Page 343 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
occurred in one patient, who died of infection-induced heart failure exacerbation afterward. Four patients, one patient and one patient suspended bortezomib due to diarrhea, intestinal obstruction and acute cholecystitis, respectively. One patient reduced the dose of bortezomib because of diarrhea.
The proportions of hematologic CR, VGPR or better in Mayo stage IIIB patients were comparable to those in Mayo stage IIIA patients (Table 2). Although the early mortality rate within 1 month was higher in the IIIB subgroup (25.0% and 5.0%, respectively), the percentages of cardiac response at 6 months were similar between IIIA and IIIB (45.0% and 50.0%, respectively). The 2-year OS rates were 74.3% (95% CI: 48.7-88.4) and 65.0% (95% CI: 40.3-81.5) in the IIIA and IIIB subgroups, respectively (Figure 1).
To our knowledge, this is the first study in AL patients with stage III disease, including those with N-terminal pro-brain natriuretic peptide >8,500 ng/L, that prospectively explored the efficacy and safety of a daratumumab-based regimen. In the current study, the hematologic and cardiac responses of Dara-VD compared favorably with those reported with borte- zomib-based therapy. Median OS was significantly extended even in the IIIB subgroup.13 Along with pursuing a rapid and deep hematologic response, minimizing side effects is equally important in the management of advanced cardiac AL pa- tients. Thus, the EMN22 study tried to explore the feasibility of daratumumab monotherapy in newly diagnosed stage IIIB patients and reported early results in 40 patients.8 The overall hematologic response rate was 70.0% at 3 months and car- diac response rate was 27.5% at 6 months,8 lower than the estimates in IIIB patients from our study. Their median OS was 10.3 months,8 inferior to the prognosis in the current study. The early mortality rate within 1 month was 7.5%, lower than the estimate from our study. As far as we know, single-agent daratumumab may compromise the rapidity and depth of the hematologic response, which is strongly associated with the cardiac response and long-term survival. Before the routine application of anti-fibrillary antibodies in AL amyloidosis, our findings highlight the importance of upfront combination treatment in late-stage patients.
Given the strong anti-plasma cell effect of daratumumab combined with bortezomib, we wondered whether it was necessary to include alkylating drugs in first-line therapy. Thus, when we designed the current trial, cyclophosphamide was abandoned to reduce myelosuppression. Chakraborty et al. recently published a retrospective analysis of 19 IIIB patients treated with Dara-VCD front-line therapy.14 The proportions of patients achieving ≥ VGPR at 3 months were similar.14 Cardiac response was achieved by 56% of Chakraborty et al.’s patients, and their 1-year OS was 67.5%,14 similar to the estimates in our study. The early mortality rate within 1 month was 10.5%. Grade ≥3 infections were noted in 21.1% of their patients,14 while the percentage in our study was 15.0%. The comparable response and survival further support the advantage of the upfront combination
Figure 1. Kaplan-Meier graph of overall survival by Mayo 2004 stage. The blue and orange areas indicate the 95% confidence interval (CI) of overall survival.
regimen in IIIB patients. As we assumed, alkylating agents do not need to be used initially.
Of note, bortezomib-related diarrhea was prominent in this group of patients with advanced cardiac damage.4 We did record grade 3-4 diarrhea in 12.5% of cases. Therefore, close monitoring and thorough patient education are key to avoiding volume deletion and electrolyte disturbances from diarrhea. It was noteworthy that five early cardiac deaths occurred in stage IIIB patients. One limitation of current study was that the starting dose of bortezomib was not reduced for these patients with very advanced disease. In a recently published retrospective study on IIIB patients treated with daratumumab either with or without borte- zomib, the percentage of patients who experienced early mortality within the first 2 months after initiating therapy was also as high as 22%.15 It remains uncertain whether a dose titration of bortezomib and dexamethasone could have potentially reduced arrhythmic deaths while maintaining a satisfactory impact on treatment response quality and rate in stage IIIB patients. Only a further comparative study might answer this question.
In conclusion, our trial demonstrates that the Dara-VD regimen is well tolerated and has promising efficacy even in AL patients with very advanced cardiac involvement.
Authors
Kai-ni Shen,1* Ya-juan Gao,1* Long Chang,1 Lu Zhang,1 Xin-xin Cao,1 Zhuang Tian,2 Yi-ning Wang,3 Dao-bin Zhou1 and Jian Li1,4
1Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union
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