Non-infectious complications after bone marrow transplant: other organs toxicity II

Non-infectious complications after bone marrow transplant: other organs toxicity II

What every physician needs to know about non-infectious complications after bone marrow transplant: other organ toxicity II:

Definition and incidence

This section summarizes endocrine and central nervous system (CNS) complications of bone marrow transplantation.

Endocrine system complications can be subtle and therefore difficult to diagnose; they will affect quality of life. The three major organs or glands that tend to be affected after bone marrow transplant are thyroid, gonads, and bones. On the other hand, CNS complications can be acute or subacute and even cause mortality.

Endocrine organ complications

• Thyroid complications

Thyroid complications can be functional abnormalities or a mass lesion. The incidence was reported in 2-56% of patients. Symptomatic hypothyroidism is approximately 10-15%. The median time to onset of hypothyroidism is 4 years post hematopoietic stem cell transplantation (HCT). Hyperthyroidism is also reported (up to 3.1% in unrelated donor transplant).

• Hypogonadism

Hypogonadism is very common, occurs approximately in 90% of patients (more females than males). Loss of fertility is more common than sexual hormone deficiency.

• Osteopenia/osteoporosis

Osteopenia/osteoporosis is common after HCT (up to 70%) and defined by a scoring system on bone mineral density using dual-energy X-ray absorptiometry (DXA) as follows:

– Normal, T-score greater than or equal to -1.0

– Osteopenia (low bone mass), T-score between -1.0 and -2.5

– Osteoporosis, T-score greater than -2.5. Z scores are age adjusted measures.

CNS complications

• During conditioning regimen administration

Seizure secondary to drugs (busulfan is the most common drug to cause seizures and requires anticonvulsant prophylaxis). Other CNS toxic drugs include:

– Ifosfomide (encephalopathy, hallucinations, and non-convulsive status epilepticus).

– High dose cyclophosphamide and vinca alkaloids (SIADH).

– High dose cytarabine (acute cerebellar syndrome with ataxia, reversible occipital encephalopathy, polyneuropathy, carmustine (BCNU) (optic neuropathy).

– Fludarabine (posterior leukoencephalopathy syndrome (also known as posterior reversible encephalopathy syndrome [PRES]). PRES-associated symptoms are confusion, cortical blindness, visual hallucinations, seizures, and focal motor deficits. Fludarabine or other agents may cause acute toxic leukoencephalopathy (ATL). Progressive multifocal leukoencephalopathy is associated with JC virus.

• During stem cell infusion

Transient global amnesia or cerebral infarct is rare but reported during hematopoietic stem cell infusion.

• Post transplant

Before engraftment, seizure, confusion and delirium are most common mental status changes. If there is no focal neurologic deficit or magnetic resonance imaging (MRI) findings, mental status change is most likely secondary to systemic metabolic abnormalities, infections, or drug toxicity. If there are focal neurologic deficits, the most common causes are CNS hemorrhage (subdural hematoma), infection (particularly fungal), or drug toxicity.

• Immunosuppressive drugs related

Calcineurin inhibitors (CNI) (that is, cyclosporine and tacrolimus) cause CNS toxicity. The most common neurologic toxicities are tremor in hands and paresthesias. However, CNI also cause much severe toxicities and can be grouped in two groups, PRES (seizures, confusion, and cortical blindness) and motor dysfunctions (parkinsonism, ataxia, palsies, peripheral neuropathies, aphasia, and quadriparesis).

• Guillain-Barre syndrome (GBS)

GBS has been described following allogeneic hematopoietic cell transplantation (alloHCT). Etiology is unknown but may be associated with graft-versus-host disease (GVHD).

• Miscellaneous

Infections:

– Fungi (aspergillosis)

– Viruses (Human herpesvirus 6 [HHV6], herpes simplex virus [HSV], and Cytomegalovirus [CMV])

– Parasites (toxoplasmosis) – Malignancies in particular, post-transplant lymphoproliferative disorder (PTLD)

– Transplant-associated thrombotic microangiopathy (TMA)

GVHD involving CNS has not been documented or accepted as a real entity.

Risk factors

Thyroid dysfunction

Total body irradiation (TBI), single dose ablation (50%) versus fractionated (15%), busulfan and cyclophosphamide (Bu/Cy) conditioning (11%), history of prior head/neck radiation, younger patients (less than 10 years), history of presence of thyroid antibody.

Hypogonadism

Female sex, males undergoingalloHCT, TBI, single dose radiation, cranial irradiation, high cumulative dose of alkylating agents.

Osteopenia/osteoporosis

General risk factors for bone fracture: age, sex, history of previous fracture, steroid use, history of smoking.

HCT related mechanisms/contributing factors for osteopenia/osteoporosis: drugs (for example, steroids, CNI), organ dysfunctions (for example, gastrointestinal [GI] and malabsorption, renal failure, gonadal dysfunction, TBI).

CNS complications

• Fludarabine

Toxicity seems to be dose dependent, a severe neurotoxicity syndrome has been described at doses greater than 40 mg/m2/day.

CNI-induced toxicity

Risk factors beyond dose and plasma levels are not described, but hypomagnesemia (particularly with seizure), hypocholesterolemia, high-dose glucocorticoid therapy, arterial hypertension, and infections have been reported as risk factors.

Cytarabine induced toxicity

Older age (in particular greater than 55 years).

Subdural hematoma

Diagnosis of acute myelogenous leukemia (AML) and persistent thrombocytopenia.

• PRES

Thrombotic thrombocytopenic purpura, TMA, and cyclosporin A (CsA)/tacrolimus.

What features of the presentation will guide me toward possible causes and next treatment steps:

Symptoms/signs

• Thyroid dysfunction

Mainly hypothyroidism symptoms such as cold intolerance, dry-coarse skin, hair loss, paresthesias, periorbital edema. Nodule(s) can be palpated. Often asymptomatic.

• Gonadal dysfunction

Hypogonadism in men: Erectile dysfunction, low libido, fatigue, osteopenia, loss of muscle mass. In women: Amenorrhea, sexual dysfunction, osteopenia.

• Osteopenia/osteoporosis

Many patients can be asymptomatic; some may have back pain and height loss due to vertebral compression fractures or fractures of other bones, even without trauma.

• CNS

Seizure (busulphan), mental status changes, coma (ifosfamide), bilateral white matter changes, focal findings can be observed. In patients with mental status changes following ifosfamide, non-convulsive status epilepticus should be excluded.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Laboratory studies to be ordered

• Lumbar puncture

Cerebrospinal fluid (CSF) should be sent to:

– Microbiology for evaluation of viruses (Epstein-Barr virus [EBV], CMV, HSV, JC virus), fungi (Cryptococcus), parasites (toxoplasmosis), and bacteria (gram stain).

– Chemistry laboratory for protein and glucose (low glucose and high protein suggest bacterial infections).

– Pathology laboratory for cell count, cytology, and flow cytometry (PTLD). Opening pressure should be measured.

• Complete blood count (CBC) with manual differential

Schistocytes indicate thrombotic thrombocytopenia purpura (TTP)/thrombotic microangiopathy (TMA), absolute lymphocytosis may indicate PTLD (order flow cytometry from blood or consider doing bone marrow aspirate and biopsy).

• Chemistry

-Calcium, Sodium (hyponatremia can be seen in hypothyroidism), magnesium, renal functions, vitamin D3, parathormone levels. LDH is elevated in TMA.

-EBV DNA in plasma, EBER in tissue (from bone marrow or other organs), clonal Ig gene rearrangement.

-Serum protein electrophoresis may reveal oligo- or monoclonal gammopathy associated with EBV and PTLD.

• Thyroid function tests

-Thyroid stimulating hormone, free T4, and free T3. Thyroid autoantibodies (for example, antibodies against thyroid peroxidase, thyroglobulin, or microsome).

-In differential diagnosis of hypothyroidism, exclusion of euthyroid sick syndrome (ESS) (FT4 can be normal or decreased, serum FT3 is decreased, thyroid-stimulating hormone [TSH] is normal) is important, because ESS can be common in transplant patients and does not require thyroid replacement therapy.

-Serum follicle-stimulating hormone (FSH), inhibin, and testosterone levels, and sperm counts for males; serum FSH, luteinizing hormone (LH), estradiol, and progesterone levels for females.

What imaging studies (if any) will be helpful?

Helpful imaging studies

• CT of brain

CNI toxicity (PRES): Decreased density of the cerebral white occurs approximately in 50% of patients with symptoms. These changes mostly involve bilateral occipital cortex, cerebellum, periventricular substance, and brainstem.

• MRI of brain

CNI toxicity: PRES induces high-signal multiple lesions are seen on T2-weighted sequences in the white matter at the same sites mentioned above in the CT section.

Cytarabine toxicity: High-intensity lesions in the central white matter on T2-weighted sequences.

Fungal infections/emboli: Multiple non-enhancing hypointensity lesions in basal ganglia, cerebral hemispheres, and corpus callosum.

Fludarabine toxicity: Classical PRES starts from subcortical white matter whereas ATL starts from periventricular white matter (corona radiata and centrum semiovale)

• DXA scans for osteopenia/osteoporosis

• Thyroid ultrasound

In cases with suspected thyroid nodules and if there is a nodule U/S guided thyroid nodule aspiration biopsy may be needed.

• CT of the chest/abdomen/pelvis

CT of the chest/abdomen/pelvis is indicated if PTLD is considered.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Seizure

Valproic acid or levetiracetam may be a good choice as an antiepileptic drug because it does not interact with hepatic metabolism of CNIs that are common drugs in alloHCT

Ifosfamide

No standard treatment has been available, however methylene blue (intravenously 50mg every 4h) until clinical improvement has been reported.

Subdural hematoma

Dexamethasone to reduce cerebral edema and aggressive transfusion to platelet counts higher than 50 to 100 x 10⁹/L.

Intraparenchymal hemorrhage

Transfusions to platelets greater than 100 x 10⁹/L.

CNS fungal infections

Voriconazole or amphotericin penetrates the CNS.

CNI toxicity

Optimal treatment is to discontinue CNI or to replace CNI with a non-CNI immunosuppressive drug. However, if patients require a CNI, then switching one CNI to another CNI and minimizing doses is advised.

GBS

Data is limited in alloHCT setting, however immunosuppressive therapy, intravenous immunoglobin (IVIG), plasma exchange should be considered

Osteopenia/osteoporosis

• T-score greater than or equal to -1

– Follow patients with DXA scan every 1 to 2 years.

• T-score less than or equal to -2.5

– Therapy with anti-resorptive agent (for example, bisphosphonates).

• T-What should you tell the patient and the family about prognosis?

– If patients on steroids for greater than 3 months, or have high risks for fracture by using the World Health Organization Fracture Risk Assessment Tool (WHO FRAX) score, consider antiresorptive therapy.

Hypothyroidism

Thyroid hormone replacement therapy with levothyroxine T4 is indicated. Younger adult patients (less than 60 years) with clinical hypothyroidism with no cardiac disease may be started on 50 to 100 microgram daily. These patients should be reassessed every 6-8 weeks and dose adjustment should be at lower doses (for example, 12.5 or 25 microgram increments) at every 6 months until TSH is normalized.

Hypogonadism

Patients with low testosterone and no contraindications (for example, hormone dependent cancers such as prostate cancer) can receive testosterone replacements via a transdermal gel patch daily, or intramuscular injections every 2 weeks. Oral preparations are associated with liver dysfunction and should be avoided.

Hormone replacement therapy should be discussed with female patients regarding its contraindications (increased risk of cancers such as breast cancers and thrombosis).

What other therapies are helpful for reducing complications?

Prevention and surveillance

• Seizure

Antiepileptics, including lorazepam, phenytoin, levetiracetam, or routine prophylaxis during busulfan administration.

• Osteopenia/osteoporosis

All adult HCT recipients should be advised to intake of calcium (at least 1,200 mg per day) and vitamin D (800 to 1,000 IU per day), regular weight-bearing and muscle strengthening exercises, avoiding tobacco and excessive alcohol use, and preventing falls. Minimizing corticosteroid use is important if possible.

• Hypogonadism

Male: Cryopreservation of sperm before conditioning regimens (if possible ideally before any chemo/radiation therapy is started) is the only technique for preserving fertility.

Female: It is not as practical as in males, however, embryo cryopreservation is often effective, but oocyte cryopreservation, ovarian tissue cryopreservation, and GnHR (gonatotropin-releasing hormone) treatment to suppress the pituitary-gonadal axis have been tried.

• Gonadal function assessment

Every 6 months for males and annually for females.

• Thyroid function tests

Annually. If there is compensated hypothyroidism (for example, normal FT4 with elevated TSH), patients should be followed every 2-3 months to assess need for thyroid replacement therapy.

• DEXA scans

Initially 3 months and 12 months after HCT in patients on steroids or on no steroids, respectively. The initial test should be repeated annually.

What should you tell the patient and the family about prognosis?

CNI induced PRES responds to discontinuing a CNI; MRI findings may take a median of 20 days but sometimes up to 1 year to resolve completely.

Ifosfomide CNS toxicity is a usually lethal complication.

The prognosis of CNS infections is very poor.

Fludarabine induced leukoencephalopathy, patients led to a median survival of only 5.6 months.

Thyroid replacement is the successful treatment for hypothyroidism.

Without preserved cells or tissue, spontaneous fertility rate is quite low.

Pathophysiology

Pathophysiology and histopathology

Chemotherapy-induced leukoencephalopathy shows gliosis, macrophage infiltrate, and demyelinization of white matter.

CNI induced PRES: Direct endothelial damage due to CsA-induced endothelial apoptosis may cause vascular edema.

Ifosfamide-induced encephalopathy is not reported histologically. However, accumulation of chloracetaldehyde, toxic metabolite of ifosfamide, in the CNS is theorized.

Cytarabine: Purkinje cell destruction.

Osteoporosis/Osteopenia: Kidney dysfunction due to multiple causes (reduced vitamin D3 production), CNI (increased osteoclast activation and kidney dysfunction), TBI (hypogonadism), chemotherapy (decreased osteoblast activity), steroids (increased osteoclast activation, increased apoptosis in osteoblasts, decreased calcium absorption through GI tract, increased calcium excretion through kidneys) and secondary hyperparathyroidism (vitamin D, and calcium).

What’s the Evidence?

Ishiguro, H, Yasuda, Y, Tomita, Y. “Long-term follow-up of thyroid function in patients who received bone marrow transplantation during childhood and adolescence”. J Clin Endocrinol Metab.. vol. 89. 2004. pp. 5981-6. (Demonstrates risk factor for hypothyroidism in long-term in children after BMT.)

Gandhi, MK, Lekamwasam, S, Inman, I. “Significant and persistent loss of bone mineral density in the femoral neck after haematopoietic stem cell transplantation: long-term follow-up of a prospective study”. Br J Haematol.. vol. 121. 2003. pp. 462-468. (Demonstrates the incidence of osteopenia/osteoporosis after HCT.)

McClune, BL, Polgreen, LE, Burmeister, LA. “Screening, prevention and management of osteoporosis and bone loss in adult and pediatric hematopoietic cell transplant recipients”. Bone Marrow Transplant. vol. 46. 2011. pp. 1(Reviews incidence, risk factors and management of osteoporosis in transplant patients.)

Beitinjaneh, A, McKinney, AM, Cao, Q, Weisdorf, DJ.. “Toxic leukoencephalopathy following Fludarabine-associated hematopoietic cell transplantation”. Biol Blood Marrow Transplant.. vol. 17. 2011. pp. 300-8. (Demonstrates clinical and radiologic findings of fludarabine induced neurotoxicity.)

Park, IS, Lee, HJ, Lee, YS, Hwang, JS, Lee, MS.. “Ifosfamide induced encephalopathy with or without using methylene blue”. Int J Gynecol Cancer. vol. 15. 2005. pp. 807-810. (Discusses ifosfamide induced encephalopathy and its treatment.)

Massenkeil, G, Fiene, C, Rosen, O, Michael, R, Reisinger, W, Arnold, R.. “Loss of bone mass and vitamin D deficiency after hematopoietic stem cell transplantation: standard prophylactic measures fail to prevent osteoporosis”. Leukemia. vol. 15. 2001. pp. 1701-1705. (Demonstrates vitamin D deficiency and prophylaxis methods after HCT.)

McKinney, AM, Short, J, Truwit, CL. “Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings”. AJR Am J Roentgenol.. vol. 189. 2007. pp. 904-912. (Demonstrates radiologic findings of PRES.)

Rizzo, JD, Wingard, JR, Tichelli, A. “Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation”. Biol Blood Marrow Transplant.. vol. 12. 2006. pp. 138-51. (Describes recommended screening for long-term transplant survivors.)

Oktem, O, Urman, B.. “Options of fertility preservation in female cancer patients”. Obstet Gynecol Surv.. vol. 65. 2010. pp. 531-42. (Reviews fertility prevention methods in female with cancer.)

Savani, BN, Griffith, ML, Jagasia, S, Lee, SJ.. “How I treat late effects in adults after allogeneic stem cell transplantation”. Blood.. vol. 117. 2011. pp. 3002-9. (Reviews late adverse effects of HCT, and their prevention and treatment.)

Josi, S, Savani, BN, Chow, EJ. “Clinical guide to fertility preservation in hematopoietic cell transplant recipients”. Bone marrow transplantation.. vol. 49. 2014. pp. 477-484. (Describes the clinical guidelines for fertility preservation for female and male patients.)

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