34 Hematologic Symptoms

Barbara Speller-Brown, Jillian Campbell, Allistair Abraham, Priyal Patel, Lisa Humphrey, and Jennifer Webb

Many patients develop hematologic symptoms requiring medical intervention. As suggested in the poem, the manner in which we go about attending to these symptoms can be as important as relief of the symptoms. In this chapter, we address hereditary anemias focusing on sickle cell disease (SCD); platelet disorders, including thrombocytopenia; bleeding disorders; and thrombosis. In each section, the critical roles of an interdisciplinary team will be highlighted (see Figure 34.1).

Palliative Domains and Hematologic Conditions

Modern medical advancements have improved the survival rates of several hematologic illnesses that were once considered fatal. The treatments discussed throughout this chapter have helped many patients live well into adulthood. While these advancements have improved the quantity of life for many, these patients are still faced with enormous challenges that impact quality of life. Therefore, the potential role of palliative care for these patients is immeasurable.

Palliative care encompasses the following domains of care: (1) structure and process, (2) physical health, (3) psychological and psychiatric health, (4) social health, (5) spirituality and religion, (6) culture, (7) end-of-life care, and (8) ethics and legality.^1,2,3 Depending on the underlying condition, children with hematologic conditions experience significant symptomatic and psychosocial burdens that are impacted by chronic pain, treatment side effects, multiple hospitalizations, and missed days from school/work. For example, the authors of the aforementioned poem depict perfectly the internal and external struggles associated with living with SCD. Such people are faced with sudden-onset, intense pain episodes referred to as “pain crises,” infections, and disease complications that lead to multiple hospitalizations, missed days from school, social separation from their healthy peers, mood dysfunction, and existential hardships. In addition, some people express feeling isolation from the medical community who may not always recognize the severity of their pain and other symptoms, which can add to their overall distress. The burdens of living with such chronic illnesses also extend to caretakers in the form of financial, emotional, and social stress. Healthy siblings also feel the impact as they often grapple with their own emotions around “survivor” guilt, redefinition of their role in the family, hidden grief, and unintended benign neglect from their parents.

Unfortunately, specialty palliative care is often overlooked in these patients as there may be a misconception that palliative care should be reserved for patients with a terminal illness. Hospice care, which is defined as end-of-life management for people who have an estimated survival of fewer than 6 months, is only a small part of specialty palliative care.⁴ This distinction is crucial to define when considering specialty palliative care for patients with chronic hematologic conditions. In fact, pediatric palliative care offers much more than end-of-life care and should be considered for any patients who have a life-limiting or life-altering illness. The World Health Organization defines palliative care as care (1) that is providing pain and symptom management; (2) does not postpone or hasten death; (3) starts at diagnosis and is continued regardless of what treatment is offered; (4) encompasses a holistic mind, body, and spirit approach; (5) includes family support and coping; (6) can be provided in the inpatient, outpatient, and/or home settings; (7) includes a broad multidisciplinary approach; and (8) includes physical, psychological, and social health.⁵ Under this definition, palliative care offers a comprehensive approach to taking care of children with serious hematologic conditions.

Sickle Cell Disease

SCD is a group of autosomal recessive hemolytic anemias characterized by erythrocytes that have a propensity to change into “sickle” or crescent shapes.⁶ It is a multisystem disease that is associated with episodes of acute illness, vaso-occlusive crisis, chronic inflammation, and progressive multisystem organ damage.⁷

Background

SCD affects millions of people around the world and is the most common genetic condition identified via newborn screen in the United States.⁸ It affects approximately 1 out of every 365 black or African American births and 1 out of every 16,300 Hispanic American births.⁹ Approximately 100,000 people are living with SCD in the United States.

SCD previously was considered a childhood disease since many patients did not survive into adulthood.⁸ The introduction of vaccines that protect against invasive pneumococcal disease led to a 42% decrease in sickle cell–related deaths in children younger than 4 years.⁹ Today, more than 95% of children with SCD survive to adulthood. However, the average life expectancy for people with SCD is just 40 years.⁸

The most common form of SCD, hemoglobin SS (sickle cell anemia), is caused by the inheritance of two sickle beta-globin genes, one from each parent.¹⁰ Other forms of the disease are caused by inheritance of one sickle beta-globin gene plus another beta-globin chain defect¹⁰; the most common heterozygous forms of SCD are hemoglobin SC disease, hemoglobin S/beta+ thalassemia, and hemoglobin S/beta0 thalassemia. People with hemoglobin SS and hemoglobin S/ beta0 thalassemia have no normal beta-globin production. They generally have a more severe clinical course compared to people with hemoglobin SC disease and hemoglobin S/ beta+ thalassemia. However, phenotypic severity can vary significantly among patients.¹¹

Acute vaso-occlusive (VOC) pain is the hallmark of SCD, which is caused by entrapment of rigid, deformed erythrocytes in the microcirculation causing tissue injury.⁷ The process of sickling and unsickling continues until the erythrocyte membrane is no longer flexible, and irreversibly sickled cells undergo hemolysis.⁶

The shift in mortality from childhood to adulthood has led to an increase in serious morbidity among teens and young adults.⁸ Chronic inflammation and vascular damage lead to progressive vasculopathy, which is characterized by systemic and pulmonary hypertension, endothelial dysfunction, and proliferative changes in the blood vessels. Parenchymal damage develops in nearly every organ system of the body, including the brain, eyes, lungs, heart, kidneys, and bones.

Symptoms and Management

Medical management of SCD generally focuses on detection and prevention of severe complications, as well as alleviating acute and chronic symptoms. Early in life, prophylactic antibiotics, supplemental vaccines, and hydroxyurea (HU) may avoid long-term complications of SCD. Folic acid may be supplemented to support red cell production. Complications can be acute (have a rapid onset and are immediately obvious) or chronic (occurring over time with more subtle symptoms), but both can lead to organ damage and failure. Many symptoms of SCD can be managed through periodic outpatient clinic visits and patient education. However, hospitalization may still be indicated.

Pain

Patients with SCD are impacted by unpredictable amounts of intermittent and constant pain, known as VOC, that is often poorly managed over their lifetime.¹¹ Pain is often the hallmark feature of SCD, and unrelieved pain contributes to life-threatening complications, such as acute chest syndrome (ACS). Pain in SCD can be acute, chronic, or mixed, and can be related to tissue injury (nociceptive), nerve injury (neuropathic), or causes unknown (idiopathic). It is often not possible to differentiate between different types of pain.¹¹

Acute pain is the most common reason for emergency room visits and admission to hospital for both children and adults. A VOC can present as excruciating pain, most common in the extremities, back, and chest; however, it can occur anywhere throughout the body. Onset can be sudden or gradual and can last from hours to days to weeks. Common triggers for VOC include dehydration, infection, exposure to extreme temperatures (hot or cold), and stress. Frequent episodes of acute pain are associated with disease severity, low fetal hemoglobin concentrations, high hematocrit, and nocturnal hypoxemia.¹²

The management of acute pain is paramount in caring for patients with SCD. Often, the goal of treatment is to minimize the frequency and duration of hospitalizations and emergency room visits and facilitate home management of pain. Treatment of VOC often requires medication. Mild to moderate pain may be treated with nonsteroidal anti-inflammatory medications (NSAIDs), while moderate to severe pain may require oral opioid analgesia in addition to NSAIDs. For severe pain, parenteral (IV) opioids may be needed.

Opioids are the standard treatment for acute and chronic sickle cell pain. There is significant variability in analgesic effect of opioids among patients with SCD.¹³ Some of this variability can be attributed to genetic variations in opioid receptors and differences in drug metabolism. Therefore, treatment plans need to be individualized for each patient.

Intermittent injection of IV opioids versus patient-controlled analgesia (PCA) may be considered for a patient hospitalized with acute pain. Studies have shown variable outcomes comparing intermittent injection to PCA; subsequently, the choice of intermittent opioids versus PCA should be individualized to the patient. PCA initiation in the emergency room compared to PCA initiation after hospitalization is associated with fewer opioid boluses and less time without analgesic treatment.¹⁴

Patients with SCD often face stigma surrounding opioid use and potential for addiction. However, there is no evidence to support increased rates of addictions or association with the US opioid epidemic. Although adults with SCD have high opioid use, total opioid use across insurance payers has remained constant over time. In comparison, reported opioid use in a broader US population has increased to epidemic levels.¹⁵ Patients with SCD on opioids can and do develop tolerance, which is often confused with addiction, and is more common in SCD patients than opioid addiction. One study found that approximately 50% of emergency department providers have concerns about addiction when treating sickle cell patients.¹⁶ Inadequately treated pain can precipitate other SCD complications, and higher VOC rates correlate with early mortality in patients with SCD.¹⁷

Among sickle cell patients and healthcare providers, there is increasing interest in and acceptance of effective alternative treatments for sickle cell pain. Adjunctive, nonpharmacologic pain management approaches have been shown to be useful, including distraction, heat application, acupuncture, aromatherapy, and healing touch. Acupuncture is a well-tolerated intervention that is associated with improved pain scores in inpatient and outpatient settings.¹⁸ One study found that more than 90% of patients with SCD used some form of complementary and alternative medicine (CAM) to treat pain.¹⁹ Prayer, spiritual and energy healing, relaxation techniques, exercise, imagery, diet, and herbal medicines were among those alternatives. However, further studies are needed to measure their effectiveness.

It is important to collaborate with families when managing frequent and chronic pain, which can become a significant source of stress. Patients and their caregivers may have feelings of hopelessness and despair. Cognitive-behavioral therapy (CBT) should be considered for all patients with chronic pain and is associated with decreased admissions and hospital days.²⁰ A psychologist who is familiar with SCD can be especially helpful. Unanticipated emergency room visits, hospitalizations, and frequent office visits can lead to many missed work and school days. Loss of employment can occur, and children can be penalized for truancy. Many children fall behind in school due to frequent absences. Social workers can help to ensure all appropriate accommodations are in place at school through implementation of Individualized Education Plans (IEP) and that parents have appropriate accommodations at work, such as access to Family and Medical Leave (FMLA). Families may need the help of an education specialist to navigate complex school issues related to SCD.

Among the most debilitating effects of SCD are neurological complications, which occur in as many as one-third of patients with SCD. There is a peak of ischemic stroke during the first decade of life. Symptoms of ischemic stroke include aphasia, hemiparesis, facial droop, and sometimes seizures. Transcranial Doppler ultrasound (TCD) is a noninvasive means of identifying patients in childhood who are at highest risk of stroke. In the Stroke Prevention in Sickle Cell Anemia (STOP) study, chronic transfusion to keep Hb S below 30% reduced the risk of stroke by 90% in patients with increased TCD velocities.²¹ Adults with SCD more commonly experience hemorrhagic stroke, which may present with severe headache, altered level of consciousness, speech impairments, and/or paralysis. By the age of 20, approximately 7–17% of children and adolescents with sickle cell anemia will have sustained a stroke.^21,22 Neuroimaging is used to confirm acute stroke, and, if present, exchange transfusion should be performed (see the section “Transfusion Support”). Care for patients with stroke requires a multidisciplinary approach that includes neurologists, neurosurgeons, interventional radiologists, critical care physicians, and hematologists working collaboratively to optimize patient outcomes.²³ Unfortunately, children and adolescents with SCD who suffer a stroke are at high risk for subsequent strokes.

Silent cerebral infarcts (SCI), which are cerebral infarctions that occur without focal neurologic deficit by exam or history,²³ typically involve watershed areas of the frontal lobes of the brain. They reflect microvascular accidents that are detectable on radiography. Approximately 20% of children with hemoglobin SS disease have SCI, which are linked to neurocognitive problems, poorer educational attainment,²⁴ and greater risk of further brain injury.²⁵ Cognitive impairment also occurs without brain infarction and may be partially attributed to chronic anemia and brain hypoxia.²⁶

Infection

Patients with sickle cell are at increased risk for life-threatening bacterial infections, which are a major cause of morbidity and mortality. The increased susceptibility results from several causes: impaired splenic function, tissue ischemia, defects in complement activation, and micronutrient deficiencies. Several organisms are of particular risk to patients including S. pneumoniae, H influenza, non-typhi Salmonella species, and Escherichia coli.²⁷ The mortality rate among children with SCD who develop S. pneumoniae septicemia or meningitis is 11–24%.²⁸ Early intervention with prophylactic penicillin has become the standard of care. Patients with SCD who have a fever should be encouraged to seek prompt medical attention. Evaluation for infection should include a complete blood count (CBC), reticulocyte count, blood culture due to risk of bacteremia, chest x-ray if respiratory symptoms are present, and urine culture when urinary tract infection is suspected. Treatment includes broad-spectrum antibiotics.

Acute Chest Syndrome

The second most common cause of hospitalization in patients with SCD is ACS. It resembles pneumonia and is characterized by a new pulmonary infiltrate and signs of lower respiratory tract disease.²⁹ ACS is caused by a combination of infection, fat embolism, and vaso-occlusion of the pulmonary vasculature.

Evaluation of ACS should include chest x-ray, oxygen saturation measurements, CBC, reticulocyte count, and blood culture. Treatment includes broad-spectrum antibiotics and supplemental oxygen to maintain greater than 95% oxygen saturation. In some cases, bronchodilators and inhaled corticosteroids may also be appropriate. Severity of ACS varies, but about 13% of patients require mechanical ventilation, resulting in approximately 3% mortality.³⁰ ACS is the most common cause of death in adults with SCD. Blood transfusions or exchange transfusions may be utilized for severe cases with rapid deterioration in clinical status.³⁰ Deep breathing exercises and use of incentive spirometry can improve lung expansion in hospitalized patients.

Other complications of SCD are reviewed in Table 34.1.

Psychological and Social Stressors

Chronic illnesses like SCD can have a profound impact on patient and family psychosocial and social functions. Painful episodes, frequent emergency visits, and hospitalizations can negatively impact physical function, sleep, academic achievement, and overall quality of life.³¹ Patients are at greater risk for poor academic functioning, frequent school absences, social withdrawal, increased anxiety, and depression as compared to their healthy peers.³² This can have an impact on siblings and other family members as well.

Physical factors that place patients at risk for low-self-esteem, anxiety, depression, and social isolation include delayed puberty (patients are usually smaller than their peers), scleral icterus (due to constant breakdown of red blood cells), physical limitations (due to chronic anemia), and learning difficulties (due to silent and overt strokes).

Patients and families are best supported by comprehensive care that addresses both medical and psychosocial needs to better control the disease and ultimately maximize function.

Patient and caregiver education has been identified as an important part of comprehensive care. Improved parental knowledge for at-risk groups like SCD has been associated with increased treatment adherence, reduced frequency of complications, and alleviation of fears associated with SCD diagnosis.³³ This leads to improved disease management and outcomes.

Prevention, education, and management are important factors to consider when caring for a patient with a chronic illness like SCD. Routine screening for stressors and for internalizing symptoms may be particularly important for these patients, and interventions focused on identifying and treating psychological symptoms are essential. Interventions should be culturally sensitive and should focus on decreasing internalizing symptoms through supportive counseling, including CBT.

Blood transfusions are a critical disease-modifying therapy for patients with SCD. In general, leukoreduced, ABO, and RhD blood group–appropriate and cross-matched red blood cells (RBCs) are used to treat patients with symptomatic anemia. Leukoreduction removes a significant number of contaminating white blood cells, thus decreasing rates of cytomegalovirus (CMV) transmission, human leukocyte antigen (HLA) sensitization, and febrile nonhemolytic transfusion reactions.³⁴ For patients with SCD, transfusions carry an increased risk of alloimmunization, or antibody formation, to additional minor RBC antigens. This is thought to be due to their intact immune system and chronic inflammation, as well as to ethnic differences in the prevalence of minor RBC antigens. It is generally recommended to match a priori at ABO, RhD, RhCE, and Kell to avoid sensitization to these antigens.³⁵ Patients with SCD should receive sickle cell–negative blood so that determinations of hemoglobin S are solely reflective of the patient and can be reliably used to guide management. Blood banks should be made aware of the patient’s underlying disease, blood transfusion history, history of transfusion reactions or antibody formation, and any prior typing of minor antigens as these help guide them in choosing the best RBC units for the patient.

In patients with SCD, acute RBC transfusions are used to improve oxygen delivery to tissues during acute RBC aplasia or aplastic crisis, hemolytic crisis, or ACS. Chronic transfusions, often performed on a monthly basis, have been shown to decrease rates of primary and secondary strokes.^21,36 When performed chronically, the goals of transfusion are to improve baseline anemia as well as decrease percentage of circulating hemoglobin S through dilution and decreased RBC production. Often, the target is to decrease circulating hemoglobin S to less than 30%, which has been shown to be protective against complications of SCD. Chronic transfusion therapy has been shown to decrease the frequency of other SCD complications including VOC, ACS, and priapism. The role of chronic transfusion therapy to mitigate symptoms of renal disease, pulmonary hypertension, and retinopathy is less supported in the literature but often attempted given the severity of these complications.

Exchange transfusions, performed manually or with automated machines, may be used for acute transfusions during stroke, ACS, intrahepatic cholestasis/hepatic sequestration, or multiorgan failure.³⁷ This procedure is able to increase the hemoglobin in the patient while decreasing the hemoglobin S% in a short (<4 hours) period of time. It may be performed chronically on outpatients receiving chronic transfusion therapy to minimize iron overload, a universal complication of long-standing transfusion therapy. Exchange transfusions are generally well-tolerated but do require increased numbers of RBC units. Obtaining a sufficient number of appropriate units in patients with a history of alloimmunization may become challenging. Chelation therapies, which facilitate iron excretion, are available in IV, subcutaneous, and oral formulations, allowing for successful mitigation of transfusional iron overload in adherent patients. Patients receiving regular transfusions should be monitored closely for elevated ferritin levels, our closest noninvasive surrogate measure for assessing iron deposition in tissues. Other noninvasive measures, such as cardiac and liver magnetic resonance imaging (MRI) to measure iron load, are also helpful for optimizing chelation.³⁸

To raise the hemoglobin 1 g/dL requires a 3–5 mL/kg transfusion of RBCs. For a child with hemoglobin in the range of 7–9 g/dL, a reasonable transfusion is 10–15 mL/kg. For patients with chronic anemia, such as SCD, symptomatic anemia may not occur until the hemoglobin falls 2 g/dL below their baseline as the body has multiple methods for compensating for chronic anemia. However, for SCD patients receiving chronic transfusion therapy, often their target post-transfusion hemoglobin is raised to 11–11.5 g/dL.³⁹ Prior to ordering a transfusion of blood, the volume to be transfused should be determined by the patient’s condition, how quickly the anemia developed, the patient’s pre-transfusion hemoglobin, and the post-transfusion goal hemoglobin. The volume of RBCs should be administered over 2–4 hours in most situations. Repeat transfusions may be required to adequately improve hemoglobin levels for patients with poor red cell production or ongoing red cell destruction. For more profound, chronic anemia, smaller aliquots of 5 mL/kg of RBCs each transfused over 4 hours may help prevent the development of congestive heart failure.

In addition to alloimmunization and iron overload, transfusions carry additional risks for reactions. The most common reactions are febrile reactions and allergic reactions. If a reaction is suspected, the first course of action is to stop the transfusion and evaluate the patient. Acute hemolytic reactions may have a fever as one of their earliest symptoms, so a temperature increase, defined as greater than 1°C and/or greater than 38.0°C, in any patient receiving RBCs warrants further evaluation by the blood bank.⁴⁰ Depending on the patient’s underlying condition, further evaluation as to the source of the fever, empiric antibiotic administration, and admission to the hospital for observation may be necessary. Additional evaluation of the blood product may include a culture of the transfused unit depending on the likelihood of septic transfusion reaction. Prophylactic acetaminophen is often used to prevent febrile transfusion reactions; however, multiple studies have failed to demonstrate benefit.^41,42 Routine administration of acetaminophen prior to transfusion is not recommended unless the child has a personal history of transfusion reaction and there is no contraindication to using this medication.

Allergic reactions may vary from the appearance of a few hives to shortness of breath and bronchospasm to anaphylaxis. Mild reactions may resolve with diphenhydramine 0.5–1 mg/kg administered IV or orally, or hydroxyzine 0.5–1 mg/kg IV or 2 mg/kg orally. Severe reactions may require the additional administration of hydrocortisone or epinephrine, according to resuscitation protocols. Some institutions may premedicate patients with a history of allergic reaction with diphenhydramine prior to transfusion, if not contraindicated by patient condition, to try to prevent transfusion reactions. Washing, saline resuspension, or dilution of the product has been shown to prevent recurrent, severe allergic reactions; however, these manipulations may cause transfusion delays and loss of RBCs, thus decreasing transfusion efficacy.

HU has emerged as a useful, disease-modifying therapy in SCD. It was approved by the US Food and Drug Administration (FDA) in 1998 for adults, as a treatment option for patients with SCD,⁴³ and in 2017, it was approved for use in children. In sickle cell anemia, administration of HU switches on production of fetal hemoglobin, decreasing the percentage of hemoglobin S, reticulocyte, and neutrophil counts and altering expression of adhesion molecules.⁴⁴ It has been shown to reduce the frequency of acute painful episodes and ACS, reduce the need for hospitalization, and reduce the frequency of blood transfusions in patients with SCD.⁴⁵ HU has also been associated with increased life expectancy for patients with SCD.

Novel Treatments

Three new medications have become FDA approved for SCD since 2017. These new medications have the potential to decrease pain and long-term complications in patients (Box 34.1).

Erythropoietin is produced by the kidney in response to anemia. Hematopoietic stem cells differentiate along the erythroid lineage in response to erythropoietin. There are two erythropoietin formulations, epoetin-alpha, which is administered 2–3 times a week, and darbepoetin, which is longer acting. Unfortunately, recent studies have led to FDA warnings about increased thromboembolic events and increased risk for cardiovascular events in patients taking these medications.⁴⁶ Poor patient survival in some studies where epoetin was used has again raised questions about whether epoetin may be a growth factor for some types of cancer. The American Society of Hematology and the American Society of Clinical Oncology caution against the use of epoetins in patients with malignancy who are not receiving either chemotherapy or radiation therapy.⁴⁶

There have been theoretic concerns about erythropoietin use in SCD, especially in the absence of use with HU. These concerns include increasing the Hb S concentration, the number of Hb S-containing reticulocytes, and the hematocrit, thereby increasing the risk of hypertension and hyperviscosity.⁴⁷

However, epoetin-alpha may be useful for patients who object to blood transfusions on ethical or religious grounds, as do many of the Jehovah’s Witness faith.⁴⁸ Indeed, patients of the Jehovah’s Witness faith have taught us that severe anemia can be better tolerated than was initially supposed.^49,50 Additionally, they have helped drive the interest in development of blood conservation programs and blood alternatives. Blood alternatives, such as hemoglobin-based oxygen carriers, are acellular hemoglobin molecules and are in clinical trials in Africa and other countries. As yet, none is available for clinical use in the United States, but they may have a future role in treatment of anemia.

Blood and Marrow Transplant and Gene Therapy

The goal of transplantation of hematopoietic stem cells in SCD is to provide a permanent source of red blood cells that do not sickle. Healthy red blood cells are produced by the hematopoietic stem cells on a continuous basis and, similar to transfusions, address SCD by stopping further injury. Following a successful transplant, the patient is protected from further chronic organ injury and acute sickling events. Transplantation may be more efficacious than red blood cell transfusion for some organs such as the brain⁵¹ since the episodic nature of transfusions likely cannot match a constant delivery of healthy red blood cells as occurs following a transplant.

Donor hematopoietic stem cells sources include bone marrow, umbilical cord blood, and the peripheral blood of donors who have received a stem cell–mobilizing agent. The best blood and marrow transplant (BMT) donors are HLA-matched siblings. Transplants using these donors, especially in younger recipients, have excellent outcomes in SCD in the modern era with an approximate disease-free survival rate of 92%.^52,53 As such, the indications for BMT are being refined to be more inclusive and treat patients with a SCD genotype associated with a severe phenotype (HbSS and HbS/beta-zero thalassemia) early in the disease course.⁵⁴ Unfortunately, most patients do not have an HLA-matched sibling donor, and alternative donor options are being explored such as unrelated marrow donors, unrelated donor cord blood, and HLA half-matched or haploidentical donors (parents, siblings). These donor options are generally reserved for more severely affected patients to balance the risk-benefit ratio and are performed as part of a clinical trial.

The risks of BMT include acute complications that are primarily due to the chemotherapy or radiation used in the pre-transplant preparative regimen (e.g., mucositis, nausea, hair loss, cytopenias requiring blood and platelet transfusions, neutropenic infections). The main acute complication arising from the BMT graft is acute graft versus host disease (GVHD), which is an immune-mediated attack of the recipient’s skin, gastrointestinal (GI) tract, or liver by the donor T cells in the graft. The risk of severe acute GVHD, manifested as widely disseminated erythematous maculopapular rash, severe vomiting and diarrhea, and/or liver dysfunction is lowest in recipients of HLA-matched donor grafts (15%)⁵³ and is managed with systemic immunosuppression. Acute complications of BMT are generally managed inpatient and include intravenously delivered antiemetics, nasogastric feeding tubes, total parenteral nutrition, and PCAs. Nonpharmacologic approaches for symptoms include aromatherapy for nausea, massage, acupressure, and acupuncture (in non-neutropenic patients with appropriate platelet counts). The most widely used approaches to BMT for SCD involve myeloablative chemotherapy, and the typical hospitalization period is 4–6 weeks. This period can be particularly stressful as the patient is restricted to the room for infection prevention. Thus, a concerted effort is made to include coping strategies facilitated by a variety of healthcare professionals such as child life specialists, art therapists, music therapists, and child psychologists.

In the long term, chemotherapy can also cause organ toxicity, and patients are monitored annually after BMT for organ dysfunction.⁵⁵ Due to the multiple organ systems that can be affected, a multidisciplinary team of specialists including pulmonologists, endocrinologists, neurologists, and cardiologists perform assessments of organ function. Most patients may not experience significant organ toxicity; however, gonadal function can be particularly affected and the majority of girls (>70%) need hormone supplementation.⁵⁶ Counseling about fertility preservation prior to BMT is thus of great importance, with sperm and oocyte collection being routinely offered pre-BMT. Testicular or ovarian tissue collection and cryopreservation may also be offered at select sites with the appropriate expertise. The main long-term complication from the graft is chronic GVHD. It is manifested as skin and connective tissue fibrosis, resembling rheumatologic diseases such as scleroderma. Fortunately, chronic GVHD requiring long-term immune suppression after matched sibling transplant is rare (3%),⁵² but it is an important consideration since the manifestations are varied and can significantly impact quality of life. This complication may be more common with other donor types,⁵⁷ but rates of chronic GVHD remain to be determined given the ongoing optimization of non-sibling transplant approaches.

While the benefit of being cured of SCD is significant, further work is needed to limit the toxicity of BMT. Only 20–25% of the bone marrow needs to be replaced to achieve a cure since healthy red blood cells last longer than sickle red blood cells.^58,59 As a result, less intense BMT regimens are becoming more commonplace. The goal is to reduce the intensity of the preparative regimen while still maintaining good long-term engraftment, preferably without the need for prolonged immune suppression. There is growing experience with chemotherapy-free preparative regimens in adults and pediatrics,^60,61,62,63 with a multicenter trial in pediatrics under way (Clinicaltrials.gov, NCT03587272). In this trial, the health-related quality of life will be assessed with the expectation that, without chemotherapy, quality of life will be preserved and possibly improved.

To avoid acute and chronic GHVD, gene therapies using the patient’s own cells are being developed for SCD. Gene-based therapies for SCD are still early in clinical trials and have primarily involved gene transfer or gene editing of patient hematopoietic stem cells.⁶⁴ The first requires addition of a globin gene that can restore normal hemoglobin function and, in some cases, impart an anti-sickling effect to the red cell. The other strategy is to reinduce expression of fetal hemoglobin by targeting the “off-switch” BCL11A that normally stops the high level of fetal hemoglobin expression after the first year of life. This approach is expected to be beneficial in some of the same ways that HU is helpful, as fetal hemoglobin is not affected by the sickle mutation and has an anti-sickling effect. Future approaches still being evaluated in preclinical testing include correction of the sickle mutation using gene editing such as inducing double strand breaks and repair with a donor template⁶⁵ and also making corrections by replacing single bases.⁶⁶ The current unknowns about gene therapy include how efficacious these modalities will be; the longevity of the effects, especially with gene addition where there may be silencing of the transferred gene over time; and the long-term safety of making changes to the genome, including unintended off-target effects. The FDA has mandated 15 years of follow-up for all patients receiving gene modification to better understand these aspects.

Currently, chemotherapy-based conditioning is still used for gene therapy, so acute and long-term concerns still exist. However, as with BMT, there is a push to evaluate non-chemotherapy, non-radiation–based approaches such as a monoclonal antibody-based preparative regimen. An antibody targeting the cell surface marker CD117 on hematopoietic stem cells has been encouraging in animal models as a way to prepare the body for BMT.⁶⁷ With an antibody-based preparative regimen, there is the hope that gene therapy will represent a low-toxicity, highly efficacious, potentially curative strategy that will be available to essentially all patients.

The decision to proceed with a potentially curative therapy is a complex one and may be the most challenging scenario patients and families face regarding care for SCD. On the one hand, BMT is elective, and families must weigh the potential risks of the many possible complications including debilitating and life-threatening ones against the chance of disease eradication. On the other hand, electing to not proceed with a BMT leaves the patient at risk of ongoing complications and early mortality from SCD. The decision is made even more complex when considering when to proceed with such a therapy. While the best outcomes with the fewest complications occur when patients receive BMT at a younger age, a major complication or death as a young child would be grave. Historically, medical providers have waited for patients to have significant sequelae from their SCD, such as a stroke, before recommending the family consider BMT. However, this approach is becoming less common given the significantly improved outcomes of potentially curative therapies over the past few decades. As a result, families are informed about these therapies much earlier in their course, leading to HLA typing within the first year of life to determine if a matched sibling donor is available. Many families also store sibling umbilical cord blood in the event the new sibling is HLA-matched to the patient, as cord blood can be used for transplantation. The decision to proceed with transplant remains based on how risk-averse a patient or family is. Interestingly, a majority of patients (~70%) may accept anywhere from 5–30% mortality risk to achieve long-term disease eradication, and this does not seem to be impacted by disease severity. In contrast, only approximately 40% of these patients would proceed with a transplant that would leave them infertile.⁶⁸ Factors that may influence how patients make the decision to proceed to a transplant include presence of a strong support system, the availability of a matched sibling donor, and the education received about transplant.⁶⁹

Considerations for Adolescents and Young Adults

Although once a life-limiting disease, adolescents, and young adults (AYAs) with SCD now survive into adulthood.⁸ As a result, one major health challenge is helping AYAs transition from pediatric to adult care. Studies show that AYAs leave pediatric care without adequate preparation or readiness to transition.⁷⁰ AYAs express fear that their new adult provider will not know them, understand their disease process, or adequately treat their pain. The time period shortly after transition to adult care has been identified as a time for increased morbidity and mortality as AYAs often do not attach to a new adult hematology provider and use the emergency room as their source of primary care.⁷¹ Transition must be a coordinated, systematic process, and it is critical that healthcare providers develop transition plans to support comprehensive care. Plans should include disease education, assessing transition readiness for both patient and parent, developing self-care management skills and advocacy, finding a new hematology adult care team, and navigating insurance issues. Successful transition has been linked to improved health outcomes, resulting in significant reductions in morbidity and mortality with decreased healthcare cost.⁷² Dedicated transition programs are necessary to ensure a successful transition, and longitudinal studies are needed to understand the impact of SCD across the lifespan.

Related posts:

Quality in Pediatric Palliative Care Program Development The Language of Pediatric Palliative Care Relationships with Children and Ensuring Their Voices in Decision-Making Advanced Heart Disease Children’s Voices: The Experience of Patients and Their Siblings

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