Considerations for patients with primary AL amyloidosis prior to autologous BMT

Evidence supporting the use of high-dose therapy with autologous bone marrow transplantation for AL amyloidosis first emerged in 1994 and it is now generally accepted that for selected patients auto-BMT may lead to durable haematological and organ responses, with some patients surviving more than 10 years post auto-BMT^rr. Unfortunately, auto-BMT may be associated with considerable mortality and morbidity, with earlier studies demonstrating treatment-related mortality (TRM) between 10-45%. This is unacceptable both because it shortens the survival of some patients but also because other therapies, including lenalidomide and bortezomib-based therapies, have demonstrated efficacy in the treatment of AL amyloidosis. In this regard it is noteworthy that in recent years outcomes of patients with AL amyloidosis undergoing auto-BMT have improved substantially, with larger, more experienced BMT units achieving 100-day TRM of less than 5% with careful patient selection, optimized stem cell mobilization and transplantation practices and clear post auto-BMT assessment, follow-up and care^rr

Selection criteria for auto-BMT vary between institutions and consensus guidelines have not been devised. In general, conventional eligibility criteria for auto-BMT, such as age and performance status, should be combined with amyloid-specific factors including organ (especially cardiac) involvement and susceptibility to treatment toxicity^r The presence and degree of cardiac involvement is the most significant parameter in predicting TRM. While traditional markers of cardiac disease in amyloidosis, such as reduced left ventricular ejection fraction and interventricular septal thickness remain valuable predictors of TRM from auto-BMT, these have been largely superseded by the use of cardiac biomarkers. The Mayo Clinic cardiac biomarker-based staging system has demonstrated that 100-day all- cause mortality is significantly higher (28% vs 7%) in patients with baseline cTnT =0.06mcg/L compared to those with cTnT <0.06mcg/L^r while other studies have demonstrated that median survival is significantly worse (4.1 months vs 27.2 months) in patients with 2 or more elevated cardiac biomarkers (cTnT, cTnI and NT-ProBNP) compared with those with normal/low biomarker levels^r. What these results make clear is that patients with significant cardiac involvement should not be regarded as suitable candidates for upfront auto-BMT.

Commonly used eligibility criteria for autologous bone marrow transplantation

Clinical factors

• Age =65
• NYHA class I-II 
• ECOG performance status = 2
• Systolic blood pressure =90mmHg
• Other ‘negative’ clinical features eg; no history of syncope, cardiac failure, pleural effusions or ventricular arrhythmias
• Other ‘positive’ clinical features eg; isolated renal amyloid or isolated non-autonomic or peripheral neuropathy

Organ function

• cTnT <0.06mcg/L or cTnI <0.1mcg/L
• BNP <300ng/L
• GFR >50ml/min
• Bilirubin <1.5 x ULN with preserved hepatic synthetic function

Given the importance of appropriate patient selection for auto-BMT the following assessments need to be done prior to listing for auto-BMT and stem cell mobilization:

Multidisciplinary care

• Cardiology referral for assessment of cardiac amyloid, optimisation of failure therapy and consideration of pacemaker, implantable defibrillator and anti-arrhythmic therapy (in all patients)
• Nephrology referral (in all patients)
• Neurology referral (as needed)

Assessment of AL clone

• Serum protein electrophoresis and immunofixation (SPEP/IFE)
• 24-hour urine protein electrophoresis and immunofixation (UPEP/IFE)
• Serum free light chain assay
• Biochemistry
• Full blood count
• Skeletal studies/imaging
• Bone marrow biopsy and flow cytometry

Assessment of organ involvement

• Assess ECOG status
• Cardiac echo
• ECG
• 24-Hour Holter monitor
• Cardiac biomarkers – cTroponin T, cTroponin I, NT-ProBNP
• Nerve conduction studies and EMG is any neurological symptoms
• Colonoscopy and gastroscopy if any symptoms of gastrointestinal haemorrhage
• Respiratory function studies and HRCT chest if any pulmonary symptoms
• 24-hour urinary protein measurement
• Abdominal ultrasound or CT to assess liver size
• PT, APTT, TT, fibrinogen and Factor Xa
• SAP scintigraphy (if available)

AL is usually associated with a low-level plasma cell clone and, unlike multiple myeloma, there is currently no data to support a benefit from cytoreduction before auto-BMT. Indeed, pre auto-BMT induction therapy may simply allow disease progression or clinical deterioration and confers no benefit in responses or survival.

Patients with AL amyloidosis experience higher rates of complications and mortality during peripheral blood stem cell mobilization and collection, with the overall complication rate around 15%. Peripheral and pulmonary oedema, symptomatic hypocalcaemia, hypoxia, orthostatic hypotension, arrhythmia and sudden death have all been reported in patients with AL amyloid undergoing stem cell mobilization and collection.

The use of cyclophosphamide mobilization is also associated with greater toxicity and higher rates of neutropenic sepsis, mucositis, bleeding and cardiac complications than mobilization with G-CSF alone in patients with AL amyloidosis and as such stem cell mobilization with G-CSF 10mcg/kg alone (given in twice daily divided doses with collection beginning on day 5) is recommended.

Given the cardiac risks associated with mobilization and apheresis (including atrial tachycardias and non-sustained ventricular tachycardia) – in patients with any degree of cardiac disease consideration should be given to cardiac monitoring/telemetry during mobilization, apheresis and stem cell infusion.

Precautions specific to this patient group include:

• Inpatient care for the entire period of auto-BMT
• Arrhythmia prophylaxis.
  • In addition to cardiac monitoring consideration should be given to the use of prophylactic antiarrhythmics, such as amiodarone (on the advice of the patient’s cardiologist).
• Careful attention to fluid balance.
  • G-CSF should be avoided in patients with nephrotic syndrome and cardiac involvement due to risk of fluid retention; albumin replacement should be considered if serum albumin <20g/L, and low-salt fluids for blood pressure support if required.
• Prevention of GI Haemorrhage.
  • Given the increased risk of GI bleeding following auto-BMT, during the cytopenic phase, routine proton-pump inhibitor therapy, higher platelet transfusion threshold (>20 to 50 x 109/L) and daily testing of the faeces for blood are recommended.
• Avoidance of nephrotoxins.
• Antiemetics.
  • Patients with AL amyloidosis experience higher rates of nausea and vomiting with auto-BMT due to impaired gastric emptying. They may therefore require higher doses and longer duration of antiemetics.
• Infection prophylaxis as per local guidelines.
• Multi-disciplinary care, particularly with cardiology and nephrology support, is essential. 

It is important to document the impact of auto-BMT on both organ function and the AL clone (remission status). Complete remission is defined as negative serum and urine immunofixation, normal serum free light chains (FLC) and normal SFLC ratio.

Post auto-BMT assessment should be done at 8-12 weeks post-transplant and include:

• Assessment of any organ systems noted to be affected by AL amyloid pre auto-BMT
• Serum protein electrophoresis and immunofixation (SPEP/IFE)
• 24-hour urine protein electrophoresis and immunofixation (UPEP/IFE)
• Serum free light chain assay
• Biochemistry
• Full blood count
• Skeletal studies/imaging
• Bone marrow biopsy and flow cytometry
• Cardiacbiomarkers – cTroponin T, cTroponin I, NT-ProBNP
• SAP scintigraphy (if available)

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