{'fraction_non_alphanumeric': 0.03616557734204793, 'fraction_numerical': 0.020261437908496733, 'mean_word_length': 5.246258503401361, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Reply to R. Warsame et al.

We appreciate the interest of Warsame and Dispenzieri in our light chain (AL) amyloidosis study. They suggest that the poorer outcome in the translocation t(11;14)–positive group is because of a higher early death rate resulting from increased toxicity, which, they suggest, does not necessarily indicate that bortezomib treatment lacks efficacy. In these critically ill patients, experiencing treatment failure, poor tolerability, and early death rate are intermingled. Nevertheless, the early death rate in our study did not differ between patients with t(11;14) or without t(11;14): 14 of 61 patients versus 6 of 34 patients, respectively (23% v 18%; P .61). When patients who experienced early death were excluded from the analysis in a subsequent step, and only patients evaluable for response were considered, our data yielded the same result. Here, the very good partial remission rate was 16 of 28 patients in the t(11;14)-negative group versus 14 of 47 patients in the t(11;14)-positive group (57% v 30%, respectively; P .03; Appendix Table A2 of our article specifies responses and early deaths by cytogenetic subgroups in detail). Likewise, in our cyclophosphamide, bortezomib, and dexamethasone–treated validation cohort, the t(11; 14)-negative group also fared better, with eight of nine patients achieving very good partial remissions versus four of 16 patients (89% v 25%, respectively; P .004). Our data suggest that the poorer prognosis of t(11;14)-positive patients truly reflects worse response to treatment with bortezomib, and not merely a higher early death rate and poorer tolerability. The poor prognosis of t(11;14)-positive patients seems to be a bortezomib-related phenomenon—our previously published melphalan-dexamethason (M-Dex) cohort showed a trend for improved overall survival in t(11;14)-positive patients. Of note, the patient characteristics of our M-Dex trial were similar to those in the reported bortezomib study, with mostly clinically poor-risk patients included. This argues against the possibility suggested by Warsame and Dispenzieri that “AL patients with the t(11;14) translocation do poorly . . . in general.” As we outlined in our article, we think that our two studies should be viewed in tandem. The divergent response to M-Dex and to bortezomib suggests that therapy matters, and that prognostic factors (especially those that are associated with hematologic response and progression) should be judged in the context of the administered therapy. Warsame and Dispenzieri state apodictically that bortezomib is a “highly effective therapy” in AL amyloidosis. Studies demonstrating the efficacy of bortezomib likely included the whole spectrum of AL amyloidosis cytogenetics, thus reflecting the response of both t(11; 14)-negative and -positive patients. In our judgment, the mere high frequency of presentation of t(11;14) does not allow the drawing of prognostic conclusions in bortezomib-treated patients. We do not question that bortezomib is a valuable therapeutic option in AL amyloidosis. However, our study aim was to optimize first-line treatment recommendations to improve rapid and sustained response in this fragile patient group. The multivariable models of the Mayo Clinic and the Heidelberg group differ in relevant points. First, our cohorts included only patients administered bortezomib as first-line treatment, whereas the Mayo Clinic cohort was not selected on the basis of therapy (including bortezomib-based therapy as a covariable). Second, our analysis included 11 factors as opposed to three factors included in the Mayo Clinic analysis. Therefore, an outright comparison of the two models might be statistically problematic. Finally, Warsame and Dispenzieri question whether the sample size of our study is large enough to provide solid conclusions. Obviously, patient numbers are a concern in a disease as rare as AL amyloidosis. However, our single center study, which included a validation cohort, together with our previous M-Dex study (n 133 and n 103 patients, respectively), are the largest studies of uniformly treated patient cohorts that have been published so far relating to the prognostic impact of cytogenetics in AL amyloidosis. In addition, results were tested in comprehensive multivariable models. Nevertheless, as we stated in our conclusion, confirmative analyses from other groups are necessary and might be best performed in a large multicenter approach. In conclusion, we maintain and assert our interpretation of the data from our studies for the reasons stated.