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Light chain (AL) amyloidosis is a potentially fatal disor- der caused by a small monoclonal population of plasma cells in the bone marrow, which synthesize monoclonal light chains. The light chains are considered toxic and aggregate into amyloid fibrils. These fibrils form extracel- lular deposits in one or more vital organs, most frequently in the kidneys, heart and liver as well as in the peripheral and autonomic nervous systems.1
The main goal of treatment is to reduce the supply of the amyloidogenic monoclonal light chains rapidly and to achieve a very good partial response (VGPR) or a complete hematologic response (CR).2 Achieving a hematologic response is closely related with survival. This has been demonstrated following both high-dose and standard-dose chemotherapy.2,3 Organ responses are also induced in patients with prolonged hematologic responses.
High-dose melphalan (HDM) followed by autologous SCT (auto-SCT) is considered the most effective treat- ment for selected patients with AL amyloidosis.4 However, this treatment is only feasible in around 20% or fewer of newly diagnosed patients. Due to more strict selection criteria for eligibility for transplantation, the treatment-related mortality of auto-SCT has decreased to below 5% and transplanted patients have an excellent survival after their transplant.5-7
In the previous HOVON (Haemato-Oncology Foundation for Adults in the Netherlands) 41 study we examined a two-step approach consisting of non-inten- sive induction therapy followed by HDM and auto-SCT.8 Although the vincristine-adriamycin-dexamethasone (VAD) induction treatment was considered too toxic, the survival of patients was good with a median survival of 8 years from registration and, for the transplanted patients, a median survival of 10 years from the date of transplan- tation. Other retrospective single-center studies have also examined the value of various induction regimens before HDM and auto-SCT and concluded that induction thera- py is associated with a better overall survival (OS), with possibly the greatest benefit for patients with >10% bone marrow plasma cell infiltration.9,10
Bortezomib (Velcade), a proteasome inhibitor fre- quently used in first-line and relapse treatment in patients with multiple myeloma (MM), has been given to newly diagnosed and relapsed AL amyloidosis patients in most- ly retrospective and only one prospective multicenter study. The hematologic response rate to bortezomib was excellent, ranging from 50% to 80% with a CR rate from 25% to 47%; furthermore, the CR occurred rapidly, espe- cially when the drug was administered bi-weekly.11-13 Common toxicities included thrombocytopenia, periph- eral sensory neuropathy, neuropathic pain, hypotension and peripheral edema.
Considering the potent effect of bortezomib in relapsed AL amyloidosis patients and the improvement in response rates achieved when used as first-line treatment in MM patients, we hypothesized that the use of this drug, in combination with auto-SCT, could also improve the response rates of AL amyloidosis patients. Because the CR rate, in particular, is closely related to progression-free sur- vival (PFS), OS and organ responses, the current trial inves- tigated the efficacy of induction treatment consisting of bortezomib and dexamethasone followed by HDM and auto-SCT to improve the CR rate after auto-SCT.
haematologica | 2019; 104(11)
Bortezomib induction and SCT in AL amyloidosis
Introduction
Methods
The HOVON 104 study was conducted in 15 centers in the Netherlands, Germany, and Belgium. The trial started with a randomized, phase III design but due to slow accrual the dexamethasone arm closed after including seven patients and the trial continued as a single-arm, phase II study.
Patients with biopsy-proven, systemic, AL amyloidosis, aged between 18-70 years, with detectable M-protein and/or involved free light chains (FLC) >50 mg/L, World Health Organization (WHO) Performance Status 0-2, and New York Heart Association (NYHA) stage 1-2 were included. Eligibility criteria at inclusion corresponded to eligibility criteria for auto-SCT with the exception of measurement of cardiac ejection fraction. Major exclu- sion criteria were concurrent MM defined as Salmon- Durie stage II or III, previous treatment of plasma cell dyscrasia, symptomatic orthostatic hypotension, sympto- matic effusions, a N-terminal pro-brain natriuretic pep- tide (NT-proBNP) level >5,000 pg/mL, troponin T >0.06 μg/L or troponin I >2 x upper limit of normal, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) sensory peripheral neu- ropathy > grade 2 or > grade 1 with pain and motor peripheral neuropathy > grade 2 (see the Online Supplement for the complete list). Inclusion and exclusion criteria were also established for stem cell mobilization. Inclusion criteria comprised a WHO Performance Status 0-2, NYHA stage 1-2, and ejection fraction >45%. The exclusion criteria are listed in the Online Supplement. The study was approved by the ethics committee of all partic- ipating hospitals and the University Medical Center Utrecht (Institutional Review Board n. 10-426). All proce- dures were conducted in compliance with the Declaration of Helsinki. Written informed consent to par- ticipation in the study was provided by all patients (EudraCT number 2010-021445-42).
Treatment design
Four 21-day cycles of induction treatment were given. The cycles consisted of bortezomib subcutaneously (sc) 1.3 mg/m2 on days 1, 4, 8, and 11 and dexamethasone 20 mg orally on each day of bortezomib administration and the following day. Dose adjustments are described in the Online Supplement. Stem cell mobilization began within 4-6 weeks after the start of the last induction cycle using granulocyte colony-stimulating factor 10 mg/kg divided in two doses, given for 5 days. The melphalan dosage was 200 mg/m2 given in 2 days. Patients with an eGFR <40 mL/min/1.73 m2 were given 100 mg/m2 melphalan. Hematologic response was measured after each induction cycle and it was planned that all patients would receive HDM. Patients not responding to induction treatment could proceed directly to stem cell mobilization and auto-SCT if eligibility cri- teria were met.
Hematologic and organ response criteria
Organ involvement and hematologic and organ responses were evaluated according to the consensus criteria of the International Society of Amyloidosis published in 2005 with some modifications such as the addition of a VGPR category and addition of NT-proBNP for cardiac response14,15 (see the Online Supplement).
Both hematologic and organ responses were measured after
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