Treatment-related Adverse Effects in MDS: Managing Them Before They Derail Therapy

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Questions and Answers

When should you discontinue therapy in patients who are experiencing fatigue?
Dr. DeZern: This often takes a lot of effort and some fairly in-depth conversations with the patient to keep a balance that some of the fatigue is from the underlying MDS, but certainly, the drugs that we use to treat it are also fatiguing. Quite often in patients who really feel that their fatigue is therapy-limiting, it is often my preference to end up discontinuing it. Sometimes even that effect of withdrawing a therapy can improve the patient's quality of life because they found the drug so debilitating in and of itself. As long as they understand that their MDS is going untreated in that context, we can have discussions going forward about how to manage the fatigue and what the next step in their therapy can be.

In addition to azacitidine, should we dose-adjust decitabine as well in patients who have renal impairment?
Dr. DeZern: I do not tend to dose-reduce the decitabine in the same ways that we discussed dose-reducing the azacitidine. As long as their creatinine is less than 2, patients usually tolerate decitabine at the standard levels quite well.

If a patient experiences grade 1 through 3 lenalidomide-induced rash, how do we know whether to interrupt therapy temporarily or discontinue altogether?
Dr. DeZern: This again requires quite an eyes-wide-open conversation with the patient. If the rash really is on the lower grades, I tend to interrupt temporarily and provide symptomatic relief as well as topical agents as we discussed as we went through the slides. I do often re-challenge with lenalidomide and require frequent visits after the challenge, keeping in mind the timeframe in which they developed the rash previously, in order to make sure we find out if it is going to happen again. I also counsel the patient to make sure they know what to look for, and both the patient and I are very aware after re-initiation of when to look again. There is a good percentage of patients that we are able to get to tolerate it on reintroduction, but if they needed some steroids topically or even some other form of symptomatic management before, I make sure we have talked through all that before we reinitiate lenalidomide.

What is the most common type of infection we see in our MDS patients?
Dr. DeZern: I say it is quite varied, but more often than not, it is either a fungal pneumonia that is demonstrated on the imaging in the context of a neutropenic fever, or a gram-positive bacteremia, as many of the patients at least receiving a hypomethylating agent tend to have central lines. Gram negatives are what we worry about the most given they can have such a florid septic presentation, but these are actually less common.

Can we still give lenalidomide if the patient has a preexisting hypothyroidism?
Dr. DeZern: The answer is absolutely yes. Sometimes, if they have an endocrinologist with whom they are already following, I do reach out and just let them know the issue and make sure we have a plan with that endocrinologist or the primary physician to monitor the TSH and free T4, and so forth, to ensure that they stay euthyroid, but it is not an absolute contraindication.

How can I tell if an older patient is fit enough for transplant?
Dr. DeZern: This is something I challenge myself with on a nearly daily basis. As I am sure you are all familiar, we are in an era where age is not considered as important as fitness and frailty. Certainly, I am always honest with myself and patients that the chronological age of their organs must be taken into account. But if they have well-managed comorbidities, they are pursuing a nonmyoablative transplant approach for their MDS, and we think their disease is under good control, I often move toward a transplant-based curative paradigm for my higher-risk patients.

In your practice, what is the biggest challenge when treating older patients?
Dr. DeZern: I consider the biggest challenges to be fitness for therapy as well as complaints of fatigue, and balancing the disease and quality of life in terms of what is the real priority for the patient in terms of longevity. It is somewhat philosophical, but some patients prefer quality over quantity and some are the reverse, and I think it is a challenge to individualize our therapy.

What underlying comorbidities am I most concerned about in my patients?
Dr. DeZern: Usually, I am most concerned about comorbidities that relate to their functional status. Heart failure and inability to manage volume shifts concern me a lot because this usually gets to renal perfusion and how we are able to manage that, as well as how well they get around if they are becoming quite edematous. I worry a bit less about things like endocrinopathies, diabetes, or thyroid conditions; I usually find we can keep these pretty well in line.

What are some common drug-drug interactions that may worsen treatment-related adverse events?
Dr. DeZern: Actually, this is a good follow-up to the question that we just had. If patients are really having trouble with something like heart failure, I worry about digoxin and furosemide, especially if they are experiencing fluctuating renal levels or are at risk for dehydration in the context that the creatinine goes up. Those are things that can cause us troubles. There are not a lot of medicines that truly interact to overtly decrease the metabolism of the hypomethylating agents, or even lenalidomide, such that we have to worry about accumulating the toxic byproducts of a drug. So, it is more so things that change the creatinine clearance that make me concerned.

How often do you monitor renal function in patients younger than age 65 years?
Dr. DeZern: If everything is normal going in and if the patient is not on any of the medicines that we have just talked about, I usually only monitor renal function once or maybe twice a cycle if there is no reason to think it would fluctuate. So, in patients that are doing really well on a standard 28-day cycle, I might just have the labs if they are not densely transfusion-dependent that one time pre-treatment.

What is your preferred therapy for treating diarrhea and why?
Dr. DeZern: It depends on what I think the diarrhea is from. Specifically talking about diarrhea related to lenalidomide, this is always a very lengthy conservation with patients. I often start slow and I titrate up, and I am very frank with patients that they need to work with me and work with their diet so that everything is a balance. I usually start with loperamide and invariably you will have the patient that comes in two days later and tells you they are constipated, which is a challenge. I titrate up from there moving through loperamide and then up through tincture of opium. I do have some patients on lenalidomide that need colesevelam,* and that is an extrapolation from people who are getting lenalidomide more for myeloma. This drug is actually used for completely different reasons, but it is very effective for diarrhea in these patients, again just making sure that if they are taking it very regularly then we do not overshoot to constipation. So, that was a long response to the “why?” part of that question, but it is really about managing diarrhea so the patient is able to get out of the house and do the things that they want, but that they do not become so backed up that that is uncomfortable as well. I’ll just mention one other pearl related to the bowels: I do not often use ondansetron with my hypomethylating agents because sometimes both of those in combination can cause too much constipation. I move more toward granisetron or prochlorperazine for the nausea with HMAs and the patients do a little bit better with that in terms of bowel tolerance.

*Colesevelam is not FDA approved for this use in the United States

In patients with renal impairment, is it better to reduce the dose or prolong the dosing interval?
Dr. DeZern: I personally think it is better to reduce the dose. I use a prolonged dosing interval for other reasons, but if we are really worried about clearance, it makes more sense to me to dose reduce.

Have you ever used premedication to prevent injection-site reactions in a patient receiving azacitidine?
Dr. DeZern: Believe it or not even though I give azacitidine all day every day, it seems like this has only happened in a handful of patients for me where we really have a lot of trouble with the injection sites. So, I do use a fair amount of EMLA cream which is not for reaction per se, but it is for the pain and this goes a long way with these patients. I have a couple of patients that I have actually either given oral diphenhydramine to in advance, or immediately after we apply some diphenhydramine cream to prevent reactions, and this has been effective.

Which treatment-related adverse events should we be counseling our patients to self-monitor for when they go home?
Dr. DeZern: I usually counsel patients to do a skin exam to monitor for rashes, making sure they use a mirror to see their upper back and upper chest. We also talk a lot about the bowels because the worst is if someone has a lot of diarrhea and they are not proactive about staying hydrated, then they come in hypokalemic five days in from having seven to eight bowel movements a day. These are the patients that worry me the most.

Are there any underlying comorbidities that can increase the risk of lenalidomide-induced rash? Are there any steps that patients can take to prevent that lenalidomide-induced rash from occurring?
Dr. DeZern: There are no underlying comorbidities to my knowledge, though certainly you could surmise if somebody had pretty significant skin conditions, they could be predisposed. Though I will tell you anecdotally, I have two patients with pretty significant psoriasis and we have had no trouble at all with the lenalidomide or rash. The answer to the second half of the question is: not really. I encourage patients to just shower per their normal routine, use non-perfumed soaps, and keep moisturized with non-perfumed, very basic lotions. Other than that, you cannot really predict whether the patient is definitely going to have the rash or not.

Do you avoid erythropoietin in patients with preexisting cardiac disorders? Do you recommend any specific monitoring parameters?
Dr. DeZern: I do not avoid EPO in patients with preexisting cardiac disorders. I do monitor their blood pressure and if I know that it is someone who has preexisting hypertension that is not well controlled, I counsel them about this before we prescribe it. We check the blood pressure before we give it, and then, I make them have a follow-up two to three days later for blood pressure monitoring, and I put hold parameters on the drugs for my nurses so that we do not administer if they are truly hypertensive at the time of the injection.

When assessing a patient’s bleeding history, what signs tip you off that platelet growth factors may be needed?
Dr. DeZern: I take a really thorough bleeding history even in my relatively mildly thrombocytopenic patients (60-, 70-, even 80-years-old), to see if they are predisposed to mucocutaneous bleeding, or if they had any procedure-related bleeding in the past. Because if we have a sense that somebody may, in addition to having a low platelet count, have some sort of platelet dysfunction, I am very attuned to that. I am a hematologist first and foremost, and so, sometimes I even do a mild workup to see if there is some other predisposition to bleeding, or if there are patients that are perhaps on an SSRI or some other medicine that we know that can slightly cause platelet dysfunction and increase the bleeding risk. It is a lot of those historical factors that indicate we need to start thinking about platelet growth factors earlier rather than later. Then certainly in our older patients, just practically speaking, if they live remotely, they live alone, or I think they are a fall risk, I am thinking about it sooner rather than later if I do not think I can transfuse them to a safe platelet count and keep them there for long enough periods between clinic visits.

When do you consider routine prophylactic antibiotics and how frequently must a patient have infections to be considered as having recurrent infections?
Dr. DeZern: This is a tricky area and it really does vary by practice pattern, by institution, and even by individual provider. In terms of routine prophylactic antibiotics, we here tend to favor quite a proactive approach. In patients who routinely have absolute neutrophil counts of less than 200 for sure, and maybe even 500, we have discussions about prophylactic antibacterials (often in the form of fluoroquinolone) and prophylactic antivirals. Sometimes in patients who we believe to be high risk, perhaps through occupation or past history for recurrent fungal infections, we even do prophylactic antifungal medications in the form of an azole. As for the question of how frequently a patient needs to have these infections to have to be called recurrent, it really only takes two for me. If older or more frail patients have a fever on more than one cycle or more than one occasion, that is enough for me to really feel concerned about their predisposition for infection.

What is an example of the transfusion threshold that differs for an elderly patient compared to a younger patient?
Dr. DeZern: This is quite patient-dependent, though I am very frank with my patients that in the world where red cells or platelets are not a completely renewable resource and there is a lot of competition, we have to be thoughtful. We also have the iron overload conversation in relation to transfusions. If an elderly patient has significant comorbidities, notes fatigue, perhaps has some underlying heart conditions (be it CHF or even atrial fibrillation), I am usually on the higher end over 8 g, 8.5 g. I will admit I have an occasional patient who really must be transfused over 9 g/dL for hemoglobin because they have symptomatic angina in that context, and so, I really get to know that patient. In terms of the younger patients who might have many life-years ahead to experience iron overload but also to continue to get transfused, I try very hard to restrict them as much as they can symptomatically tolerate. I have a couple of patients that can actually tolerate 7 g with no trouble, and we have not had any trouble with high output cardiac failure in that context. So, I will let some patients go down to 6.9 in that context.

Are there any patients for whom you would dose pegfilgrastim at 6 mg?
Dr. DeZern: Yes. I have a few patients that come from very far, or for whatever reason we have some sort of insurance hurdle, and that is reasonable. I do it very rarely, I am not a huge pegfilgrastim proponent, but in the appropriate person who cannot come back and forth, cannot get shots at home, and has a need for that, it is something reasonable to consider.

Managing MDS would like to recognize and thank Celgene Corporation for their educational support of

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