expert roundtables

The Evolving Treatment Landscape for Sickle Cell Disease

by Stella T. Chou, MD; Michael Rutledge DeBaun, MD, MPH; and Julie Kanter, MD

Overview

Established treatments for sickle cell disease (SCD), such as hydroxyurea, have significantly improved outcomes. As novel therapies that target distinct aspects of the pathophysiology of SCD emerge, there is a great deal of interest in their use. The advent of these newer therapies may presage an increasingly multimodal approach to the treatment of SCD.

Q:

How are established and emerging therapies for SCD changing clinical practice?

Julie Kanter, MD

Associate Professor, Division of Hematology and Oncology
Director, Adult Sickle Cell Program
Codirector, Lifespan Comprehensive Sickle Cell Center
University of Alabama at Birmingham
Birmingham, AL

“I find it exciting that we now have multiple disease-modifying agents for SCD, and my patients are equally excited to learn more about these newer treatment options. Patients want options, and they appreciate knowing that hydroxyurea is a choice, but not their only choice.”

Julie Kanter, MD

My focus is on adults living with SCD, and many more children in high-resource countries are surviving into adulthood today. We are also starting to better understand their comorbidities and predictors of complications. Continuity of care and access to specialized care remain issues for many. One concerning pattern is that of a child, say 10 to 12 years of age, who falls out of care while feeling reasonably well, only to show up again at the age of 21 years with a host of new complications, increased pain, and morbidity. In my practice, hydroxyurea, while effective, has been much more of a game changer for children than for adults who have a significant number of comorbidities. Further, there are many patient concerns about hydroxyurea, including its safety and its side-effect profile. I estimate that, among adults who are offered hydroxyurea in my practice, 70% will try it and only 40% of those patients will continue to take it on a regular basis.

Thus, we have seen a great deal of interest in newer therapies, simply owing to the unpopularity of hydroxyurea. We have had many patients who are interested in starting a newer therapy and stopping hydroxyurea, and I explain the importance of multimodal therapy to these individuals. Novel therapies for SCD include crizanlizumab, voxelotor, and L-glutamine.

Crizanlizumab is a selectin blocker that was recently approved by the US Food and Drug Administration (FDA) to reduce the frequency of vaso-occlusive crises based on data from the phase 2 SUSTAIN trial, which showed a median annual rate of vaso-occlusive crises leading to health care visits of 1.63 with crizanlizumab 5.0 mg/kg vs 2.98 with placebo, or a 45.3% reduction with crizanlizumab compared with placebo. The annual crisis rate was 32.1% lower with crizanlizumab than with placebo among those taking hydroxyurea and 50% lower among those who were not taking hydroxyurea. Intravenous infusion of crizanlizumab is on week 0, week 2, and every 4 weeks thereafter, and, in my experience, patients with frequent pain crises tend to be very accepting of monthly administration and are actually usually appreciative that their pill burden is not increased. Voxelotor is a hemoglobin S polymerization inhibitor that recently received FDA approval for the treatment of SCD. I believe that there has been less uptake of voxelotor, in part because it increases the pill burden (ie, 3 tablets daily) but also because it does not seem to significantly decrease pain, at least based on early data. The increase in hemoglobin that is achieved with voxelotor use is not sufficient (or equal in efficacy) to replace transfusion therapy in patients at risk for stroke. L-glutamine, an antioxidant agent, was recently FDA approved for the reduction of acute complications in patients with SCD. I am not yet certain of the overall impact of L-glutamine in SCD, but we have many adult patients who are interested in naturopathic medicine. I offer L-glutamine as an option, as a natural alternative.

I find it exciting that we now have multiple disease-modifying agents for SCD, and my patients are equally excited to learn more about these newer treatment options. Patients want options, and they appreciate knowing that hydroxyurea is a choice, but not their only choice.

Michael Rutledge DeBaun, MD, MPH

Professor of Pediatrics and Medicine
Vice-Chair for Clinical and Translational Research
J.C. Peterson Endowed Chair in Pediatrics
Director, Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease
Vanderbilt University Medical Center
Nashville, TN

“Favorable clinical outcomes among children with SCD have increased dramatically in high-income countries. With therapeutic advancements in SCD, we have seen a dramatic decline in the mortality rate for children, and there have been substantial improvements in academic attainment and quality of life.”

Michael Rutledge DeBaun, MD, MPH

The treatment for SCD has changed significantly over the last 40 years, and favorable clinical outcomes among children with SCD have increased dramatically in high-income countries. In the 1980s, folic acid and penicillin were the only options available for newborns and children with SCD. Vaccinations to prevent life-threatening bacterial infections were only available for children over the age of 2 years. At that time, the mortality rate for patients with SCD in high-income countries during the first 5 years of life was 20%. With therapeutic advancements in SCD, we have seen a dramatic decline in the mortality rate for children, and there have been substantial improvements in academic attainment and quality of life. SCD is no longer considered a debilitating disease associated with a shortened lifespan. In fact, multiple cohort studies have shown a 99% overall survival rate among newborns with SCD who were followed into adulthood. In addition, we have seen a decrease in comorbidities, including stroke, among patients with SCD. In the past, approximately 11% of children (<18 years) with hemoglobin SS disease had a stroke. Today, the rate of strokes is less than 1% through screening with transcranial Doppler and the treatment of high-risk patients with initially chronic blood transfusions and, later, hydroxyurea in a select group.

We have noticed that the vast majority of individuals with SCD who have received comprehensive medical care from birth through 20 years of age are doing well, particularly those with the more severe genotype (hemoglobin SS) who have been adherent to hydroxyurea throughout childhood and adolescence and remain on this therapy as adults.

Stella T. Chou, MD

Associate Professor of Pediatrics
Chief, Division of Transfusion Medicine
Children’s Hospital of Philadelphia
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA

"Over the last decade, one of the biggest impacts to our clinical practice has been the wider use of hydroxyurea in pediatrics. In recent years, newer therapies have been developed that target different aspects of the pathophysiology of SCD, and I am optimistic that these therapies will one day play a role in the treatment of my pediatric patients.”

Stella T. Chou, MD

From the perspective of pediatric hematology, my experience with the more recently introduced disease-modifying therapies for SCD is limited, but I anticipate that this experience will grow in time. Now that hydroxyurea is offered to nearly every child with SCD, we have seen a dramatic decrease in the number of vaso-occlusive episodes and hospitalizations for acute chest syndrome. We have also observed a decline in the number of children with abnormal transcranial Dopplers, which correlates with a decline in the need for chronic transfusion therapy. So, over the last decade, one of the biggest impacts to our clinical practice has been the wider use of hydroxyurea in pediatrics. In recent years, newer therapies have been developed that target different aspects of the pathophysiology of SCD, and I am optimistic that these therapies will one day play a role in the treatment of my pediatric patients.

References

Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5-11.

Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-439.

Carden MA, Little J. Emerging disease-modifying therapies for sickle cell disease. Haematologica. 2019;104(9):1710-1719.

Chaturvedi S, DeBaun MR. Evolution of sickle cell disease from a life-threatening disease of children to a chronic disease of adults: the last 40 years. Am J Hematol. 2016;91(1):5-14.

Kutlar A, Kanter J, Liles DK, et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. Am J Hematol. 2019;94(1):55-61.

Matte A, Zorzi F, Mazzi F, Federti E, Olivieri O, De Franceschi L. New therapeutic options for the treatment of sickle cell disease. Mediterr J Hematol Infect Dis. 2019;11(1):e2019002. 

Niihara Y, Miller ST, Kanter J, et al; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A phase 3 trial of l-glutamine in sickle cell disease. N Engl J Med. 2018;379(3):226-235. 

Quinn CT. l-Glutamine for sickle cell anemia: more questions than answers. Blood. 2018;132(7):689-693. 

Riley TR, Riley TT. Profile of crizanlizumab and its potential in the prevention of pain crises in sickle cell disease: evidence to date. J Blood Med. 2019;10:307-311.

Vichinsky E, Hoppe CC, Ataga KI, et al; HOPE Trial Investigators. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519. 

Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016;387(10019):661-670.

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