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Letters to the Editor
of the 165 patients with a +sIFE can be found in the Online Supplementary Table S1.
Frontline treatment, response, and outcomes are depicted in Table 2. Two-hundred and thirty (42%) patients received some treatment during follow-up. The median TTFT was 10 years, and no significant differ- ences were seen according to the sIFE (Figure 1A). Frontline regimens were comparable between patients with a negative and positive sIFE, as was the proportion of patients achieving a complete response after treat- ment.
With a median follow-up of 6.7 years, median OS for the entire cohort was 10.9 years, being significantly shorter for +sIFE compared with –sIFE patients (8.5 vs. 11.9 years; 10-year OS: 42 vs. 57%; P=0.003, Figure 1B). When a two-variable Cox regression, including age (as a quantitative variable) and sIFE, was performed, we observed that both parameters retained independent prognostic impact on OS. Furthermore, despite being sig- nificantly older, relative survival analysis showed that excess mortality (survival reduction) with respect to the sex- and age-matched general population was more prominent for patients with a +sIFE (50% at 10 years) compared to that of patients with a −sIFE (33% at 10 years). In a multivariate model for OS, with 286 cases and 108 events (including age >60 years, ECOG PS ≥1, elevated B2M, Rai stage III-IV, unmutated IGHV genes, del(17p), CD38 expression >30%, and a +sIFE), only age, ECOG PS, B2M, and IGHV status retained prognostic impact on OS.
When evaluating OS among patients with a +sIFE according to the heavy chain isotype, no global statisti- cally significant differences were seen. However, when pairwise combinations were performed, biclonal cases had a significantly poorer OS (Online Supplementary Figure S1A), whereas the light chain isotype did not have a sig- nificant impact on OS (Online Supplementary Figure S1B). The presence of immunoparesis was evaluated in patients with +sIFE and –sIFE, and it was not an adverse prognostic factor for OS in either of the groups (Online Supplementary Figure S2). No significant differences were found between light chain-concordant and discordant cases with regard to OS. Richter syndrome was seen in 15 patients (3%). For the entire series, the 10-year RRS was 3% (95% Confidence Interval [CI]: 2−5%), without significant differences according to the sIFE (Online Supplementary Figure S3A). A second tumor was identified in 104 patients (19%), and no patient developed multiple myeloma. The 10-year risk of developing a SM was of 23% for all patients, with similar rates irrespective of sIFE (Online Supplementary Figure S3B).
In conclusion, we found a 30% prevalence of a +sIFE in our cohort of CLL patients, which is in line with previous studies.5–10 Patients with a +sIFE had a more advanced stage and clinical, radiological, biochemical, and genetic poor prognostic markers, as already reported.5,9,10 Contrary to previous data,9,10 however, we observed a clear relationship between a +sIFE and age. In our series, IgM-κ constituted the most common isotype, which is in accordance with the report by Xu and colleagues.9 Eleven percent of cases were biclonal, a finding that has been previously interpreted as: i) the malignant transformation occurring at the time of isotype switching from IgM to IgG,12 ii) the persistent isotype switching capability of CLL cells, independently of IGHV mutation,13 iii) the presence of multiple simultaneous clonal lymphoprolifer- ative disorders,14 or iv) the emergence of a subclone secreting a different Ig isotype, due to clonal evolution. The light chain concordance rate was 72%, pointing to
the fact that, in most cases, the sMC is a product directly secreted by the tumor population. It had been suggested that concordance was higher in the case of IgM pro- teins,15 and we obtained similar findings. Despite compa- rable TTFT, frontline regimens, and response, we demon- strated that a +sIFE is a predictor of a poorer OS and rel- ative survival, irrespective of age. However, due to its association with other clinical and biological adverse prognostic features, the sIFE did not retain its negative impact in the multivariate analysis. Biclonal cases had a poorer prognosis, possibly reflecting a higher degree of immunological dysfunction.
The sIFE is positive in one in three CLL patients at diag- nosis, and this finding is associated with adverse prog- nostic baseline features and shorter survival. The study of the sMC in CLL could be an aid to advance in the under- standing of B-cell malignancies, anticipate patient out- comes, and eventually tailor therapy.
Pablo Mozas,1* Juan A. Piñeyroa,1* Ferran Nadeu,2,3
Laura Magnano,1,2 Andrea Rivero,1 Alfredo Rivas-Delgado,1 Alex Bataller,1 Aleix Fabregat,4 Eva Giné,1,2 Tycho Baumann,1 Neus Villamor,2,3,5 Juan Ignacio Aróstegui,6 Marta Aymerich,5 Armando López-Guillermo,1,2,3,7 Elías Campo,2,3,5,7
and Julio Delgado1,2,3
1Department of Hematology, Hospital Clínic, Barcelona; 2Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona; 3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid; 4Department of Biochemistry and Molecular Biology, Hospital Clínic, Barcelona; 5Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona; 6Department of Immunology, Hospital Clínic, Barcelona and 7Universitat de Barcelona, Barcelona, Spain
*PM and JAP contributed equally as co-first authors. Correspondence: PABLO MOZAS - mozas@clinic.cat doi:10.3324/haematol.2020.263228
Received: June 17, 2020.
Accepted: October 23, 2020.
Pre-published: November 5, 2020.
Disclosures: no conflicts of interest to disclose.
Contributions: PM and JAP designed the study, collected and analyzed the data, and wrote the manuscript; FN, LM, AR, ARD, AB, AF, EG, TB, NV, JIA, MA, ALG, EC and JD contributed to data collection and reviewed the manuscript.
Funding: this study was supported by “Becas de Investigación de la FEHH” (Fundación Española de Hematología y Hemoterapia) to PM; FN received a pre-doctoral fellowship of the Ministerio de Economía y Competitividad (MINECO, BES-2016-076372); LM received the PI19/00925 grant (Instituto de Salud Carlos III); AL-G and EG received the PI19/00887 grant (Instituto de Salud Carlos III); EC is supported by grants from “La Caixa” Foundation (CLLEvolution- LCF/PR/HR17/52150017), the Instituto de Salud Carlos III, the European Regional Development Fund (FEDER – “Una Manera de Hacer Europa”) (PMP15/00007), and is an Academia Researcher of the Institució Catalana de Recerca i Estudis Avançats (ICREA) of the Generalitat de Catalunya.
References
1. Azar HA, Hill WT, Osserman EF. Malignant lymphoma and lym- phatic leukemia associated with myeloma-type serum proteins. Am J Med. 1957;23(2):239-249.
2. Cox MC, Di Napoli A, Scarpino S, et al. Clinicopathologic charac- terization of diffuse-large-B-cell lymphoma with an associated serum monoclonal IgM component. PLoS One. 2014;9(4):e93903.
3.Li Y, Wang L, Zhu HY, et al. Prognostic significance of serum immunoglobulin paraprotein in patients with diffuse large B cell
haematologica | 2021; 106(6)