Emerging Therapies in the Management of Sickle Cell Disease - Episode 7
Biree Andemariam, MD: We have hydroxyurea oral pills; they need monitoring. We have L-glutamine as another option to reduce vaso-occlusive crises; it’s a powder, has to be mixed and ingested twice a day. Both are indicated in adults and children, specifically down to the age of 5 years for L-glutamine, and recommended as early as 9 months of age for hydroxyurea. What about transfusions? Transfusions have been around a long time. Elliott, what are the indications for red blood cell transfusions in sickle cell disease? Are there any adverse effects associated with putting someone on chronic transfusions?
Elliott Vichinsky, MD: The reality of transfusion is that it’s an incredibly strong therapy. Sadly, it hasn’t gone through the quantitative therapeutic studies in sickle cell other than in gross ways, like giving blood and measuring hemoglobin F and hemoglobin S. I think it could be more effective if we approached it as a therapeutic drug rather than just a transfusion. But there’s no question.
Has anyone ever looked at a child who had a stroke or an abnormal TCD [transcranial doppler] at 3 years of age and has been on chronic transfusions, and seen what their life is like when they’re 20? They don’t even come to clinics. They don’t identify with the disease anymore. I’m talking about those who were started young on the drug before the disease caused some ravaging damages. They’re tall, their growth patterns are improved. There’s improvement in cognitive function and their energy level. Their pain is better. Globally, that subgroup of patients who were started in a preventive way and managed appropriately have a very different phenotype.
It is also quite effective in intermittent use and selective indications. The growth delay curve does change during that period. It clearly protects against stroke recurrence or primary stroke. In patients who have acute chest syndrome or acute lung disease, it can induce an improvement in oxygenation in a relatively short period. I think transfusions can have some benefit with almost every complication, but not all of them.
The problem with transfusion therapy is that it has a number of adverse events that are significant. No. 1 in people with sickle cell is that you can develop alloimmunization. That means the proteins exposed on the red cells you’re getting may be different than the ones you have and you develop a reaction that can drop your hemoglobin and cause life-threatening problems. So it requires specialized blood. Red cells are made up of iron, and once you’re on enough transfusions, you need to start on a medication to prevent you from getting too much iron.
Thirdly, because doctors have limited availability of many therapies, it’s often used when it shouldn’t be used. It’s commonly used for pain in a transient setting. I think we need more studies, but it’s a dramatically powerful tool in sickle cell disease, and it will remain that way for now.
Biree Andemariam, MD: Let’s talk about that. There are practices out there and emergency departments—not to pick on them—where someone will come in with a hemoglobin of 8 g/dL, their usual, or maybe even better than usual, hemoglobin level and they’ll get transfused before being sent home. That’s on the one end, which we all, as hematologists, cringe at. But what are the clear-cut indications for both acute and chronic transfusional therapy in sickle cell disease?
Julie Kanter, MD: Certainly primary and secondary stroke prevention. Something I see that’s different between sickle cell specialists, like all of us, and some of the community hematologists and oncologists, is the continued use, especially for secondary stroke prevention. I see adults who have recurrent strokes because they should have continued on transfusion therapy. Someone will see iron overload and stop it, as opposed to really treating that iron overload or looking into erythrocytapheresis. As Elliott says, this is an immense therapy. It’s most limited by incorrect use and that it’s not an infinite supply. We don’t have an infinite supply of blood. If we did, it would probably be our leading therapy.
Elliott Vichinsky, MD: We designed a trial to start transfusing children from infancy on, before they got sick, but we never got anywhere. It’s something to consider once we are able to work out treating the complications of iron overload. But it is powerful.
Julie Kanter, MD: I wanted to do that, too. I wanted to treat them, at least for the first 2 years of life, and see if you have enhanced brain development with fewer potential neurocognitive problems later if you transfused early.
Michael DeBaun, MD, MPH: We talked about our adolescents and adults with chronic pain. When we try to support them through their opioid dependency and chronic pain with a multimodal approach, we will put these individuals on transfusions to get their hemoglobin S levels to less than 30% to mitigate the acute pain that we know occurs when the hemoglobin S level is near baseline.
This is multimodal, and we’ve used this in a very time-limited fashion. If there’s no benefit over 6 months, we’ll stop the transfusion. If there’s progressive decline in the use of opioids and eventual weening of the methadone, and support with the psychosocial services, including counseling for addiction or opioid abuse, then we will continue. In some cases, this has lasted about a year, but the transfusions have been very helpful.
For men who have unremitting painful priapism episodes, even while on hydroxyurea, we will switch them over to transfusions to try to break the cycle and to stop the abrupt ischemic events that occur continuously for a period of time.
We have also used transfusions for the group of patients who have recurrent acute chest syndrome that is life threatening despite being on hydroxyurea and being treated for asthma. They are rare, but we have used it for those patients, as well.
There’s clear evidence that women with sickle cell disease have multiple complications, including higher rates of pain and higher rates of acute chest syndrome. Most of those events are in the third trimester of pregnancy. I would say that when you have a pregnancy that is a severely complicated in a third trimester, transfusions may be of benefit. I highlight may. The evidence from randomized controlled trials has not been conclusive that transfusions are beneficial for the entire group of women who are pregnant. But at least in the third trimester, there’s strong evidence that transfusions may mitigate the complications that we all know too well.
Last but not least, I would like to point out that in the randomized controlled trials STOP and SIT, where transfusions were given routinely to keep the S levels at less than 30%, we saw a decrease in the rate of pain episodes and a decrease in the rate of acute chest syndrome episodes. We also saw a decrease for the boys in the SIT trial in the rate of priapism. These are all indirect pieces of evidence that transfusions can abate the incidence of acute manifestations of the disease.
Biree Andemariam, MD: Thank you.
Elliott Vichinsky, MD: I’d like to mention something I forgot to include. There were a number of studies, many I’ve been involved in, randomizing sickle cell patients to elective surgery. Recently, I acted as the father for one of my patients who was getting married, because he the father was ill at the time and really relieved….
But then, 6 months later, she died, and I was involved in her funeral. They had moved to a nice suburban area that was not familiar with sickle cell disease. She developed severe abdominal pain, and she was operated on for what they thought was something in her abdomen. It was a pain crisis, and there were just nodes. They did not transfuse her preoperatively, and in the perioperative period, she got acute chest syndrome and was put on a ventilator and died. She haunts me that way. I do think elective transfusion for major surgery is beneficial in decreasing the morbidity of major surgery, and it should be a standard.
Biree Andemariam, MD: Absolutely. Thank you for making sure that we highlighted that indication as well, Elliott.
Transcript Edited for Clarity