Safaa Ramadan1,2, Giusy Ceparano1, Alessandro Cignetti3, Simona Sammassimo1, Vincenzo Bagnardi4, Eleonora Pagan4, Daniela Gottardi3, Stefano Fiori5, Rita Passerini6, Tommaso Radice1, Giuseppe Saglio3 and Corrado Tarella1,7.
1 Division of Onco-Hematology, European Institute of Oncology, IRCCS, Milan, Italy.
2 NCI-Cairo University, Egypt, Cairo, Egypt.
3 Divisione Universitaria di Ematologia e Terapie Cellulari, A.O. Ordine Mauriziano, Torino, Italy.
4 Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milano, Italy.
5 Haemolymphopathology Unit, European Institute of Oncology IRCCS, Milan, Italy.
6 Divisione di Medicina di Laboratorio, European Institute of Oncology, Milano, Italy.
7 Dipartimento Universitario di Scienze della Salute (DISS), Università di Milano, Italy.
Received: October 26, 2020
Accepted: February 6, 2021
Mediterr J Hematol Infect Dis 2021, 13(1): e2021018 DOI 10.4084/MJHID.2021.018
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
immune homeostasis as an independent prognostic indicator has been
inadequately evaluated in aggressive non-Hodgkin's lymphomas (NHL). The
present study addresses the prognostic significance in aggressive NHLs
of the immunologic profile evaluated by pretreatment serum levels of
immunoglobulins (Ig) and lymphocyte-monocyte ratio (LMR). In this
series of 90 patients with aggressive lymphoma, the median level for
IgG was 1,024mg/dl (range 436-2236), and for LMR was 2.2 (range
0.2-13.8). CR rate was higher with IgG levels ≥1,024mg/dL (91% vs 77%
p=0.059). LMR ≤ 2.2 was associated with lower 1-year PFS (73% vs. 92%,
p 0.016). Patients with good/very good R-IPI showed a reduced PFS if
IgG or LMR was low, while patients with poor R-IPI did better if LMR or
IgG levels were high. We combined both parameters with the R-IPI and
produced a four-risk prognostic score showing one-year PFS of 95% (95%
CI 68%-99%), 100% (95% CI 100%-100%), 73% (95% CI 52%-86%), and 59%
(95% CI 31%-79%), in patients with zero, one, two and three risk
factors, respectively. The results indicate for the first time
the value of baseline serum Ig levels in the prognostic assessment of
Serum immunoglobulin (Ig) levels can mirror immune homeostasis and may be of prognostic relevance in hematologic malignancies. Low levels of serum Ig have a well-documented adverse prognostic role in various indolent lymphomas.[4,5] Interestingly, pre-transplant hypogammaglobinemia had a negative impact on RFS in patients with DLBCL undergoing autologous transplant, with 18-month RFS 44% if the levels of IgG <600mg/dl, and 63% if higher. To our knowledge, there are no other reports on the prognostic impact of immunoglobulin levels at diagnosis in patients with aggressive NHL. Therefore, we evaluated the prognostic role of LMR and pretreatment levels of immunoglobulins in aggressive NHL patients. In addition, we investigated the role of these factors in the current standard prognostic score system, the R-IPI score. Finally, we developed a scoring system that includes patients' immunologic profile and R-IPI to optimize their outcome prediction.
All patients were treated with chemo-immunotherapy according to the Center guidelines, after giving informed consent. The study has been approved by the local Ethical Committee in Milan. PFS and O.S. were assessed using the Kaplan-Meier method and compared between groups using the log-rank test. Hazard ratios were calculated using univariate and multivariate Cox proportional hazard models. Analyses were performed with SAS software, version 9.4 (SAS Institute, Cary, North Carolina, USA).
IgM levels were higher in females compared to males (median 102mg/dL, vs 81mg/dL, respectively, P=0.038). Patients with no bone marrow (B.M.) infiltration showed higher IgG and IgA levels than patients with B.M. involvement. There was no association between Ig levels and LMR.
A trend of higher CR rates was seen in patients with IgG levels ≥1,024mg/dL (91.3% vs 76.7%, respectively p=0.059) and in patients with LMR > 2.2 (91.1% vs 77.3%, p=0.073).
At a median follow up of 16 months, the 1-year O.S. and PFS of the whole series were 92% (95% CI: 83%-96%) and 83% (95% CI: 73%-89%), respectively.
All risk factors included in the revised IPI (R-IPI) score (i.e., age > 60, advanced stage, high ECOG PS, 2 or more extranodal sites, high LDH) were associated with a worse prognosis (Table 1). PFS was significantly lower in patients with poor R-IPI score compared to the other two groups (Figure 1A, 73% vs. 91%, p=0.018). Patients with IgG lower than 1,024mg/dl had lower 1-year PFS (73% vs 91%, respectively p=0.135), and patients with LMR <= 2.2 had also inferior 1-year PFS (73% vs 92%, respectively p=0.016).
The prognostic role of IgG and LMR on PFS was further investigated according to the R-IPI score. Having a low IgG at diagnosis (<1,024mg/dl) worsened the 1-year PFS in good or very good R-IPI patients (84% vs. 96%). Interestingly, the poor R-IPI risk group with high IgG levels had 1-year PFS similar to the good risk group with low IgG levels (87% vs. 84%). The lowest PFS (63%, 95% CI 40%-80%) was seen in the poor R-IPI group with low IgG (Figure 1B). Similarly, a low LMR ratio strongly worsened the PFS of all R-IPI risk groups (Figure 1C).
Poor R-IPI, low IgG, and low LMR were then assessed in a new 4-level risk score, taking 1 point for each adverse factor. The 1-year PFS was 95% (95% CI 68%-99%) in patients with zero risk factors, and 100% (95% CI 100%-100%), 73% (95% CI 52%-86%), 59% (95% CI 31%-79%) in patients with one, two and three risk factors, respectively (Figure 1D).
|Table 1. Univariate and multivariate analysis on PFS according to the revised International Prognostic Index (R-IPI) and immunological parameters.|
Overall, hypogammaglobulinemia was recorded at baseline in only eight patients (9%), which is less than the 15% reported in a previous study. Interestingly, four out of these eight patients had primary refractory disease with rapidly fatal outcome. Among the remaining 82 patients, more than half had Ig values towards the low normal range, according to the reference laboratory values, and that is in line with similar results previously reported in NHLs. Therefore, we chose to use the median immunoglobulin values at diagnosis corresponding to IgG 1,024mg/dL to categorize patients with high or low IgG levels in correlative analysis. In univariate analysis, patients with IgG value <1024mg/dL had a worse 1-year PFS than patients with higher levels.
In the present series, patients with LMR <=2.2 had an inferior 1-year PFS. Baseline LMR was matched with IgG levels, and the two parameters were not correlated.
This finding could be explained by the fact that low LMR was due to high absolute monocytic count in 11 out of 45 (24.5%) patients. Besides, IgG levels were low only in 60% of patients with lymphopenic versus 40% of those with lymphocytes in the normal range. Due to the lack of correlation between IgG levels and LMR at baseline, both parameters were assessed in combination with the R-IPI. Patients with good/very good R-IPI showed a reduced PFS if associated with either low IgG or low LMR. Patients with poor R-IPI did better if they had either high LMR or high IgG levels. Dismal outcome was seen in those patients with poor IPI and low levels of either IgG or LMR. Based on these observations, a novel clinical and immunological prognostic score was developed. The score distinguished four groups with different 1-year PFS ranging from 95% if no or one risk factor was present to 59% if the three factors were present.
Our study introduces the baseline serum immunoglobulin levels in the prognostic assessment of aggressive lymphoma patients. We are aware of some weak points of the study: in particular, the retrospective analysis and the relatively small number of patients, with the inclusion of different aggressive lymphoma subtypes, although most of them were DLBCL; lastly, the follow up time is short. However, C.R. achievement and the 1-year PFS are considered reliable surrogate endpoints to predict the ultimate outcome in DLBCL.[11,12]
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