Page 283 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Bendamustine and rituximab as first-line treatment for symptomatic splenic marginal zone lymphoma: long-term outcome and impact of early unmeasurable minimal residual disease attainment from the BRISMA/IELSG36 phase II study
Splenic marginal zone lymphoma (SMZL) is a rare histotype of non-Hodgkin lymphoma, accounting for only 2% of all cases.1 At diagnosis, up to 30% of patients may be asymp- tomatic, while others may present with cytopenia(s), abdom- inal lymph node swelling, splenomegaly, B-symptoms, and secondary autoimmune diseases.2 SMZL follows an indolent course that, similarly to other indolent lymphomas, can be complicated by the histological evolution into diffuse large B-cell lymphoma (DLBCL).3 After the diagnosis of SMZL, the risk of lymphoma-related death increases significantly, es- pecially in patients who experience progression within the first 24 months.4 However, the 5-year conditional survival of the remaining patients is comparable to that of the general population,3 and the overall survival (OS) exceeds 10 years. Rituximab immunotherapy is a commonly used first-line treatment due to its effectiveness and mild toxicity.5-6 Al- though splenectomy is an effective procedure, it can lead to severe and potentially fatal acute and late complications.5 Additionally, the role of bendamustine-rituximab chemo- immunotherapy has yet to be defined, and the preferred first-line treatment is undetermined due to the lack of randomized studies.
It is unclear if the quality of clinical response, complete versus partial (CR vs. PR), correlates with the time-relat- ed outcomes. Additionally, insufficient evidence prevents evaluating the prognostic role of acquiring an undetectable minimal residual disease (MRD-) status.7-8 Given this context, the IELSG conducted the BRISMA-IELSG36 phase II study (EudraCT number: 2011-000880-28; clinicaltrails gov. Iden- tifier: NCT02853370). Approval by local ethics committees and written informed consent by all participants before study entrance was required. Through a series of 56 SMZL patients, the primary study objective aimed to assess the efficacy and toxicity of combining bendamustine with rit- uximab (BR) as a first-line therapy.9 Herein, we present the updated results integrated with MRD data (median follow-up [FU]: 69 months; 95% confidence interval [CI]: 67-72). Eligible patients needed to exhibit active/symptomatic dis- ease, and the clinical responses scored according to the criteria described below, proposed by the Splenic Lympho- ma Study Group (SLSG)10 for non-splenectomized patients: partial response (PR): ≥50% improvement in the disease manifestations including resolution or decrease in spleen
size, improvement on cytopenias and resolution or decrease in lymphadenopathy. Bone marrow (BM) should show a re- duction in lymphoid infiltration; complete response (CR): res- olution of organomegaly, normalization of the blood counts (Hb>12 g/dL, platelets >100x109/L; neutrophils >1.5x109/L and no evidence of circulating clonal B cells); no evidence of lymphoma in BM through immunohistochemistry. Online Supplementary Table S1 compares the SLSG and Lugano response criteria for non-PET-avid NHL.
In addition, we adopted the term “unconfirmed complete response” (CRu).6;9 CRu describes patients who still exhibit some degree of cytopenia and splenomegaly at the end of treatment (EOT) but who subsequently meet the criteria for CR at the first FU visit.9 The MRD analysis was performed centrally in a EuroMRD standardized laboratory (https:// euromrd.org/) by droplet digital polymerase chain reaction (ddPCR) with ASO primers targeting IGH rearrangements in the BM and peripheral blood (PB) samples, expressed as copies out 250 ng of genomic DNA as previously described.11 The MRD assay was considered reliable when reaching a sensitivity of at least 1x10-4, calculated considering the tumor infiltration at baseline. Accordingly, in each ddPCR experiment, the “10-1” (as control) and the “10-4” dilution points were included.
Patients with a molecular marker underwent MRD assess- ment after three cycles (early restaging [ER]) at EOT, and yearly at each annual FU assessment.
Clinical information has been updated for all living patients except for two. Presenting features are shown in Online Supplementary Table S2. The median age was 66 years, and 41 patients (73%) were older than 60 years. Fifty-one patients (91%) achieved a major response (34 CR; 7 CRu; 10 PR). All the CRu patients and one in stable disease (SD) at EOT improved slowly and steadily, meeting the criteria for CR without additional treatment. Progression-free survival (PFS) events included three progressions documented in pa- tients scored in SD at EOT, six relapses, and one death (due to sepsis at 1,6 months). According to the intention-to-treat analysis, the 5-year PFS was 83% (95% CI: 71-91), and the OS was 93% (95% CI: 82-97) (Figure 1A, B). These results are nearly identical to those achieved with six weekly in- fusions of rituximab followed by 1-2 years of maintenance therapy.6 None of the ten patients in PR progressed during
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