Page 171 - 2019_11 Resto del Mondo-web

Bortezomib induction and SCT in AL amyloidosis
rized the patients’ characteristics separately for those who proceeded to auto-SCT and those who did not. The median age of all the patients included was 59 years [interquartile range (IQR), 51-63]. The median number of organs involved was two (range, 1 to 5). Two or more organs were involved in 36 patients (72%) and three or more in 19 (18%). The kidney was the organ most fre- quently involved, with renal disease in 82% of patients, followed by the heart (in 66% of patients) and liver (in 26% of patients). The median eGFR at inclusion was 72 mL/min/1.73 m2 (IQR, 59-90) and 20, 25 and 5 patients had renal stage I, II or III, respectively.16 Mayo cardiac stage was I, II and III for 16, 16 and 17 patients, respec- tively (data unavailable for 1 patient).17 The initial median NT-proBNP level was 832 pg/mL (IQR, 204-1638). Echocardiography data were available for 47 patients.
Fourteen patients (28%) had a plasma cell infiltration of ≥10% in the bone marrow. Most patients presented with λ light chains (80%). The median concentration of involved FLC was 180 mg/L (IQR, 73-352) for λ light chains and 169 mg/L (IQR, 61-879) for κ light chains. The median difference between involved and uninvolved FLC (dFLC) was 213 mg/L (IQR, 80-397) and 50% of patients had a dFLC ≥180 mg/L. Of note, seven patients were included without an M-protein or dFLC value that could qualify them for the PR or VGPR category and three of these patients also did not have a urine protein elec- trophoresis >0.1 g/day.
In the group of seven patients enrolled in the dexa- methasone arm of the closed, phase III part of the trial one patient was not eligible. The median age of the other six patients was 57 years and these patients’ other base- line characteristics were also comparable to those of the 50 patients in the phase II part (data not shown). Three patients underwent auto-SCT and the estimated 3-year PFS was 83%. These six patients are not included in this final analysis.
Treatment characteristics
All patients started with induction treatment. Most patients (88%) received four cycles of bortezomib-dexa- methasone, two patients received three cycles, two patients received only two cycles and two patients had to discontinue induction treatment after the first cycle. Half of the patients had dose modifications in the adminis- tered cycles as prescribed per protocol: in 50% of patients the bortezomib dose was modified and in 44% the dexa- methasone dose was modified. The reasons for dose modifications for bortezomib were mostly neurotoxicity, both sensory and autonomic neuropathy (9 patients) and infection (3 patients) and for dexamethasone heart failure (4 patients), edema (3 patients), infection (3 patients) and myopathy (2 patients).
Eleven patients did not have their stem cells collected after induction therapy. Five patients did not fulfill the eli- gibility criteria, including two patients who stopped induction due to progressive heart failure and kidney fail- ure. Two patients died, one during the first cycle of induc- tion, three patients experienced bortezomib-related toxi- city and were taken off the trial during induction treat- ment (1 patient with bronchial hyperreactivity, 1 patient with gastrointestinal necrosis and 1 patient with NCI CTCAE grade 4 sensory neuropathy) and one patient refused stem cell collection.
The median number of stem cells collected was 6.3x106
CD34/kg (IQR, 4.6-9.3). Ten patients needed 2 days of apheresis and cyclophosphamide was given to nine patients according to local policy. After stem cell collec- tion, four patients did not proceed to HDM and stem cell reinfusion. All four had clinical deterioration: two patients developed symptomatic pleural effusions, one patient started dialysis and one patient had several toxic- ities, a worsening clinical condition and was taken off the trial by decision of the treating physician.
In total 35 patients (70%) received HDM and stem cell reinfusion as an inpatient procedure. Thirty-one patients were given a full dose of HDM, per protocol; in four patients the melphalan dose was reduced to 100 mg/m2 because their eGFR was <40 mL/min/1.73 m2. All patients engrafted without granulocyte colony-stimulating factor support in a median time of 13 days for white blood cells and 16 days for platelets. A CONSORT diagram summa- rizes the treatment course of all 50 patients (Figure 1).
Based on a univariate logistic regression model we could not identify a prognostic baseline characteristic such as NYHA stage, NT-proBNP, Mayo stage, ≥10% plasma cells, dFLC ≥180 mg/L, or number of involved organs that was related to proceeding to auto-SCT after induction therapy. As shown in Table 1 the baseline Mayo stage was not statistically different between the groups of patients who did or did not proceed to auto- SCT (P=0.80). In the 35 patients who underwent auto- SCT, 22 received full-dose bortezomib and 23 full-dose dexamethasone. In contrast, in the 15 patients who did not proceed to auto-SCT only three received full-dose bortezomib and five full-dose dexamethasone. Because troponin levels were only measured at baseline, a Mayo stage assessment could not be calculated after induction treatment or before auto-SCT.
Hematologic responses
Hematologic responses are summarized in Table 2. The overall response rate (ORR) after induction treatment was 80%, which included the 38% of patients with a VGPR and 20% with a CR. The median time to first response was 28 days (IQR, 21-43) and the median time to best response was 67 days (IQR, 28-240). Eighty percent of the responses were detected within the first 3 months after starting treatment (Figure 2). Ten patients (20%) had a CR after induction treatment and eight of them proceeded to auto-SCT. Responses assessed 6 months after auto-SCT, which was the primary endpoint of the study, improved but were assessed in 35 patients only, since 15 patients did not proceed to auto-SCT. In these 35 patients, the CR rate doubled from 23% after induction treatment to 46% at 6 months after auto-SCT. The ORR increased to 86% at 6 months after auto-SCT. In the intention-to-treat analysis the CR rate at 6 months after auto-SCT was 32% and therefore the primary endpoint of the study was not met. In the group of 15 patients who did not proceed to auto-SCT, ten (67%) had a hematologic response. In uni- variate logistic regression analyses a dFLC ≥180 mg/L and bone marrow plasma cell infiltration ≥10% at diagnosis were not related to the depth of the hematologic response.
Flow cytometry
Samples for flow cytometry were available at diagnosis for 26 patients. Of this group, 20 patients proceeded to auto-SCT. The median percentage of clonal plasma cells
haematologica | 2019; 104(11)
2277