Episode 112: Sickle Cell Series - Chronic Management of Sickle Cell Disease
In this week’s episode, we discuss the management of sickle cell disease in the chronic setting. This is a follow up to episode 111 where we discussed acute management of SCD. And furthermore, this is also in addition to our prior discussion about long-term chronic complications from SCD in episode 110. We highly recommend checking out these prior episodes if you haven’t done so already!
What is the mechanism of action for hydroxyurea SCD?
Prior to its discovery, intermittent transfusions were used.
Exact mechanism is unknown but it increased HbF.
Mild immunosuppression induced by hydroxyurea counteracts pro-inflammatory effects of sickle cell disease.
Direct nitric oxide release from breakdown of the hydroxyurea molecule could counteract some of the NO scavenging related to chronic hemolysis
What is the history of hydroxyurea?
1970s- noted HbF red cells had longer survival than HbS red cells. Persistence of HbF is also noted to have milder disease phenotype.
Early 1980s- alterations in DNA methylation and chromatin modification increased HbF production, also with hypomethylating agents such as azacitidine (in animal models).
Mid 1980s- azacitidine noted to increase HbF but it is a chemotherapy and not a viable long term medicine.
Non-methylating agent cytostatic hydroxyurea shown to increase HbF levels.
Early 1990s- 1st phase I/II trial showed increased HbF levels with hydroxyurea.
1995- 1st RCT- Multicenter Study of Hydroxyurea in Sickle Cell Anemia
299 patients with >/=3 crises per year enrolled.
152 received hydroxyurea
Significant reduction in crises seen (2.5 vs 4.5 per year) and double the median time to first crisis (3.0 mo vs 1.5 mo)
ACS rates were ~½ the rate when compared with placebo.
Transfusion rates were fewer in the hydroxyurea arm.
Adverse effect: transient myelosuppression improved with 2 weeks off treatment.
1990s- hydroxyurea became a SOC in pediatric and adult patients with SCD
What baseline labs to obtain prior to starting treatment with hydroxyurea?
CBC with differential and reticulocyte count
B12, folate, and iron labs
Hydroxyurea causes macrocytosis. Make sure to check for any potential nutritional deficiencies
Baseline (pre-treatment) HbF fraction
Pregnancy test in individuals who could potentially be pregnant
What is the dosing strategy of hydroxyurea?
Starting dose:
Normal kidney function: 15-20 mg/kg/day.
Abnormal kidney function: 7.5 mg/kg/day.
Increasing the dose tolerated to therapeutic effect:
Increase every 8 weeks by 5 mg/kg/day until one of the following maxima is reached (whichever is reached at the lowest dose)
35 mg/kg/day total dosing
2500 mg/day total dosing
Other hematologic parameters that we need to monitor for:
ANC of 1500-3000 (if baseline is lower than 1500, use 1000 as the threshold)
Absolute retic of 80k - 100k/uL
Platelet count of 80-150k/uL
If the ANC drops below 1000 or the platelets below 80k, hold hydroxyurea until counts recover
If recovery is within a week, resume at the same dose
If recovery takes longer, reduce the dose by 5mg/kg/day when restarting
What are the other side effects of hydroxyurea besides myelosuppression?
GI side effects (nausea or reduced appetite)
Cutaneous side effects: leg ulcers (debatable if hydroxyurea effect or sickle cell related)
What is the impact of sickle cell disease on fertility?
In men: reversible impact on spermatogenesis; hold hydroxyurea for 3 months prior to attempting to conceive.
In women: hold hydroxyurea prior to conception. Hydroxyurea may reduce ovarian reserve with long-term treatment (area of active research).
Fetal health: increased risk for miscarriage or stillbirth with continuation, but no evidence of increased rate of congenital anomalies in humans. A few animal studies indicate teratogenicity.
In pregnancy: individualized decision whether to continue vs not based on disease phenotype.
What is the carcinogenic effect of hydroxyurea?
Older studies where the drug used for MPNs which carry a risk of leukemia development (confounding effect).
Observational cohort studies: Long term treatment in sickle cell disease showed no evidence of increased rates of cancer with hydroxyurea use.
What are the other disease modifying drugs for sickle cell disease other than hydroxyurea?
L-glutamine
Crizanlizumab
Voxelotor
What is the role of L-glutamine (brand name Endari) in sickle cell disease?
Amino acid L-glutamine - mixed evidence on meaningful effect on red cell sickling but role in NAD(H) synthesis, which could provide protective effects against oxidative damage.
2014- a phase 2 trial: no significant decrease in VOC through 48 weeks of follow up (p=0.07)
2018- a phase 3 trial (published in NEJM) (the approval came prior to this publication based on trial data that had already been presented at numerous conferences)
230 patients who had 2 or more VOC during the year prior to enrollment, in a 2:1 randomization to L-glutamine vs placebo
48 weeks of follow-up: median VOC were 3 in the L-glutamine group and 4 in the placebo group, with a similar trend in hospitalizations: 2 with L-glutamine and 3 with placebo.
Increased time to first crisis was also seen in the L-glutamine group, with median time of 84 days vs 54 days with placebo
There were high rates of study discontinuation in both groups, 36% in the L-glutamine group and 24% in the placebo group
Administered as a powder to be dissolved in liquid
Costs around $18-27k/year at time of recording.
Still unanswered questions regarding if it can be used in earlier lines.
What is the role of crizanlizumab (brand name Adakveo) in sickle cell disease?
A monoclonal antibody targeting P-selectin, which is an adhesion molecule thought to be important in mediating interactions between sickled red cells and the vascular endothelium - less vaso occlusion related to sickle cell disease
IV medication given on days 1 & 15 of 1st cycles, followed by every 28 days.
2019- approved by the FDA
SUSTAIN trial
198 patients with 2 or more VOC per year were enrolled and randomized 1:1:1 to placebo vs crizanlizumab 2.5mg/kg vs crizanlizumab 5mg/kg and the drug was given over the course of a year.
Median rate of vaso-occlusive crises/year (1.63 vs 2.98)
Median time to first crisis (4.07 months vs 1.38 months)
Adverse events: joint pains, diarrhea/vomiting, and infusion reactions that included chest pain and itching
STAND trial
Ongoing trial but prelim data available.
1:1:1 comparing placebo to crizanlizumab 5mg/kg and crizanlizumab 7.5 mg/kg
Mean number of VOC per year were 4.5 in the low dose criz group, 3.1 in the high-dose criz group, and 3.7 in the placebo groups
Median time to first VOC was 3.6 months for low dose criz, 6.2 months for high dose criz, and 6.2 months for placebo
Free from VOC requiring hospitalization in the first year of treatment was 29.8% in the low-dose criz group, 37.3% in the high-dose criz group, and 40% in the placebo group.
Image source: Source: x.com (formerly known as twitter). No copyright infringement intended.
When do we reach for crizanlizumab?
Consider adding if voc despite maximally tolerated hydroxyurea.
Consider starting if unable to adhere to/tolerate hydroxyurea.
Cost: $85-113k/year depending on the dose used.
What is the role of voxelotor (brand name Oxbryta) in sickle cell disease?
Voxelotor binds to alpha-globin, keeping hemoglobin in the oxygenated conformation, reducing polymerization.
FDA approved in 2021
HOPE (Hemoglobin Oxygen Affinity Modulation to inhibit HbS Polymerization) trial
449 patients who had between 1 and 10 VOC in the year prior to enrollment
Randomized 1:1:1 to receive voxelotor 1500 mg, voxelotor 900 mg, or placebo over the study period of 72 weeks
Outcomes: incidence of VOC, change in hemoglobin and other biochemical markers for hemolysis.
Increased Hb by >1g/dL
VOC incidence: unimpressive with a median of 2.5/year for high-dose voxelotor, 3.0/year for low-dose voxelotor, and 3.1/year in the placebo group, with overlapping confidence intervals.
Markers of chronic hemolysis: median change from baseline hemoglobin was +1.3 in the voxelotor 1500 mg group, +0.7 in the voxelotor 900 mg group, and 0.0 in the placebo group.
Adverse effects: gastrointestinal
Best use: patients with symptomatic anemia primarily secondary to sickle cell disease.
Post-hoc analysis: voxelotor may help with leg ulcer pain and healing, so this is also considered an indication for starting treatment, but definitive evidence for this practice is lacking.
Cost: ~$100,000/year
What are non-pharmacologic ways to reduce crises and optimize health in sickle cell disease?
Routine screening (check out previous episode show notes)
Sleep hygiene
Hydration, nutrition, mental health
Avoid tobacco, inhalation of toxins.
How do we manage perioperative transfusions/complications in sickle cell disease?
Simple transfusions >10g/dL to improve O2 delivery.
Side effects of transfusion: iron overload, alloimmunization, volume overload, hemolytic transfusion reactions.
What guidance should we provide in the perioperative period for a patient that is planned to undergo an upcoming surgery?
The TAPS trial (to assess the benefit of RBC transfusion in the perioperative setting)
67 patients with HbSS or HbSbeta0 were randomized to preoperative transfusion 10 days prior to surgery or no preoperative transfusion.
The trial stopped early, as interim results showed that 39% of patients in the control arm had clinically important complications where only 15% of patients in the transfusion arm did.
Patients with baseline hemoglobin of < 6.5 were excluded from the trial, so someone with a baseline hemoglobin in the low 6’s or high 5’s may not need to get all the way up to 10g/dL to have benefit from this strategy.
Patients with a higher baseline hemoglobin, 9 g/dL or greater, were actually given partial exchange transfusions to get their HbS down below 60%; patients with high baseline hgb should be considered for exchange on a case-by-case basis
Besides pre-operative transfusion:
Use intravenous fluids, maintain high oxygen saturation (SpO2 >95% ideally), frequent incentive spirometer use during recovery, including after discharge, to reduce risk for secondary PNA and acute chest.
Postoperative pain management is also a critical component of care.
References:
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The crew behind the magic:
Show outline: Dan Hausrath
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Srijan Valasapalli, Joshua Zweigle
Social media management: Ronak Mistry
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