Page 284 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR AB
Figure 1. Progression-free survival and overall survival at 5 years with a median observation time of 69 months. (A) Progres- sion-free survival (PFS). (B) Overall survival (OS). CI: confidence interval.
the median observation time of 69 months (range 64-103). At baseline, 53 of 56 patients assessable for MRD had at least one FU sample and were screened for a monoclonal IGH rearrangement. A reliable MRD molecular marker was found in 42 of 53 (79%) patients, consistent with the litera- ture.8 The ASO assay achieved adequate sensitivity for MRD analysis (at least 10-4) in 37 of 53 (70%) cases. Among these 37 cases, 14 were identified in both BM and PB samples, 18 in PB only, and five in BM only (Figure 2B).
MRD data were available in five of ten PR patients; at EOT, four were MRD-, and one was MRD+. Four of six CR patients who relapsed had MRD EOT assessment: three were MRD+ and one MRD-. Figure 2A shows the clinical response, MRD status at different time points, and outcome for each of the 37 evaluable patients. The baseline MRD burden was not associated with presenting features, PFS, and OS (P>0.5). Four patients died: one due to sepsis and three due to lymphoma at 1.6, 27, 40 and 42 months, respectively. Two cases of G>2 infections occurred during treatment,9 and three cases (2 acute bronchitis, 1 lung tuberculosis) oc- curred during the follow-up. Two hundred and eighty-four cycles were administered during the study, with 85% given at full dose. Bendamustine dose was reduced in four pa- tients in cycles 4-6. Relative dose intensity was 0.99 for bendamustine and 0.98 for rituximab.
Seven patients developed a second primary cancer (SPC); the SPC includes one follicular thyroid cancer, one DLBCL, one renal-cell carcinoma, one basal cell carcinoma, one
5q- myelodysplastic syndrome, one malignant peripheral nerve sheath tumor, and one prostate adenocarcinoma. The 5-year cumulative incidence rate of SPC was 11%.
BR treatment resulted in high rates of undetectable MRD: 40% at the ER (17/37), 54% (14/26) at the EOT, and 65% (20/31) after 1 year (Figure 2B). Interestingly, a significant reduction in MRD had already been attained at ER assess- ment (median 4.7x10-5 in BM and below the quantitative level in PB, respectively). The additional BR courses (1/3 CR patients and 3/9 PR patients) did not contribute to a significant further reduction in residual MRD levels (me- dian 1.4x10-5 in BM and BQL in PB, respectively) (Online Supplementary Figure S1A, B). MRD+ predicted a statisti- cally significant inferior PFS at each evaluated timepoint (ER, EOT, and FU1) (Figure 3A-C). Notably, acquiring early MRD- status in non-invasive peripheral blood samples was associated with a significant improvement in PFS (MRD- vs. MRD+ 100% vs. 68%; 95% CI: 35-86; P=0.006) (Figure 3D). Our analysis of MRD assessment aligns with published data for rituximab-chemotherapy-treated SMZL patients.7-8 Cervetti et al. generated MRD data assessing by real-time quantitative PCR (RQ-PCR) IGH rearrangements in a ret- rospective series of 50 SMZL (EOT MRD- 48%; PFS: 100% vs. 73%; P=0.023).8 Lyu et al. investigated MRD status by employing multi-color flow cytometry (MFC) in a prospec- tive series of 71 patients (EOT MRD- 77%; PFS: 74,8±6,5% vs. 31,4±12,6%; P<0.001).7 In our study, the EOT MRD status in a landmark analysis was significantly associated with
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