Page 174 - 2019_11 Resto del Mondo-web

M.C. Minnema et al.
points had a higher renal response rate (72% vs. 28%, P=0.03). Although more patients in this group also had a higher cardiac response rate (65% vs. 35%), the difference was not statistically significant for cardiac response at any time-point after auto-SCT.
Overall survival and progression-free survival
The median follow-up of the 43 patients still alive is 38.3 months (IQR, 34-46) while that of all 50 patients is 36.9 months (IQR, 29-46). Five patients died during the follow-up, in most cases due to amyloid-related organ failure. None of the transplanted patients has died. Kaplan-Meier PFS curves for all 50 patients and the 35 transplanted patients are shown in Figure 4. The median OS and PFS were not reached. The 3-year estimated OS and PFS rates are 86% and 63%, respectively. In total seven patients had progression of their plasma cell dyscrasia after auto-SCT, including one patient with a previous CR, three with a VGPR, two with a PR and one patient who did not have any response. None of the eight patients with a CR before auto-SCT has progressed, whereas eight of the patients who had not achieved a CR prior to auto-SCT have done so (P=0.13). Using univari- ate Cox regression prognostic baseline characteristics, such as type of hospital (high vs. low number of included patients), eGFR (>30 and <50 vs. ≥50 mL/min/1.73 m2, NYHA class (I vs. II), NT-proBNP (as a continuous vari- able), plasma cell infiltration (<10% vs. ≥10%), dFLC <180 mg/L vs. ≥180 mg/L, number of organs involved (≤2 vs. >2), Mayo stage, nervous system involvement and car- diac involvement were tested but none of these variables was statistically related to OS.
Adverse events and mortality
Adverse events were commonly seen during induction treatment in all patients. The most frequent adverse events seen during induction treatment are summarized in Table 3. The most commonly experienced adverse events were neurotoxicity, gastrointestinal symtpoms, infections and cardiac disorders. Although dizziness, orthostatic hypotension and syncope may also have car- diac origins, all these events were grouped together as autonomic neuropathic events if no cardiac cause, such as arrhythmias or deterioration in ejection fraction, was detected. In total, 10% of patients experienced autonom- ic neuropathy and 34% had sensory neuropathy related
to bortezomib. Interestingly, patients with nervous sys- tem involvement at the start of therapy did not require more dose adjustments for bortezomib compared to patients without nervous system involvement. No engraftment syndrome was seen after auto-SCT.
Overall, 47 serious adverse events were reported in 29 patients, 34 during induction treatment, three during stem cell mobilization and ten following 30 days after HDM and auto-SCT. The serious adverse events were mostly due to hospitalization (81%) and 28 were consid- ered related to the treatment. Twenty-nine serious adverse events resolved completely, the others were ongoing. Two patients died during the study treatment phase. One patient had a sudden cardiac death during the first induction cycle, probably related to the cardiac amy- loidosis, and one patient died due to hepato-renal syn- drome after receiving four cycles of induction treatment. There were no cases of transplant-related mortality.
Discussion
The aim of the current prospective, multicenter study was to investigate whether a more effective induction regimen before HDM and auto-SCT could lead to better outcomes in newly diagnosed AL amyloidosis patients. Bortezomib is considered the first drug of choice both because of the high response rates that it induces and the fact that the responses tend to occur rapidly.19 We there- fore hypothesized that using a two-step approach with effective induction, starting immediately after diagnosing and staging the AL amyloidosis, would not only improve response rates after auto-SCT but would also rescue more patients from amyloidosis-related organ damage.
The ORR of 80%, with 20% CR, 38% VGPR and 22% PR rates achieved after induction treatment, is indeed comparable to that reported previously by Reece et al. in relapsed AL amyloidosis patients (ORR 66.7%).13 In their study a median of six cycles of bi-weekly bortezomib was given compared to the four cycles of bi-weekly bortezomib in the current study. In retrospective analyses high response rates up to 80% have been reported in both relapsed and newly diagnosed patients.11,12 We confirm a rapid time to response with median times to first response of 28 days and to best response of 67 days.
Because of these fast and deep responses we expected
Table 3. Percentages of the most common treatment-related adverse events of bortezomib-dexamethasone induction treatment.
Adverse event
Nervous system, total -sensoryPNP
- autonomic (syncope, dizziness,
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Total
1224122-50 12 14 6 2 - 34
-64--10 -4---
na30104-44
na2010--30 na12122228 na186--24 na102--12
orthostatic hypotension)
-motor --2--4
- neuropathic pain
Gastrointestinal (constipation, diarrhea,
nausea, vomiting) Infections
Cardiac Metabolic/nutrition
Fatigue
PNP: polyneuropathy, na:not assessed .
2280
haematologica | 2019; 104(11)