Abstract
Introduction: The current standard of practice for patients with systemic immunoglobulin light chain amyloidosis (AL) if transplantation-eligible is to proceed directly to high-dose melphalan (HDM) and autologous stem cell transplant (ASCT) without induction therapy. This approach has been associated with higher response rates and improved overall survival compared to chemotherapy alone. However multiple recent studies have shown the merits of bortezomib induction in AL patients who are transplantation-eligible and ineligible, and it is also increasingly used when significant bone marrow clonal plasma cells are present. These therapies have shown to be well-tolerated with favorable hematologic and organ responses, often enabling patients who were originally transplantation-ineligible to become eligible. The purpose of this study is to update our previously performed retrospective analysis of a single-institution population of patients with AL treated with bortezomib induction followed by HDM + ASCT.
Methods: All patients with biopsy-confirmed AL who underwent HDM + ASCT at Oregon Health and Science University from 2006 to 2017 were included (n=53). Organ involvement and responses were assessed using the consensus criteria reported by the Roundtable on Clinical Research in Immunoglobulin Light-chain Amyloidosis. Institutional eligibility criteria for performing HDM + ASCT for AL patients included: Eastern Cooperative Oncology Group performance status ≤2, left ventricular ejection fraction >45%, New York Heart Association class <3, cardiac biomarker stage 1 or 2, carbon monoxide diffusing capacity >50%, and serum creatinine ≤3.0 mg/dL unless receiving dialysis. Patients received melphalan 200 mg/m2 or dose-reduced melphalan (100-140 mg/m2) for those at higher risk.
Results: Of the 53 total patients, 13 proceeded directly to ASCT after diagnosis, whereas 34 received a bortezomib-containing induction regimen (increased from 12 in our previous study), and 6 received some other form of induction treatment (Table 1). Twenty-three patients received dose-reduced melphalan prior to ASCT. Twenty-five patients had cardiac involvement. Two patients (3.7%) died within 100 days after ASCT (one due to exsanguination from AL-involved splenic rupture, the other due to congestive heart failure). The overall hematologic (ORR) and organ response rates (OR) in the entire cohort after ASCT were 85% and 67%, respectively. ORR was 94% in the group that received bortezomib induction compared to 69% in the group that received no induction (p=0.04); OR in these groups were 77% and 54%, respectively (p=0.17). The mean time to maximum hematologic response was significantly shorter in those who received bortezomib induction compared to no induction (3.4 months vs. 16.8 months, p<0.0001). The overall cardiac response rate was 65.0%, with a rate of 71.4% in those pre-treated with bortezomib versus 43% in those who did not receive induction therapy (p=0.35). With a median follow-up of 2.9 years, 3-year progression-free (PFS) and overall survival (OS) in the entire cohort were 62% and 82%, respectively (Figure 1); in those with cardiac involvement, these rates were 59% and 83%, respectively. 3-year OS (Figure 2) in the bortezomib-induction group was 87% compared to 77% in the group that received no induction (p=0.22), 3-year PFS (Figure 3) in these groups were 61% vs. 69%, respectively (p=0.52)
Conclusion: With the update of our institutional analysis, we have continued to observe that bortezomib-based induction is well-tolerated in patients with and without cardiac involvement and is associated with higher ORR and shorter time to hematologic response compared to those who receive no induction. In our analysis, bortezomib-based induction did not significantly impact OR, cardiac response rate, PFS, or OS, but these are likely limited by sample size and short follow-up time. Our results otherwise appear comparable to those seen at other major transplant centers. These findings therefore continue to support the emerging roles for bortezomib-based induction regimens for the purposes of improving response and even increasing eligibility for patients to safely undergo HDM + ASCT. Larger scale analyses in the form of prospective multi-center trials would be beneficial to further study these roles.
No relevant conflicts of interest to declare.
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