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Bortezomib induction and SCT in AL amyloidosis
that a higher proportion of patients would be able to pro-
ceed to HDM and auto-SCT. However, the discontinuation
rate of 30% in the current study was similar to the 33%
observed in the previous HOVON 41 study in which VAD
induction therapy was given.8 The discontinuation rate
was substantially higher than those in two other prospec-
tive, single-center studies in which bortezomib-dexa-
methasone induction was given prior to HDM and auto-
SCT (0% and 14%).20,21 These differences could be
explained by different treatment designs; for example, in
the studies by Sanchorawala et al. and Huang et al., only
two cycles of bortezomib and dexamethasone induction
were given, instead of four. Perhaps more importantly,
these were single-center studies in large, experienced hos-
pitals, while the HOVON 104 trial was performed in 16
hospitals, which enrolled between one and eight patients
per site which may impair the quality of care. We therefore
think that our prospective data may better represent the
real-life outcome of patients following first-line AL amyloi-
dosis treatment. Although the discontinuation rate could
not be assessed in other retrospective studies because only
transplanted patients were included, these studies do sug-
gest that induction regimens can be beneficial in patients
by inducing deeper hematologic responses and better OS.9,10
The reasons for 15 patients not proceeding to HDM and auto-SCT were mostly non-eligibility according to protocol, generally caused by symptomatic effusions and poor Performance Status. Some patients had borte- zomib-related toxicity and in four patients the physician decided that the patient should not proceed to auto-SCT because of organ progression. The other toxicities seen during induction treatment are summarized in Table 2. These toxicities are comparable to those reported by Reece et al., and most involved the gastrointestinal tract, heart, and nervous system or were infections.13 Although 78% of patients received four cycles of bortezomib-dexa- methasone, half of the patients needed dose reductions of bortezomib and 44% needed reductions of dexametha- sone. Due to the multiple organ dysfunctions typically seen in AL amyloidosis, these patients do not tolerate the same chemotherapy schedules as MM patients do. This also seems to hold true for the “fittest” patients who appeared to be eligible for auto-SCT at diagnosis. Encouraging data from retrospective analyses illustrate that other bortezomib-based regimens with reduced doses of bortezomib to 1.0 m/m2 bi-weekly or 1.5 mg/m2 once weekly, combined with dexamethasone and cyclophosphamide once weekly, could maintain the high response rates but data on toxicity are limited.22,23 Once weekly dosing of bortezomib could therefore be the pre- ferred schedule in AL amyloidosis patients.
Using flow cytometry analysis at diagnosis we identi- fied a negative association between aPC/BMPC ≥95% and PFS. In addition, we found that patients with aPC/BMPC ≥95% had a lower probability of proceeding to auto-SCT; however, due to our small sample size of 26 patients this was not statistically significant. A high ratio of clonal plasma cells may reflect a more aggressive plas- ma cell clone in the bone marrow and its prognostic value has been determined in patients with monoclonal gam- mopathy of undetermined significance and smoldering MM.18 In patients with AL amyloidosis it has been demonstrated that the persistence of 5% or more normal plasma cells at diagnosis was related to OS, but due to the
shorter follow-up and excellent survival in the current study, this association could not be confirmed.24 The small sample size of the current study could perhaps be the reason that we could not confirm that other baseline characteristics, such as ≥10% plasma cells or a dFLC ≥180 mg/L, were negatively associated with survival.
There was no transplant-related mortality among the 35 patients who did receive HDM and auto-SCT and the patients had an excellent outcome. This is remarkable, because a previous prospective, multicenter study per- formed by Jaccard et al. reported a high mortality rate of 24% related to the auto-SCT procedure. This study, like ours, was also conducted in less experienced centers.25 It could be speculated that the induction treatment before HDM and auto-SCT functions as a selection mechanism because only patients who are able to tolerate chemother- apy proceed to high-dose treatment. Indeed, more patients who received the full doses of the induction reg- imen without dose adjustments proceeded to auto-SCT. A randomized trial is needed to investigate the role of induction therapy before auto-SCT. Interestingly, our study demonstrates that HDM with auto-SCT is also pos- sible for some patients with the highest cardiac Mayo risk score of III, which was present in 34% of our study pop- ulation. These patients did not experience more toxicity than the other risk groups. However since the start of this study new prognostic cardiac scoring systems have been published which may improve the selection of patients suitable for HDM and auto-SCT.26,27
The hematologic responses improved to 86% at 6 months after auto-SCT. In particular, the CR rate increased steadily after auto-SCT. Since the quality of response in AL amyloidosis patients is closely related to survival this is a very important observation. The hema- tologic responses after auto-SCT are less than those reported in the two other prospective, single-center trials but are better than those reported in larger retrospective cohorts.7,20,21,28,29 However, due to the high discontinuation rate before auto-SCT the primary endpoint of the study, an improvement, in intention-to-treat analysis, of the CR rate from 30% to 50% was not achieved.
Organ responses were already detected after induction therapy and the rates were 24%, 24% and 23% for the kidney, heart and liver, respectively. The new renal response criteria set was also prospectively evaluated and was 27% after induction treatment.16 In total, six patients developed kidney failure, defined as an eGFR <30 mL/min/1.73 m2: two of them had renal stage I at diagno- sis, two had stage II and two had stage III. After auto-SCT organ response rates continued to improve to 60%-80% (Figure 3) which are comparable to those after auto-SCT in previous reports.29
In conclusion, although the primary endpoint of the study was not met, in this first, multicenter, prospective trial with twice-weekly bortezomib, combined with dexamethasone treatment, we documented a high hema- tologic response rate of 80% in patients with newly diag- nosed AL amyloidosis. However, these responses cannot prevent amyloidosis-related organ failure and the treat- ment-induced NCI-CTCAE grade 2 and higher gastroin- testinal, cardiac, metabolic and neurotoxicity in more than 70% of patients, leading to a high discontinuation rate of 30% before auto-SCT. Possibly due to the unin- tended selection of induction treatment prior to HDM and auto-SCT, the transplants were performed without
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