Elliott Vichinsky, MD: Thoughts on Hemoglobin Guidelines for Sickle Cell Disease

A sickle cell expert discusses the shifting therapeutic landscape as well as a need to rethink hemoglobin level threshold guidelines for patients.

Current guidelines for raising hemoglobin levels in patients with sickle cell disease suggest a limit of 100 g/l. Case and anecdotal reports have raised concerns that exceeding this threshold in red blood cell (RBC) transfusion may lead to whole-blood viscosity-related complications.

A perspective published in The British Journal of Haemtology acknowledged that such guidelines may need to be revaluated in regard to the use of disease-modifying therapies, such as hydroxyurea and new agent voxelotor.

“The 100 g/l Hb threshold alone may not accurately reflect the risk of viscosity-related complications with disease-modifying therapies,” the authors wrote. “The mechanisms whereby these therapies improve Hb levels differ substantially from that of RBC transfusion.”

Hb concentration may not be the only indicator of blood viscosity-related safety issues when utilizing these drugs, the article went on to note. Further, there is no evidence to suggest that Hb increases during hydroxyurea use is associated with viscosity-related complications.

Even more, in trials for voxelotor, a rise in Hb concentrations was generally associated with reduced pain events.

Elliott Vichinsky, MD, the article’s co-author, spoke to HCPLive® about the complex treatment landscape for sickle cell disease and this need to ensure that all therapies can be used optimally for each patient.

Below are Vichinsky’s perspectives on these and other related issues.

Contextualizing the 100 g/l threshold:

“The guidelines of what to do and levels to be at are really deducted from different kinds of datasets and different methods. And so the evidence [of this threshold] is a really abstract, artificial number that was based on individuals’ experiences with sickle cell, and — in certain circumstances — reported cases. [We were] trying to come up with something to use without evidence, in my opinion.”

On adverse events:

The case reports that led to these [adverse events] largely occurred in patients who were hospitalized with an acute event – and they were transfused rapidly. These were 2 precipitating factors in sickle cell complications. Rapid transfusions and comorbid acute events were going on. The summary of these cases implies that the problem of hemoglobin level and how high you go up may be one part. However, these other variables are probably much more important. 

In elected transfusions, where they can transfuse appropriately, these kinds of events are not well-established as happening. In patients with acute events, they don’t want to take chances — and it makes sense because there have not been good studies done."

On the STOP Trials:

“These were studies that accumulated sickle cell children who had an abnormal doppler. And they were documented to be at risk for impending stroke, since their doppler was high. It indicated a functional narrowing of the critical carotid arteries in their brain.

They were randomized to get chronic transfusions or nothing; however, the study was stopped because it dramatically stropped strokes from happening.

The problem with that study was that, when it first started, the goal was to get the sickle level low, and—at the same time—sustain a hemoglobin that wasn’t violating the threshold. But that was largely not doable in that trial.

So, we modified really early the attempts on how to do that so we can get the sickle cell level down and allow the hemoglobin to go much higher. […] In that study, what was clear was that in the initial acute period, if you can lower the S level to a certain level, then raising the hemoglobin actually seemed beneficial beyond the standard. […] That said, these were elective transfusions.”

On disease-modifying drugs:

“In drugs that are targeted to alter the cellular pathology of all (or most of) the cells, you are in a very different situation. What we find is that the disease is different in terms of risk of any of those kind of problems. In the studies with voxelotor or hydroxyurea, the problems of high hemoglobin or acute viscosity have not been recorded. There’s no evidence in those trials that the hemoglobin going up can cause problems.

In fact, it’s been the reverse. It’s very important to note that the higher the (good) hemoglobin is, in my opinion, the better the patient will be.

On the risk of low hemoglobin:

"Low hemoglobin is associated with some fundamental issues. Clearly, cognitive functioning and exercise tolerance are different. A number of the growth and organ functions are impaired. It is clear that lower hemoglobin in sickle cell disease is a risk factor for renal disease, pulmonary hypertension, cognitive function, silent strokes, full strokes, and leg ulcers.”

On patient treatment goals:

Unfortunately, a number of these drugs that are developed [are used for] short-term outcomes. What we really need is a sustained change over years in the delta of their organ degeneration—their doppler gets better, their cognitive function gets better, they have less renal failure and pulmonary hypertension.”

On working with patients:

My goal is to share with [patients] the information and give them my take on what the risk and benefit is, what my perspective is, and what exists—and work with them to make a plan.

So, I really believe the answer in this is twofold: The doctors need to work together to optimize therapies so that we can determine the curve of where the optimal doses are and how to do that. We also have to educate our patients, tell them the truth, what you think the data is and what the risk and benefit could be, and come up with a plan that is uniquely important for them.”

A final thought:

“To me, it’s likely that if we are smart enough to integrate drugs in a strategic way, we could probably shift the disease out of the severe environment into more of a benign picture. Some patients clearly wouldn’t need a transplant.”