Miscellaneous Complications of Hematopoietic Cellular Transplantation

Introduction

Advancements in hematopoietic cell transplantation (HCT) have been associated with expanding indications and eligibility, alternative donor options, and improvement in overall survival (OS). Yet, HCT for hematologic malignancies are still associated with the potential for significant toxicities that may be influenced by the primary diagnosis, prior treatment history (including but not limited to prior HCT and/or immunotherapies), comorbid conditions, and/or preparative regimen and/or donor source. Candidates for HCT undergo comprehensive medical evaluations to confirm eligibility and inform ultimate preparative regimen and donor selection. Acute toxicities associated with HCT can generally be classified as infectious or noninfectious. Infectious complications of HCT are outside the scope of this chapter. Toxicities of HCT may occur during administration of the preparative regimen, around HCT infusion, and/or following HCT ( Fig. 34.1 ). Early toxicities are usually related to the specific agents used as part of the preparative regimen. These agents and/or prior toxic injuries to the endothelium may also contribute to post-HCT endotheliopathies such as preengraftment or engraftment syndrome, venoocclusive disease (VOD) now more commonly referred to as sinusoidal obstructive syndrome (SOS), transplant-associated thrombotic microangiopathy (TA-TMA), and/or diffuse alveolar hemorrhage (DAH). Poor immune reconstitution post-HCT may be associated with clinical sequelae such as posttransplant lymphoproliferative disease (PTLD), which historically was associated with very poor outcomes. Patients undergoing HCT may also develop endocrinopathies, acute fluid overload, acute kidney injury, acute respiratory failure, and/or neurologic sequelae. A significant number of patients undergoing HCT may develop multiorgan dysfunction syndrome (MODS) and/or require critical care support. High vigilance and/or early initiation of specific therapies when available and/or appropriate supportive care may significantly mitigate toxicities.

Prehematologic Cell Transplantation Risk Factors for Toxicity

Before the introduction of the HCT-Comorbidity Index (HCT-CI) by the Center for International Blood and Marrow Transplant Research (CIBMTR), advanced age was the primary determinant of an adult patient’s ability to tolerate the conditioning regimens for allogeneic HCT. The HCT-CI, a composite score of 17 weighted comorbidities, was designed to capture organ dysfunction and modeled to predict nonrelapse mortality (NRM) among allogeneic HCT recipients ; its utility continues to be debated in the literature. Regardless of whether the HCT-CI is the optimal tool to predict NRM among post-HCT patients, it has become increasingly apparent that comorbidities influence treatment outcomes.

For example, preexisting hypertension may be exacerbated by the use of medications such as corticosteroids, tyrosine kinase inhibitors, proteasome inhibitors, and lifestyle choices such as smoking. Calcineurin inhibitors such as cyclosporine and tacrolimus can exacerbate hypertension and contribute to the risk of posterior reversible encephalopathy syndrome (PRES). Patients with hematologic malignancies who also have sickle cell disease may also be at increased risk for post-HCT complications such as PRES. Other comorbidities such as diabetes mellitus can result in poor stem cell mobilization thereby limiting apheresis yields in autologous collection and increase the risk of mucormycosis post-HCT.

The use of checkpoint inhibitors pre-HCT may be associated with a more robust donor T-cell response post-HCT, with the potential for enhanced graft-versus-tumor effect but also an increased risk of graft-versus-host disease (GVHD). Patients may also have ongoing toxicities from immune checkpoint inhibitors including colitis, transaminitis, and endocrinopathies. Patients with a history of prior HCT or repeatedly relapsed disease are heavily pretreated and are more likely to have baseline organ dysfunction and develop complications post-HCT. Arrhythmias and cardiac dysfunction, for example, are more likely in patients with prior anthracycline use and total body irradiation (TBI), and preexisting liver cirrhosis, iron overload, and use of monoclonal antibodies-inotuzumab and gemtuzumab are risk factors for developing SOS.

A history of prior infections can also impact the HCT course. Patients who are positive for hepatitis B or hepatitis C are at increased risk for SOS as well as viral reactivation and fulminant hepatic failure and should be evaluated to determine the utility of prophylactic or preemptive therapy. Patients with prior viral infections such as Epstein-Barr virus (EBV), cytomegalo-, adeno-, and herpes simplex viruses are at risk for viral reactivation, and patients with a history of invasive aspergillosis are at increased risk of invasive fungal disease post-HCT. EBV seropositive patients receiving allografts from seronegative donors or those undergoing T-cell depleted allogeneic transplantation are at highest risk for developing PTLD, and human immunodeficiency virus (HIV)-positive patients have a higher risk of developing opportunistic infections ( Fig. 34.2 ).

Recipient Medical Clearance

All patients must undergo a comprehensive evaluation including organ assessment and disease evaluation to confirm that they are medically suitable and eligible to proceed to HCT ( Table 34.1 ). Assessment of organ function can identify patients at higher risk for developing organ toxicities. Abnormal diffusion capacity for carbon monoxide and the alveolar-arterial gradient, for example, on pulmonary function tests are independent predictors for the need for mechanical ventilation and mortality post-HCT, and decreased baseline glomerular filtration rate (GFR) is a risk factor for acute kidney injury (AKI). Infectious disease screening to exclude active or occult infections is essential. The HCT team should work in close collaboration with a HIV specialist for patients undergoing HCT who are positive for the virus. Patients who have previously received an HCT should be evaluated for active GVHD as this represents a contraindication.

Pretransplant evaluation should also include screening for smoking, alcohol, or drug abuse. Screening tools such as Cut Down, Annoyed, Guilty, Eye-Opener (CAGE), opioid risk tool, and multisymptom assessment scales such as the Edmonton Symptom Assessment Scale may help universally screen and identify patients who are at risk for substance abuse disorders. Baseline neurocognitive testing should also be performed when feasible. Undoubtedly, HCT can result in many stressors that negatively impact a patient’s quality of life (QOL). These include physical stressors such as treatment-related toxicities requiring prolonged hospitalization, financial stressors as the patient and/or the caregiver is unable to work for extended periods of time, social stressors as patients may feel isolated or a physically separated from their support team, and psychologic stressors with high rates of cognitive impairment and exacerbation of underlying medical illness. Anxiety and depression are the most commonly reported mental concerns, seen in 15% to 40% of patients pre-, during, and post-HCT, and posttraumatic stress disorder is reported in 3% to 38% of patients undergoing HCT. All of these can lead to a high level of psychologic distress, which may be associated with worse health outcomes and decreased QOL. Psychosocial distress may manifest in a multitude of ways depending on the patient’s chronologic and developmental age. Toddlers and preschool children may experience separation anxiety from caregivers while older children and adults may experience changes in confidence, self-esteem, negative body image perceptions, and demoralization because of disease recurrence, treatment toxicities such as skin GVHD, alopecia, and neurocognitive decline. Ideally, patients should have psychologic screening pretransplant to identify underlying mental health concerns and stressors particular to each patient. Understanding specific ethnic, religious, and cultural practices that may impact outcomes may be important to proactively identify and discuss, and patients may also benefit from resources that allow them to share their experiences, fears, and hopes with peers.

Preparative Regimen and Toxicities

The preparative regimen is an essential component of HCT, administered before infusion of the cellular product. Preparative regimens can vary in intensity as outlined in Chapter 10 . Common short-term toxicities associated with preparative regimens include bone marrow suppression and cytopenias; hypogammaglobinemia; gastrointestinal (GI) symptoms such as nausea, vomiting, and diarrhea; and alopecia. In HIV-positive patients, it may be recommended to stop combined antiretroviral therapy during periods of therapy-related mucositis/enteritis to reduce GI toxicity. Some chemotherapy agents have higher toxicity risk associations, such as melphalan and mucositis, carmustine and pulmonary fibrosis, and busulfan and SOS. Busulfan has also been associated with seizures, and both busulfan and carmustine can cause hemorrhagic cystitis.

Acutely, transient parotitis and xerostomia can occur after high-dose TBI, and long-term effects include renal insufficiency, cataract formation, infertility, hyperthyroidism, thyroiditis, delayed puberty, and delayed growth and development in children. Secondary malignancies have also been associated with TBI and in up to 7% of patients postmelphalan ( Table 34.2 ).

Infusion-Related Toxicities

Cellular therapy infusion, while generally safe, may be associated with infusion-related adverse events (IRAEs). While the cryoprotectant dimethyl sulfoxide (DMSO) and the presence of dead cells have been implicated as a cause of infusion-related toxicity in patients receiving cryopreserved products, other studies have demonstrated a lower incidence of infusion-related toxicities in patients receiving cryopreserved products than those receiving fresh products. These findings suggest that there are other DMSO-independent, plasma factors that may contribute to infusion-related toxicities. The infusion of large product volumes (>100 mL in children), higher volume of DMSO in the product, stem cell source, and a history of transfusion reactions have been identified as risk factors for infusion-related toxicities. Other IRAEs risk factors include patient age and total nucleated cell dose.

Reported IRAEs include fever, chills, flushing, bradycardia, hypotension, hypertension, shortness of breath, chest pain, malodor, nausea, vomiting, abdominal pain, chest pain, back pain, and allergic reactions. If there is ABO mismatch between the donor and recipient or other red cell antigen incompatibility, acute hemolytic reactions can also occur and result in many of the aforementioned symptoms as well as bleeding, disseminated intravascular coagulation, and shock. Rare but life-threatening adverse events may also occur, including severe respiratory depression, cardiac arrythmias, and neurotoxicity.

Given the risk of infusion reactions, at the time of infusion, oxygen, suction, and emergency medications such as epinephrine, diphenhydramine, and corticosteroids should be at bedside or readily available. Premedication given before cellular infusion may vary based on institutional protocols. Patients may benefit from antiemetics and antipyretics to reduce the risk of nausea and febrile reactions. Antihistamines and corticosteroids can also be considered to decrease the risk of allergic reactions in patients receiving hematopoietic stem cells. Patients should also be adequately hydrated before product infusion, as free hemoglobin in the product or that generated because of ABO-mismatched HCT can be nephrotoxic. Careful attention should be paid to the patient’s urine output and overall fluid status, as infusion of large product volumes can result in fluid overload prompting the need for diuresis. Transfusion-associated circulatory overload can also occur and result in cardiogenic pulmonary edema. In the event of noncardiogenic pulmonary edema, transfusion-related acute lung injury should be considered.

Before infusion, the details of the cellular product and patient information should be verified and confirmed. Baseline vital signs should be obtained and patients should be closely monitored during and after the infusion for any IRAEs. The patient and/or caregiver should be counseled to report any symptoms such as chills, rash, shortness of breath, chest, back, or abdominal pain. General management principles for IRAEs include slowing or pausing the infusion if needed, verifying the product that is being infused, appropriate supportive care, and activation of emergency protocols as per institutional guidelines. Bacterial contamination of the product can also occur, so prompt empiric treatment with appropriate antibiotics should be initiated along with other supportive care for fever and hypotension. Early consideration should also be given to transferring the patient to a higher level of care if needed. Careful attention must also be paid to differentiate transfusion-related reactions because of blood products from transplant-related toxicities while patients are transfusion dependent.

Sinusoidal Obstructive Syndrome

SOS also known as VOD is a potentially fatal complication post-HCT. Toxic metabolites from the preparative regimen may trigger a cytokine cascade that results in endothelial injury. This may result in activation and damage of the sinusoidal endothelial cells and hepatocytes of zone 3 of the hepatic acini. This leads to defenestration and gaps in the sinusoidal barrier, allowing red blood cells, leukocytes, and cellular debris to pass through into the space of Disse below the endothelial cells so dissecting and detaching the endothelial lining. The sloughed endothelial cells then embolize downstream, leading to the progressive narrowing and obstruction of sinusoidal flow and occlusion of microcirculation, resulting in the clinical syndrome of SOS.

SOS typically develops within 3 weeks post-HCT, though late-onset disease may occur in 15% to 20% of cases and at an even higher rate in pediatric patients. The incidence of SOS can vary widely based on risk factors. SOS is known to disproportionately affect children and adolescents and young adult (AYA) patients with a reported incidence of 20% to 30% compared to <5% to 15% in adults post-HCT. Risk factors for SOS can be divided into patient/primary disease factors, treatment-related factors, and transplant-related factors ( Table 34.3 ). Proposed risk stratification systems to identify patients at highest risk for SOS remain to be validated in prospective studies. These include the CIBMTR system based on age, Karnofsky score, sirolimus use, hepatitis B and C status, conditioning regimen and disease, and the endothelial activation and stress index based on lactate dehydrogenase, creatinine, and thrombocytes. Liver stiffness as assessed by shear wave elastography (SWE) may represent an important noninvasive diagnostic modality of liver disease. Increased SWE velocity (area under the curve =.90), with a cutoff value of >1.95 m/s, was 87.5% sensitive and 85% specific for severe or very severe SOS, 2 to 13 days before the date of severe SOS grading. Similar findings were observed in a series of 78 adult patients who underwent HCT.

The diagnostic criteria used to diagnose SOS also significantly impact its reported incidence. Historically, diagnosis of SOS was made by the Baltimore, Seattle, or modified Seattle criteria based on hyperbilirubinemia, weight gain, ascites, and painful hepatomegaly. Reported incidence may vary two- to fourfold depending on the historical criteria used for adults and children. In 2016 and 2017, new diagnostic and severity criteria were established by the European Society for Blood and Marrow Transplantation (EBMT) for SOS in adult and pediatric patients, respectively. The new adult criteria accounts for patients who may have late-onset SOS (occurring >21 days posttransplant) and recognizes adults who may develop late-onset SOS in the absence of hyperbilirubinemia. As up to 30% of children develop anicteric SOS, the new pediatric criteria accounts for anicteric SOS as well as patients who may have a baseline bilirubin level >2 mg/dL. Importantly, the new pediatric criteria also include consumptive and transfusion refractory thrombocytopenia as a diagnostic criterion ( Table 34.4 ). In a single-center retrospective analysis of 226 pediatric and AYA HCT patients, the difference in the incidence of SOS using Baltimore, modified Seattle, and pediatric EBMT (pEBMT) criteria was 6.6%, 12.3%, and 15.9%, respectively ( P < .01). Retrospective application of the pEBMT diagnostic criteria identified 14 additional patients who were suspected but not previously diagnosed with SOS as they did not meet historical criteria.

Currently, SOS remains a clinical diagnosis. Liver biopsy is not recommended for diagnosis given the risk-benefit ratio of this invasive procedure. Updated severity grading for SOS have been established by EBMT, and mortality increases with disease severity ( Table 34.5 ). In one study of 203 pediatric patients in Korea with SOS, data was collected according to the modified Seattle diagnostic criteria and were analyzed for validation of the revised pEBMT severity criteria. According to the traditional severity criteria, none of the patients were mild grade, while 63.1% were moderate and 36.9% were severe grade. However, according to the revised pEBMT criteria, the majority of patients (63.1%) were very severe, 18.2% were severe, 12.8% were moderate, and 5.9% were mild grade. In this cohort, patients with very severe SOS showed a significantly lower OS than patients with milder grades (58.6 vs. 89.3%, P <.0001). These findings suggest that the pEBMT criteria may be both sensitive and specific for diagnosis and severity grading of SOS in children.

Current management of SOS includes definitive therapy with defibrotide and supportive care that includes avoidance of acute fluid overload, correction of coagulopathy and thrombocytopenia, and pain control. Importantly, prompt recognition of SOS and early intervention with definitive treatment with defibrotide has been associated with improved OS. Defibrotide is currently the only medication with proven efficacy for the treatment of severe/very severe VOD. This drug is a polydeoxyribonucleotide that acts locally in the hepatic region at a microvascular level and has antiischemic, antithrombotic, and antiinflammatory properties. While its exact mechanism of action has not been fully elucidated, it is thought to be protective of the endothelial cells and restore the body’s thrombotic-fibrinolytic homeostasis.

In the United States, defibrotide is approved for SOS with renal or pulmonary dysfunction after HCT, and it is approved for treatment of severe SOS syndrome in patients older than 1 month in Europe. The dose for defibrotide is 6.25 mg/kg every 6 hours given over 2 hours. Dose adjustments should be made in obese patients, and corrected body weight should be used for dosing; conversely, no dose adjustment is required for patients with renal failure or if receiving renal replacement therapy. While on defibrotide, patients should be monitored for thrombocytopenia and coagulopathy. The recommended duration of treatment with defibrotide by the U.S. Food and Drug Administration is 21 days or until there is resolution of multiorgan dysfunction and SOS, whichever is longer. For patients whose symptoms resolve before 21 days, it may be possible to stop treatment sooner with close monitoring, though this has not been validated in prospective studies.

Among patients with SOS, incremental measures should be implemented to maintain euvolemia. These include fluid restriction, inclusive of blood products, and maximally concentrating medications and parenteral nutrition. Controlled diuresis with care to avoid hemodynamic instability is recommended for progressively positive fluid balance. In patients with worsening fluid overload >10% despite medical management, electrolyte abnormalities, or progressive oliguria or anuria, renal replacement therapy (RRT) should be considered early. Paracentesis may be considered in children and AYA patients with ascites despite medical management, particularly in the presence of intraabdominal hypertension, abdominal compartment syndrome, or pulmonary dysfunction because of tense ascites. Volume-controlled drainage at an initial rate of 5 mL/kg/h is recommended to avoid sudden fluid shifts and hypotension. Similarly, thoracentesis is advised in this population for pleural effusions that are contributing to pulmonary dysfunction. Again, volume-controlled drainage is advised at 10 mL/kg (with a 1.5 L maximum within the first hour). Peritoneal drains and pleural drains can be clamped once drainage is <5 mL/kg/day and <3 mL/kg/day, respectively, and patients closely monitored for respiratory compromise, abdominal discomfort for those with peritoneal drains, and reaccumulation of fluid. In the absence of these finding, these drains may be removed. In adults, drainage is advised in the setting of ascites and/or pleural effusions if causing major discomfort or restrictive pulmonary syndrome.

Patients may experience pain from hepatomegaly, massive ascites, or from procedures such as thoracentesis or paracentesis. Appropriate pain control should be selected with renal, hepatic, or pulmonary impairment in mind. When possible, discontinuation of hepatotoxic medications, such as antifungals in the azole category, is recommended. Likewise, medications should be appropriately adjusted based on changing renal function. Nutritional support should be maintained and enteral nutrition is preferred.

Presently, there is no universally accepted prophylaxis for SOS, though ursodeoxycholic acid has shown promising results and has a favorable safety profile. The use of prophylactic defibrotide in pediatric patients post-HCT was associated with an incidence of SOS of 12% in the prophylactic group versus 20% in the control arm. A phase 3, multicenter, randomized study of pediatric and adult patients evaluating defibrotide for the prevention of SOS in high- and very high-risk patients for SOS was halted in April 2020 because of futility (primary endpoint: SOS free survival at day +30 post-HCT).

Currently, there are no universally accepted biomarkers for prediction or confirmatory tests for the diagnosis of SOS. While some biomarkers such as von Willebrand factor, thrombomodulin, and plasminogen, among others, show promise as markers of endothelial injury, they remain to be validated in clinical practice. In one study, hyaluronan with an area under the receiving operator curve of 0.81 on day + 7 and 0.79 on day +14 post-HCT was a strong single biomarker for development of SOS. In the future, a prognostic biomarker signature or ultrasound sheer wave elastography may identify patients with SOS or those at risk early after HCT, days to weeks before clinical diagnosis.