the procedure. If the test results turn out to be negative, the procedure is typically conducted.

However, in the relapse setting, providers are a bit more conservative with regard to selecting the time and type of transplant for patients. In cases where patients can safely delay treatment, the procedure may occur a few weeks later than previously planned in an effort to make it past the peak of the pandemic, explained Daver.

“Most of our patients are on treatment in clinical trials. If we proceed to transplant, especially in the frontline setting, we usually try to do so after either the induction or the induction plus consolidation,” said Daver.

At this time, age and comorbidities must also be carefully considered when evaluating patients for stem cell transplant. If these factors indicate that transplant might be risky, then patients might be given more cycles of consolidation therapy, according to Daver.

“In today's era, if patients are concerned, or for particular reasons like their age or comorbidities we are worried that transplant may be risky [in that there may be] a high potential [for a] severe occurrence of COVID-19—then we may give them 1 or 2 additional consolidations. Each consolidation usually lasts 4 to 6 weeks, so if you give 1 consolidation, that will buy you 6 weeks; if you give 2, that could give you another 12 weeks. ”

The utility of hematopoietic growth factor has not changed in light of the pandemic, added Daver, nor has the use of erythropoietin stimulating agents. Although a blood shortage was reported during the first weeks of the pandemic, the transfusion threshold has since been reset to a slightly lower level. Although it’s not at baseline, said Daver, providers are able to start transfusing more, if needed; as such, growth factors are not being used more frequently at this time.

In an interview with OncLive, Daver, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, discussed the impact of COVID-19 on stem cell transplant for patients with hematologic malignancies and other measures put into place to prevent patients from infection.

OncLive: How has the transplant eligibility criteria changed in light of the COVID-19 pandemic? Are you trying to delay transplant in most patients?

Daver: Due to COVID-19, we have reassessed both our induction and transplant eligibility. In general, we are trying to continue with the procedures as we normally would. For transplant, especially in the frontline setting, whether it’s [in patients with] AML or ALL, we are continuing to proceed with allogeneic stem cell transplant. We do check for COVID-19 before proceeding with [the procedure]. If the patient is negative, we usually do continue with the transplant in the frontline setting.

In the relapse setting, we are becoming a bit more conservative about selecting both the timing and the type of transplant. For patients who are in remission but maybe were measurable residual disease (MRD) negative, we may consider giving them 1 or 2 more cycles of therapy to get them into a deeper remission or to buy some time. Then, we’ll consider doing the transplant at a later time point. I have several such patients in my clinic. If we believe that it's absolutely needed, it's curative, and the patient is in a very good remission, we don't want to delay [the transplant]; however, in situations where we could safely proceed with 1 more cycle in 6 to 8 weeks, it may give us time to hopefully get over the peak of the pandemic, which will hopefully be in the next few weeks. We are deferring transplant in those situations.

Are you putting patients on longer dosing schedules to delay transplant?

We're not changing the cycles, dosing, or intensity of therapy. Rather, we're just giving more consolidation cycles. In relapse, it’s the same thing; when we're using targeted therapies either as a single agent or in combination with azacitidine or venetoclax (Venclexta), the cycles usually run between 28 to 42 days, depending on count recovery. I have a few patients where I'm giving them 1 or 2 additional cycles, even though they may have a donor ready, because they may not be MRD negative or there may be concern of doing the transplant given that this may be a peak time of COVID-19. Therefore, we use additional cycles to buy additional time, if needed, in this situation.

Has the utility of hematopoietic growth factors changed in light of COVID-19?

In general, no; however, there is a bit of a controversy regarding this aspect. We are not sure whether hematopoietic growth factor use at a broader level is necessarily going to be beneficial. I have spoken with colleagues in other countries who have noticed a paradoxical, less severe COVID-19 presentation in patients with AML or ALL who come in with very low neutrophil counts. These are case reports, but we know that the terminal stage of COVID-19 is often a hyper inflammatory stage similar to what we are seeing with cytokine release, high levels of pH1 type cytokines such as interleukin-1, TNF alpha, and ferritin LDH.

The concern is that if we gave growth factors like filgrastim (Neupogen) to increase the white count, it may unmask an inflammatory response. A lot of this is theoretical or based on case reports, but we’re basically using the same guidelines that we did for growth factor use like filgrastim or filgrastim-sndz (Zarxio), which is for patients who have very prolonged neutropenia after receiving induction consolidation, meaning beyond 42 days, or those who are admitted with any kind of severe infection. We are not routinely increasing our use of filgrastim at this time based on COVID-19 incidence or recurrence.

What could a greater use of growth factor support do for patients at risk for COVID-19?

That's what we don't know: whether the use of growth factors in an asymptomatic patient at risk for COVID-19 could potentially prevent the infection; that is the hypothesis for using them, but we're also worried that if patients do have a subclinical COVID-19 infection, and their neutrophils are low, they may not be able to mount the hyperinflammatory response. When we give them filgrastim and get their neutrophil count up, is it possible that they will have higher-functioning T cells that could then produce a cytokine release or hyperinflammation? This is why we are not really using growth factors more often than we did as a standard practice in the past.

Are there any issues with using erythropoietin stimulating agents given the limited blood supply?

Erythropoietin agents, such as darbepoetin alfa (Aranesp) or epoetin alfa (Procrit) are usually used more predominantly in myelodysplastic syndromes (MDS) and in certain types of myelofibrosis that present with anemia to try and maintain the hemoglobin at a level that will not cause clinical symptoms. We have not changed our practice regarding the use of these agents.

There was initially a shortage of blood during the first weeks of [the pandemic] and we did reset our transfusion threshold at a slightly lower level, especially for those patients who are younger or asymptomatic. We are now seeing that there is more availability of blood products. It's still not back to baseline, but we are able to start transfusing more, if needed. As such, we’re not using growth factors more frequently at this time. Now, with COVID-19, there's also a concern of venous thromboembolic events; this is emerging in more patients, especially in the perioperative time points. So again, growth factors, such as darbepoetin alfa, are also known to slightly increase the risk of blood clots and thrombosis. As such, I would be careful with regard to using them very frequently beyond how we've used them traditionally in MDS or myelofibrosis.

Do any thrombocytopenia-related considerations exist, given the limited blood supply?

In general, we are worried about thrombocytopenia in our patients; it is associated with higher risk of bleeding events. In general, we try to keep the platelet count above 12. Historically, we would often try to do 15, but in the current era, we're shooting more for 10 or 12 in patients who are not actively bleeding or having signs of bruising. In those patients, we may actually go for a higher platelet level. There are no good platelet-enhancing agents available in the setting of leukemia that have shown the ability to increase and maintain platelet counts without adverse events such as liver problems or bone marrow fibrosis. In general, we are continuing to monitor platelet counts and transfuse as needed.

Some of our patients who are above 60 years, may be candidates for either intensive chemotherapy or for moderate- or lower-intensity therapies, such as hypomethylating agents (HMA) plus venetoclax. There was always a debate, especially with regard to those who have adverse cytogenetic TP53 complex or bad risk features, that HMA plus venetoclax may be equal, potentially even better, than standard induction cytarabine and anthracycline. Now with COVID-19, there is more enthusiasm and more push to use HMA plus venetoclax in those borderline patients between 60 and 75 years who may have moderate fitness but intermediate adverse cytogenetics or adverse molecular features where we may have previously hesitated and not been sure which one to select. Now, [in light of COVID-19] we're leaning toward HMA plus venetoclax, which usually has less transfusion support requirement, less inpatient stay, and less prolonged myelosuppression. This approach will hopefully provide us with some very useful data that will inform us in the future of this borderline population of patients who are 60 to 75 years with moderate fitness. Is there a clear role for HMA plus venetoclax to be used preferentially over induction-based therapies?

What other measures are you implementing in practice during the COVID-19 pandemic?

The biggest thing is hyper-accentuating the standard precautionary measures that everyone has heard of both on the news and in their institutions, which is hand hygiene. Washing the hands very frequently with good antiseptic soap and doing it for 20 seconds is very critical. Twenty seconds is actually quite a long time and most people, when they start counting, realize they probably never washed their hands for 20 seconds in their lives. I noticed the same thing. You really have to count and wash very carefully. Wash frequently, especially anytime that you leave the house or your office.

The second thing is, we are using mask precautions, as has been recommended by the Centers for Disease Control and Prevention. We use masks at all times when we are in or around the institution. Even outside the institution, I prefer to use masks whenever I can. The third thing is, any early signs of fever, shortness of breath, cough, respiratory distress must be evaluated immediately, regardless of whether it's your patient or an employee. We now have access to rapid COVID-19 testing, both for employees as well our patients, so we will try to identify those [who may be infected] quickly.

Whenever interacting with patients in clinic, whether they are suspected to have COVID-19 or not, use proper person protective equipment (PPE), including mask and gloves. You need to practice appropriate handwashing between each patient and minimize contact [with others]. For example, we are not shaking hands with patients. These are all key precautionary measures that we are trying to implement very rigorously. Even in a social setting, we’re trying to minimize the number of people in a gathering to less than 5, if possible, and maintain distance between people. Obviously, do not share food or drinks; this sounds very simple, but needs to be implemented at a very rigorous level.

Many institutions are experiencing shortages in supplies, such as face masks or gowns. Is your institution experiencing any shortages?

At this time, we don't have any acute shortages; however, we’re all very concerned about this. We have not been hit by a number of patients, like has been seen in the northeast or California. However, that does not mean that the situation may not change. It is always possible that we will either see a chronic kind of COVID-19 infection over many months, as opposed to the large spikes that we're seeing in New York and other very large metropolitan systems. As such, we are being very cautious and conservative in our use of PPE so that we can avoid an acute shortage scenario. Many efforts are ongoing, both at the national and international level, to enhance production and to bring [supplies] to the large institutions and hospitals across the United States, Italy, and Spain. Hopefully in the next few weeks, if we can hold out, these [supplies] will be available. However, I think it is very important for the nonmedical individuals to avoid purchasing large amounts of PPE and hoarding these. Try to reuse masks if you have them available because it is critical for the nurses and physicians, especially those who are actually seeing patients with COVID-19 in New York and other institutions across the country, to use this equipment when caring for their patients; PPE is needed to keep them and their patients safe.

Have you shifted to the use of telemedicine at your institution? What are some other ways that you’re addressing the disruptions in care caused by COVID-19?

That's a big change in our practice; there is at least a 5 to 8 times increase in the number of telephone calls that I am making daily—not just with patients, but with the local hematology/oncology providers who have been a great assistance in the management of our patients with leukemia [on a] local [level. With] very close collaboration with the physicians, research nurses, and data coordinators, we've been able to continue almost all our patients on treatment locally. We ship out the oral component of the medication and they will do the intravenous component if it's something that's available.

We have not seen a huge disruption [overall]. However, by the nature of the travel bans, as well as the national reduction in flights, the number of patients coming to a tertiary referral center, such as The University of Texas MD Anderson Cancer Center, has gone down. We are hoping that this situation will start improving as we get through the peak. Officially, we have not closed any of our major studies. We continue to be able to follow and monitor the patients who are already on studies and we are using and working very closely with our colleagues in the local community setting. In the future, this will be very important; this may show us that we can work very closely with community hematologists and oncologists, which might allow us to potentially enroll more patients on trials [with the option that they can receive] local care with the oversight and monitoring of the principal investigator or treating physician at The University of Texas MD Anderson Cancer Center. [COVID-19] may be a bad scenario in general worldwide, but it may help us develop new strategies and approaches that may, in a few years, turn out to be helpful for patients, trials, and institutions.

What can people do to help healthcare professionals and patients with cancer during this pandemic?

In the United States, it has taken a while for this to start sinking in: We need to take the preventive precautions for the virus seriously. COVID-19 is absolutely a severe disease; it is very prevalent, and the number of cases is going up. We do not believe this is going to be very short lived and go away; however, we expect this will continue for a few months. It may be a big social or emotional impairment, but isolating oneself, avoiding contact externally, or minimizing contact as well as taking very stringent cautionary measures, such as handwashing, using of antiseptics and face masks, and avoiding physical contact with external individuals as much as possible, are all things that will help the situation. As they say, try to stay home as much as possible.

Another big burden for our patients is that we have had to, like most big cancer centers across the country and world, limit visitors or ban visitors to minimize the community spread within the hospital. This is something that upsets many people, but we all have to do it for the benefit of our patients [with cancer] as well as others who are in the hospital. Just try to realize and be patient regarding that aspect. I will say, 99% of our patients have been stars at doing this and have been outstanding with regard to coping with these changes during this difficult situation.

Is there anything that you would like to add?

The good thing is, from a clinical research perspective, we are seeing that the research community has come together to try to identify therapies for COVID-19 as well as potential vaccines and serum strategies. We have never seen this happen with a pandemic before. [In response to COVID-19], we were able to mobilize so much research data and get publications out so quickly. We’re very optimistic that we will eventually develop serum- and/or vaccine-based approaches that will conquer and overcome the virus. The hope is that we can minimize the number of cases and mortalities by that time. Let’s all work toward that, and hopefully sooner rather than later.