AABB News: Sickle Cell Treatments Expand Rapidly in Recent Years

This article originally appeared in AABB News, a benefit of AABB membership. Join AABB today to read the rest of this month’s issue.

Once upon a time, the only treatment for patients with sickle cell disease (SCD) was transfusion… chronic transfusion. As treatments go, chronic transfusion is a less-than-ideal therapy.

Transfusion doesn’t fix the underlying genetic abnormality that causes the red blood cells (RBCs) of some individuals to curve or “sickle,” clogging blood vessels and causing painful crises. But it may help in preventing strokes and organ damage that are often a comorbidity of SCD.

Transfusion can only dilute sickled RBCs and add capacity to carry oxygen throughout the body. Along with being a limited therapy — eventually RBCs from transfusion die — transfusion carries significant risks for individuals with SCD. Of course, every transfusion carries potential risks, but chronic transfusion can lead to alloimmunization, which eventually may make it difficult to find well-matched blood for some patients.

“Transfusion is our oldest disease-modifying therapy for sickle cell disease, and it’s still important for many individuals, especially pediatric patients, who are at risk for stroke,” said Deepika Darbari, MD, a hematologist specializing in SCD at Children’s National Hospital in Washington, DC.

Patients with sickle cell anemia are screened with transcranial doppler (TCD) starting as young as 2 years of age. Those with abnormal transcranial doppler studies are typically started on monthly transfusion. Transfusion is also still an important treatment for patients who develop other complications, like acute chest syndrome, or before surgery to avoid post operative complications.

“Alloimmunization is the big challenge with transfusion therapy,” said Darbari. “Thankfully not everyone who receives transfusions gets alloimmunized. It’s a small percent. But the risk is there, not only for patients receiving repeated blood transfusion, but also for those who receive sporadic transfusions.”

Transfusion history is very important when treating adults with SCD, said Cheryl Mensah, MD, a hematologist specializing in SCD, an assistant professor of medicine at Weil Cornell School of Medicine, and assistant attending physician at New York Presbyterian Hospital in New York.

“Because I treat adults, most of the patients that I see have had at least one transfusion. So, every time I see a patient, I ask them about their transfusion history and any transfusion reactions that they’ve had in the past,” Mensah said. When considering transfusion for patients, standard type screens are performed. Mensah added that, on occasion, phenotyping is also conducted, “but it’s not as standard as it should be.”

Pain Crises

Pain is the most common problem for patients with SCD, and it can start early in life.

“In pediatrics, our patients generally experience some episodes of pain. Care depends on how severe that pain is,” said Darbari. Once patients start to experience an episode of pain, treatment typically starts with over the-counter medications, acetaminophen and ibuprofen.

If pain is still not controlled, many patients opt for opioids. “Most of our patients, if not all, have small supply of opioids, so they can try to avoid visit to the emergency department,” said Darbari. “We have been treating pain crisis how it was treated 20 or 30 years ago,” said Darbari.

When patients have acute pain, in the ED they typically get intravenous opioids. They also get anti-inflammatory drugs, like ketorolac (toradol), along with intravenous fluids. There are a few drugs being studied in the setting of acute pain crises, she noted.

Treatment of pain crises has started to change in the last decade for both pediatric and adult patients. “The main thing about our approach today that is different from 30 years ago is that we focus more on prevention of pain crises,” Darbari said. “We try to use disease-modifying therapies to prevent acute pain from happening.”

Hydroxyurea

In the last decade, several treatments have come online as preventatives, starting with hydroxyurea. This drug has been indicated for the treatment of SCD in adults since the late 1990s.

In 2017, the drug was approved as a treatment to reduce the frequency of painful crises and the need for blood transfusions in patients 2 years of age and older with sickle cell anemia with recurrent moderate to severe painful crises.

Hydroxyurea works by increasing the synthesis of fetal hemoglobin (HbF), which inhibits the polymerization of sickle cell hemoglobin (HbS), which causes RBCs to sickle.

“There are many patients who are doing well with hydroxyurea treatment — who have been treated with it for 12 or 15 years — who come to the ER for pain, maybe once a year or once every couple of years. There are even patients who have not been to ER and doing fine since starting hydroxyurea,” said Darbari.

L-Glutamine

In 2017, the US Food and Drug Administration approved L-glutamine oral powder to reduce the acute complications of sickle cell disease in adult and pediatric patients aged 5 years and older. In the pivotal study, patients receiving L-glutamine had fewer pain crises than those receiving placebo. In addition, L-glutamine treatment resulted in fewer hospitalizations due to sickle cell pain and fewer cumulative hospital days. L-glutamine can be used with or without Hydroxyurea.

Crizanlizumab

Crizanlizumab (Adakveo) was approved in 2019 to reduce the frequency of vaso-occlusive crises (pain crises) in adults and pediatric patients with SCD aged 16 years and older. The drug is given as a monthly infusion. Crizanlizumab works by making RBCs less sticky, reducing vaso-occlusion, and thereby decreasing pain crises.

In the SUSTAIN clinical trial, 5 mg crizanlizumab-tmca resulted in fewer pain crises per year compared with placebo. The time to first pain crisis was also extended with use of the drug. This reduction was unrelated to SCD genotype or hyrdroxyurea use. Crizanlizumab is now being investigated as a treatment for younger patients.

Mensah noted that crizanlizumab is covered by Medicaid in New York state. “So it’s been easy to start patients on it,” Mensah said. “However, if there isn’t a reduction in hospitalizations or ER visits after a certain number of months, sometimes insurance companies push back about continuing to cover it.”

In terms of patient response, she said that along with hospitalizations and ED visits, she looks at changes in opioid requirements and how the patient feels generally.

Voxelotor

Also in 2019, the FDA approved voxelotor (Oxbryta) for the treatment of SCD in adults and pediatric patients aged 12 years and older; the indication has been extended to patients aged 4 years and older.

Voxelotor works by inhibiting polymerization of hemoglobin S into the long chains that cause RBCs to deform. In the pivotal phase III study, more patients receiving voxelotor had a hemoglobin increase of more than 1.0 g/dL from baseline at week 24 — 51% vs. 7% with placebo.

This was regardless of anemia severity at baseline or use of hydroxyurea. Markers of hemolysis were reduced with voxelotor vs. placebo. The annualized incidence of pain crises was slightly lower with 1,500 mg voxelotor than with placebo — 2.77 vs 3.19. However, the drug’s effect on stroke risk and organ damage, among other complications of SCD remains unknown.

“I think initially there were issues getting access to Oxbryta, but I think things have improved and people are able to access the drug more easily now,” said Darbari.

Multidrug Therapy

None of these drugs are curative, and none work 100% for any patient. However, the effectiveness of combining SCD drugs has yet to be studied systematically. There remains much work to determine which drug works best for which patients and how best to combine drugs.

“In the real world, there are patients who are on both hydroxyurea and crizanlizumab. Because the two work differently, both can play a role in reducing pain,” said Darbari.

With several available drugs now, treating SCD complications may become more like treating cancer with multidrug therapy — increasing hemoglobin with voxelotor and reducing pain with crizanlizumab, for example.

So far, there is no defined algorithm for which drugs to use in which order or in which combinations. Mensah said that for patients treated with transfusion or those with organ problems, she tends to recommend treatment with veloxetor.

“I consider Adakveo [crizanlizumab] for patients who have multiple pain crises or they’re treated with hydroxyurea and they haven’t really had much of a benefit. There are a few patients that — if insurance allows — I recommend dual therapy or even triple therapy with hydroxyurea, Oxbryta, and Adakveo,” Mensah said.

Gene Therapy

Gene therapy has become a potential curative treatment for patients with hemoglobinopathies, including SCD, in the past few years. A number of trials are ongoing, and preliminary results for SCD are promising. At the time of writing this article, the FDA approved Zynteglo (betibeglogene autotemcel) — the first cell-based gene therapy for the treatment of adult and pediatric patients with beta-thalassemia (a disorder related to SCD) who require regular red blood cell transfusions.

Bone Marrow Transplant

Bone marrow transplant (BMT) remains an important treatment option for SCD, with the potential to cure the disease. It’s not available or optimal for all patients though.

“Obviously transplant is not like taking a medication. It’s an involved process. But there are certain patients for whom transplantation, if possible, is a good choice,” said Darbari. For example, “for someone who is on chronic transfusion, we know that sooner or later this will become a serious problem for them. Those patients, in my mind, are very likely to be the best candidates for transplantation as early possible.”

BMT is also limited by human leukocyte antigen (HLA) matching with the best results coming from related donors, like full brothers or sisters. It’s estimated that only 20% to 30% of candidates have an exact match.

Work is ongoing to improve success with unmatched related donors, matched unrelated donors, and unmatched unrelated donors to expand the number of patients who can be cured with BMT.