Autologous stem cell transplantation in the age of ANDROMEDA
2021; Wiley; Volume: 193; Issue: 5 Linguagem: Inglês
10.1111/bjh.17445
ISSN1365-2141
Autores Tópico(s)Chronic Myeloid Leukemia Treatments
ResumoSystemic light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by abnormal immunoglobulin production that misfolds into amyloid fibrils and deposits in organs causing morphologic and physiologic dysfunction. Given its insidious onset and non-specific symptomatology, diagnosis is often delayed, and significant organ compromise is common. The goal of treatment is to target the offending plasma cells and rapidly reduce the burden of toxic immunoglobulins such that organ recovery can occur. Plasma cell-directed therapy in amyloidosis has been largely borrowed from the advent of novel treatments in multiple myeloma. However, patients with amyloidosis face unique challenges and require personalization and optimization of such treatment. In the last month, for the first time, the FDA has approved a regimen for the treatment of AL amyloidosis.1 Daratumumab, an anti-CD38 monoclonal antibody, was approved in combination with bortezomib, cyclophosphamide and dexamethasone (DVCd) for newly diagnosed AL amyloidosis based on the phase III randomized ANDROMEDA (NCT03201965) study which compared DVCd with VCd.2, 3 The addition of the monoclonal antibody resulted in significant improvement in haematologic response (the primary end-point, overall response rate, 92% vs 77%, odds ratio 3·8, P < 0·0001), including complete response (CR, 42% vs 13%, P < 0·0001), and major organ deterioration progression-free survival (PFS; median not reached in either arm at 11·4 months median follow-up, hazard ratio 0·58, P = 0·02). The quadruplet was also associated with improved organ response at six months in those evaluable (cardiac response 42% vs 22%, P = 0·002; renal response 54% vs 27%, P < 0·0001). Patients achieved responses faster (median time to very good partial remission 17 vs. 25 days) and stayed on therapy longer (9·6 vs. 5·3 months) in the quadruplet arm. While this historic approval is a landmark for patients with this devastating disease and certainly a step in the right direction, the battle against AL amyloidosis is far from over. Currently, a third of patients go undiagnosed for a year or longer, and two-thirds see three or more physicians before they receive the diagnosis.4 Early diagnosis remains a key challenge in our efforts to improve patient outcomes. Educating our colleagues about maintaining a high index of suspicion and screening patients with monoclonal gammopathy of undetermined significance for clinical signs and symptoms of AL amyloidosis is a starting point. Additionally, ongoing efforts to improve on the progress made with ANDROMEDA are crucial. High-dose therapy followed by autologous stem cell transplantation (ASCT) is the cornerstone of therapy in multiple myeloma, and when applied to carefully selected patients, it has been a treatment strategy with durable responses in AL amyloidosis.5, 6 The long-term follow up of large series from the Mayo and Boston group has shown survivals exceeding 15 years in a third of patients with this one-time treatment. AL amyloidosis has several characteristics that lend itself favourably to ASCT compared to multiple myeloma, such as low tumour burden, low proliferative potential and low rate of high-risk cytogenetic changes.7 The obvious challenge is a high burden of vital organ involvement and treatment-related mortality (TRM). In recent time periods, with a deeper understanding of disease biology, improvements in supportive care, and careful patient selection, the TRM is now less than 3%.8 In recent publications, using refined patient selection criteria, the haematologic complete response and organ responses range between 50% and 60%. When used in the context of induction with novel agents, ASCT is associated with improvement in response rates, a rapid decrease in light chains, and improvement in overall survival.9-11 The current rapid and deep responses afforded by DVCd in AL amyloidosis could serve as a platform to further improve outcomes of patients by offering ASCT to those not in complete haematologic response and, more importantly, those who with measurable residual disease.12 This is even more important in the context of organ response.13, 14 A cardiac response rate of 42% and a renal response rate of 54% at six months is far from optimal for patients in a disease where a third of patients die in the first year. The use of quadruplets alongside ASCT provides an opportunity to deploy complementary treatment strategies and adapt therapy based on response. Those patients with exceptional response could be candidates for treatment-free observation and surveillance without being subjected to the cost and toxicity of ongoing maintenance strategy. In comparison, others with persistent disease could be treated with ASCT and considered for extended maintenance. Additionally, it is crucial to understand the safety and efficacy of the quadruplet in the patients excluded from the ANDROMEDA study, such as ethnic minorities (African American only constituted 3% of the study population) and patients with advanced cardiac disease (stage IIIB and IV). It is time to celebrate our victories, of which the first regulatory approval of drugs in AL amyloidosis is a big one. However, we owe it to our patients to not rest on our laurels. Instead, we must continue to forge a path to build on this improvement and incorporate the time-tested strategy of ASCT in combination with these agents to further improve the outcomes in this devastating illness. The authors declare no competing interests.
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