Sickle Cell Disease: Updates on Newer Therapeutic Options
Clinicians are increasingly gaining experience with the recently introduced treatments for sickle cell disease (SCD). Although it is still too early to determine the utility of these therapies in preventing the sequelae and the long-term complications of SCD (eg, end-stage renal disease [ESRD]), the mechanisms for longitudinal observation are in place to study these important unknown elements.
What is your experience with the newer therapies for SCD, and what are you excited about for the future?
Associate Professor, Division of Hematology and Oncology
“I am excited to use our multicenter clinical registry GRNDaD to answer some of these important questions about the potential impact of these treatments.”
We have had hydroxyurea for some time, and now 3 newer agents (L-glutamine, crizanlizumab, and voxelotor) have received US Food and Drug Administration (FDA) approval and are available for patients with SCD.
It is too early to determine the utility of these newer therapies in preventing the sequelae and the long-term complications of SCD such as ESRD, but I am excited to use our multicenter clinical registry Globin Research Network for Data and Discovery (GRNDaD) to answer some of these important questions. GRNDaD was developed by physicians who treat SCD to collect longitudinal data on patients living with the disease and on the potential impact of these treatments. Further, GRNDaD can be used to measure quality improvement, real-time implementation of novel therapies, and real-world comparative assessments of both single-agent and multiagent treatments.
While vaso-occlusive crisis (acute pain crisis) is often the focus of treatments, we need to examine the impact of these therapies on end-organ complications. For example, chronic kidney disease is common in patients with SCD, with many adults eventually developing ESRD or chronic kidney disease that could progress to ESRD. Thus, it is gratifying to see that crizanlizumab is being evaluated in a study exploring its effects on kidney function in patients with SCD with chronic kidney disease due to sickle cell nephropathy (NCT04053764).
However, it is not just the novel medications and those in development that we are excited about. Gene therapies are promising and are under investigation. We have certainly seen an increase in both allogeneic transplantation and gene therapy in recent years. A very important question with these therapies is that of organ function, so having very solid pre- and posttreatment organ assessments are important to see organ stabilization and/or the improvement of long-term organ function.
Professor of Pediatrics and Medicine
“The three newly FDA-approved therapies and hydroxyurea could be studied in a factorial, randomized, controlled trial to determine the optimal treatment combinations, if any. Hopefully, the SCD community can come together and submit such an application. . . .”
As Dr Kanter noted, obtaining longitudinal data is a critical issue for informed decision making and patient management. Based on longitudinal studies in children, we now know that 99% of children born with the disease in the United States live into adulthood. We expect children born with SCD today to become adults. As a result, the SCD that we see today is no longer the disease that many of us experienced 20 years ago. However, in comprehensive SCD programs, the median survival age for adults with SCD (ie, roughly 50 years) has not changed substantially over 30 years.
I agree with the importance of organ function assessments before and after interventions such as gene therapy, gene editing, haploidentical transplantation, or match-related donor transplants. An interesting question remains regarding whether a patient with SCD today who receives potentially curative therapy can significantly extend survival. That is, let us say that we have “cured” the SCD. The families and health care providers must know whether we have attenuated or accelerated progressive heart, lung, or kidney disease and how the curative therapy compares with the recently FDA-approved therapies L-glutamine, voxelotor, and crizanlizumab, as well as with the well-established, FDA-approved therapy hydroxyurea.
The three newly FDA-approved therapies and hydroxyurea could be studied in a factorial, randomized, controlled trial to determine the optimal treatment combinations, if any. Hopefully, the SCD community can come together and submit such an application to the National Heart, Lung, and Blood Institute to help support these multimodal therapy trials to ascertain which combinations alleviate pain and suffering and improve long-term clinical outcomes. The field needs some systematic approach to determine how to use the FDA-approved therapies.
Associate Professor of Pediatrics
“It will be important to compare the potential added efficacy and safety benefits of the newer treatments with the potential benefits of the older therapies.”
To dovetail with Dr DeBaun’s thoughts on clinical trial designs and future investigations with the newer therapies, I think that it will be important to compare the potential added efficacy and safety benefits of the newer treatments with the potential benefits of the older therapies. For instance, if you start a toddler with SCD on hydroxyurea and they have an excellent response, what is that protective effect on that child’s end organs in adulthood compared with the level of protection in the scenario that we were just talking about (eg, a patient who, as an adult, receives a haploidentical transplantation)?
At present, there will be some patients at a typical pediatric facility who are on one of the new drugs mentioned previously (ie, crizanlizumab or voxelotor), but this is a minority of patients, in part because many children have now been started and maintained on hydroxyurea from very early on. From the transfusion medicine perspective, I see the potential utility of voxelotor in heavily alloimmunized patients, in whom transfusion may be a challenge.
Some of our patients may eventually move on to transplantation, the only curative treatment for SCD. Many of the parents of pediatric patients are looking toward curative treatments and are therefore moving forward with transplantation earlier or are receptive to curative therapies as they emerge. We have a dedicated clinic called the Sickle Cell and Red Cell Disorders Curative Therapy Center (CuRED) at Children’s Hospital of Philadelphia where we discuss options including allogeneic stem cell transplantation and ongoing clinical trials for gene therapy–directed curative treatment. This is an exciting time for new therapies and curative options for SCD.
Allali S, Taylor M, Brice J, de Montalembert M. Chronic organ injuries in children with sickle cell disease. Haematologica. 2021;106(6):1535-1544. doi:10.3324/haematol.2020.271353
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. doi:10.1056/NEJMoa1611770
ClinicalTrials.gov. Study exploring the effect of crizanlizumab on kidney function in patients with chronic kidney disease caused by sickle cell disease (STEADFAST). Accessed July 12, 2021. https://clinicaltrials.gov/ct2/show/NCT04053764
DeBaun MR, Ghafuri DL, Rodeghier M, et al. Decreased median survival of adults with sickle cell disease after adjusting for left truncation bias: a pooled analysis. Blood. 2019;133(6):615-617. doi:10.1182/blood-2018-10-880575
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. doi:10.1056/NEJM0a1715971
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. doi:10.1056/NEJMoa1903212