ISA 2022 - Highlights article 1

Key considerations when selecting treatment for patients with AL amyloidosis

The first highlight article from the 18^th International Symposium on Amyloidosis (ISA) 2022 is an overview of the Satellite Symposium, “Navigating the patient journey in AL amyloidosis: a multidisciplinary” presented by Giovanni Palladini from the Amyloidosis Research and Treatment Center, University of Pavia and IRCCS Fondazione Policlinico San Matteo, Italy on Monday 6 September 2022 in Heidelberg, Germany.

We interviewed Professor Giovanni Palladini about ISA 2022, watch the video below to hear his highlights.

AL amyloidosis is a haematological and organ disease

Professor Giovanni Palladini opened his lecture by observing that amyloid light-chain (AL) amyloidosis is both a haematological and an organ disease. This fact can help inform treatment decisions for AL amyloidosis, because healthcare professionals can follow the efficacy of treatments with biomarkers specific to haematologic and organ response.

A rapid and clinically significant reduction in the amyloid protein (free-light chains) is essential to achieving beneficial haematologic and organ responses. As Professor Giovanni Palladini stated, “The deeper [reduction] the better, the quicker the better”. One month is the ideal window to achieve amyloid reduction. Watch the following video with Professor Giovanni Palladini to hear about validated diagnostic and screening tools for AL amyloidosis or transthyretin amyloid cardiomyopathy (ATTR-CM).

Watch the following video to hear Professor Giovanni Palladini explain advice for cardiologists and neurologists in detecting AL amyloidosis or ATTR-CM.

Choice of treatments for AL amyloidosis

Treatment selection in AL amyloidosis is determined by several interacting factors:

• Expected efficacy (response speed, rate, and duration)
• Characteristics of the clone (size, chromosomal abnormalities)
• Access to drugs (clinical trials)
• Severity of organ involvement (biomarkers)
• Specific contraindications (renal failure, neuropathy)
• ‘Frailty’ (age, comorbidities)
• Patient’s preference (occupation, family issues)

First-line treatment that is well-chosen can trigger early improvement of organ dysfunction, permitting consideration of more aggressive second-line treatments

Guideline recommendations: treatment selection for AL amyloidosis

Step 1. Assess patient eligibility for autologous stem-cell transplant (ASCT)

The first step in treatment selection for AL amyloidosis, based on clinical practice and guidelines^1,2, is to assess patient eligibility for autologous stem-cell transplant (ASCT). In many European countries, ASCT is a second-line treatment. Well-selected patients for ASCT can reduce patient mortality. Biomarkers, patient age (≤65 years of age), and residual organ dysfunction are key inclusion criteria for ASCT¹.

Induction is a sequential response-driven approach offering patients ASCT, only if they show an unsatisfactory response following a bortezomib-based regimen ± daratumumab, for 2–4 cycles¹. If the patient responds well to induction treatment (‘complete response’, CR), there is an option to observe without ASCT¹.

In most cases of ASCT, patients receive melphalan 200 mg. Lower doses of melphalan can be used in patients with lower glomerular filtration rates. The endpoint of ASCT is haematologic ‘very good partial response’ (VGPR)¹.

Step 2. Assess specific comorbidities in people who are not transplant candidates

The most common comorbidity in AL amyloidosis is neuropathy. Neuropathy can prevent patients from using bortezomib².

If there is no evidence of neuropathy, the standard of care for cardiac stage I-IIIa is Dara-CyBorD (daratumumab-cyclophosphamide, bortezomib, dexamethasone). If this first option is not available, CyBorD, or BMDex (bortezomib, melphalan, dexamethasone), can be considered. In cardiac-stage IIIb, first-option is dose modified Dara-CyBorD, or daratumumab single agent².

In there is evidence of neuropathy, for all cardiac stages, first option is daratumumab single agent².

In ANDROMEDA, a phase 3 trial of daratumumab plus CyBorD versus CyBorD, higher rates for haematologic, cardiac and renal responses, including VGPR and CR, were shown for daratumumab plus CyBorD³.

Professor Giovanni Palladini noted that access to Dara-CyBorD is still limited in specific populations, such as pre-treated patients, or patients with comorbidities.

Watch the video below with Professor Palladini to hear about his perspective on the most promising investigational treatments for AL amyloidosis or ATTR-CM.

Step 3. Assess response to treatment

Reduction in free-light chains should be assessed for improvements in organ dysfunction using the BNP (brain natriuretic peptide) biomarker.

Grading of organ response is a new development in the AL amyloidosis field. Greater reduction in biomarkers of organ damage is associated with longer patient survival. Professor Giovanni Palladini opined that these markers should be carefully monitored during patient follow-up.

New frontiers in AL amyloidosis

Monitoring schedule during and after treatment

In treatment monitoring, CR or VGPR plus organ response at 6–12 months is insufficient; a ‘deep’ organ response is also needed. The concept of ‘haematologic treatment relapse’ in the AL amyloidosis setting is not yet defined in the field.

If CR or VGPR plus organ response at 6–12 months, VGPR after 2 cycles, and PR after 1 cycle, is not evident, Professor Giovanni Palladini suggested that rescue therapy, based on daratumumab, ixazomib, or venetoclax, among others, be considered.

Conclusions

For managing AL amyloidosis, healthcare professionals are ‘well armed’. A standard of care has been developed, although further clinical trials of new agents are needed, especially for patients exposed to daratumumab, or those with comorbidities. Collaborative studies are required to determine treatment endpoints, and a definition of haematologic relapse.

About Professor Giovanni Palladini

Giovanni Palladini is a Professor of Clinical Chemistry at the University of Pavia and the Director of the Amyloidosis Research and Treatment Center at the Foundation IRCCS Policlinico San Matteo, Pavia, Italy. He has contributed to the introduction of novel agents in the treatment of AL amyloidosis. His studies led to the establishment of standards of care for the treatment of patients with AL amyloidosis, to the introduction of NT-proBNP as a marker of diagnosis, prognosis, and response of cardiac involvement in this disease, and to the establishment and validation of criteria for hematologic and organ response to therapy in AL amyloidosis.

Disclosures: Professor Giovanni Palladini has been involved with Janssen-Cilag, The Binding Site, Gate Bioscience, Alexion, Protego, Argobio, Pfizer, Prothena, Sebia and Siemens.

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